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    Top User gdpawel's Avatar
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    Carcinomatous Meningitis

    Leptomeningeal Carcinomatous (Carcinomatous Meningitis)

    The most common cancers to involve the leptomeninges are breast cancer, lung cancer and melanomas, and now, because of dose-intense combination chemotherapies, even ovarian cancer is more common.

    Unfortunately, cancer cells are too small to find on any scans unless they have grown into a lump. There can still be cancer cells in the body even though scans may have indicated that all the cancer had gone. Leptomeningeal metastasis (Lepteomeningeal Carcinomatous or Carcinomatous Meningitis) is a condition caused by cancer cells getting into the thin sheets of body tissue that surround and protect the brain and spine. These sheets are called the meninges. Meningitis means inflammation of the meninges. Carcinomatous just means acting like a cancer. Most people are familiar with the type of meningitis caused by an infection, but with carcinomatous meningitis, it is the cancer cells in the meninges that cause the inflammation, not an outside infection.

    Tumor cells reach the meninges by hematogenous (blood) spread or by direct extension from pre-existing lesions and are then disseminated throughout the neuroaxis by the flow of the cerebrospinal fluid. Patients present with signs and symptoms from injury to nerves that traverse the subarachnoid space, direct tumor invasion into the brain or spinal cord, alterations in blood supply to the nervous system, obstruction of normal cerebrospinal fluid (CSF) flow pathways or general interference with brain function.

    Secondary cancers from a primary cancer can develop in different parts of the body, including the brain or spine. Cancer cells do not always develop into an active secondary tumor when they have spread to a new site. Sometimes they stay inactive for many years. So, even after a cancer appears to have been successfully treated, some cancer cells may still be elsewhere in the body. No one knows why some cancer cells stay inactive or what triggers them to form a secondary cancer.

    Symptoms from neoplastic meningitis include pain, headaches, mental status decline, loss of sensation in the face or elsewhere on the body, or difficulties with vision, hearing, or swallowing, among others. Diagnosis is most commonly made by lumbar puncture, although the CSF cytology is persistently negative in about 10% of patients with leptomeningeal carcinomatosis. Radiology studies may reveal subarachnoid masses, diffuse contrast enhancement of the meninges or hydrocephalus without a mass lesion.

    Doctors estimate that about 5 out of every 100 patients who have cancer develop carcinomatous meningitis. It is most common in breast cancer, but it can occur with any type of cancer. The cancer cells in the meninges can cause a range of symptoms, including confusion, headaches and weakness.

    The condition is very difficult to treat. The main aim is to help control symptoms and not cure the disease. Chemotherapy injected into the spinal fluid (via Ommya Reservoir in the brain) or radiotherapy to the brain are both treatments for Carcinomatous meningitis. Some patients respond to these treatments, but the prognosis is generally poor. There are no set guidelines for treating this condition as oncologists don't really know which treatments work best.

    Without treatment, the median survival of patients is 4 - 6 weeks and death occurs from progressive neurologic dysfunction. Radiation therapy to symptomatic sites and disease visible on neuroimaging studies and intrathecal chemotherapy increases the median survival to 3 - 6 months. Major favorable prognostic factors include excellent performance status, absence of serious fixed neurologic deficits, normal CSF flow scans and absent or responsive systemic tumor.

    Oncologists have been looking at using different combinations of chemotherapy drugs to treat Leptomenigeal Carcinomatous secondary to the primary cancer (Chemosensitivity Testing may help in this process). They found that giving both chemotherapy injected into the bloodstream and chemotherapy given directly into the spinal fluid may improve the outlook for some people. However, current available therapies are toxic though, and provide limited benefits.

    Approximately 50% of lung and breast cancer patients who survive more than one year with Leptomeningeal metastasis treated with repeated injections of intrathecal methotrexate develop leukoencephalopathy which includes confusion, dementia, somnolence or focal neurologic signs. This usually occurs when intrathecal methotrexate is combined with irradiation and this combination should be avoided if possible. The leukoencephalopathy may improve if intrathecal methotrexate is discontinued, although it may also progress to coma and death. Leucovorin is a faster acting and more potent form of folic acid. It is used as a rescue after dose-intense methotrexate therapy to lessen and counteract the effects of methotrexate toxicity and other folic acid antagonists.

    A medical oncologist involved with Chemosensitivity Testing has stated that their lab has only received maybe four Lepomeningeal Carcinomatous specimens over the years. Of those, only one specimen had sufficient tumor cells for testing. The problem is that it requires a specimen of cerebrospinal fluid, and it's not safe (with LC) to take more than a few ml of spinal fluid, and there are typically not enough cells to test more than one drug, if that. If there would be another site of the disease (lymph node, pleural fluid, etc.), then that could be biopsied. The biology of the disease, in all probability, would be similar to that of the lymph node, pleural fluid, etc. tumor.

    If an assay test could not be performed and the disease had to be treated empirically, one protocol could be giving intrathecal thiotepa plus systemic gemcitabine (the gemcitabine given prior to the thiotepa). Thiotepa may be safely given intrathecally. Gemcitabine can probably be given intrathecally (it is somewhat similar to cytarabine), but it is thought that no one has ever done a clinical trial to prove that this is feasible and safe. In principal, the best shot would be intrathecal gemcitabine + intrathecal thiotepa.

    Another alternative to Methotrexate is Cytarabine (cytosine arabinoside) or Ara-C. It is an anti-metabolite (like Methotrexate) which stops cells making and repairing DNA. Cancer cells need to make and repair DNA in order to grow and multiply. Ara-C is a clear liquid that can be dripped into a vein (intravenous infusion), into the spinal fluid (intrathecally) or by an injection just under the skin (subcutaneously).

    A small molecule drug may be able to penetrate the blood-brain barrier (BBB). Small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain.

    What may be another alternative is high doses of two small molecule EGFR pathway drugs, Tarceva (erlotnib) and Iressa (gefitinib), given together. It might cross the blood-brain barrier and some patients may get a long-lived remission with these drugs.

    High-dose tamoxifen could then be given continuously as a potentiator and an anti-angiogenic effect. This suggestion comes from cell function analysis.

    There has been clinical trials with molecularly-targeted Iressa for Leptomeningeal Carcinomatous from NSCLC.

    Iressa and Tarceva are very similar drugs, small molecule inhibitors of tyrosine kinase, a key intermediary in the EGF cascade pathway. They act on multiple receptors in the cancerous cells.

    EGF is epidermal growth factor. EGF is a receptor on many normal tissues/cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called EGFR (epidermal growth factor receptor).

    It then activates signalling pathways withing the cell (a cascade of biochemical events). One type of enzyme which is involved in the pathway is called tyrosine kinase.

    Targeted treatments like Iressa and Tarceva take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer.

    So, in different tumors, either Iressa or Tarceva might get inside the cells, better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

    I'm sure that Tarceva or Iressa would be more tolerable than Methotrexate, a mean and nasty drug. And you don't have to take Tarceva intrathecally.

  2. #2
    Top User gdpawel's Avatar
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    CARCINOMATOUS MENINGITIS: TAXANE INDUCED?

    CARCINOMATOUS MENINGITIS: TAXANE INDUCED?

    Isolated Leptomeningeal Carcinomatosis (Carcinomatous Meningitis) after Taxane-Induced Major Remission in Patients with Advanced Breast Cancer

    Christos Kosmasa, Nikolaos A. Malamosa, Nikolas B. Tsavarisc, Melina Stamatakib, Achilleas Gregorioua, Sofia Rokanaa, Maria Vartholomeoua, Minas J. Antonopoulosa

    aDepartment of Medicine, Medical Oncology Unit and bDepartment of Cytopathology, Helena-Venizelou Hospital and cDepartment of Pathophysiology, Medical Oncology Unit, Laikon General Hospital, Athens University School of Medicine, Athens, Greece

    Abstract

    Objectives: To identify the incidence of leptomeningeal carcinomatosis (LMC), as the first site of systemic progression, in breast cancer patients after having obtained a major response (CR or near CR) to first-line taxane-based chemotherapy and compare these findings in retrospect with a matched-pair group of historical control patients from our database treated with nontaxane regimens.

    Patients and Methods: Patients with histologically proven breast cancer having either metastatic disease or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155), and compared, as regards the incidence of LMC, to a matched-pair retrospective group of 155 patients treated with nontaxane regimens in our unit.

    Results: Seven patients with a median age of 54 years (range 40-70) developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range 2-18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while 1 patient received i.t. methotrexate and RT to the lumbar spine.

    Two patients responded to treatment for LMC, while 2 achieved stable disease and 3 progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range 1-17+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, p = 0.019).

    Seven out of 86 responders (8.13%) in the taxane group versus 1 out of 72 responders (1.4%) in the non-taxane-treated group developed LMC as the first sign of progression after a major response to first-line chemotherapy (p < 0.1).

    Conclusions: LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased, but not significantly so, when compared retrospectively to non-taxane-treated patients.

    Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multi-institutional trials is warranted and identification of potential prognostic factors might help to identify patients requiring appropriate prophylactic therapy.

    American Journal Clinical Oncology 2002;63:6-15

  3. #3
    Top User gdpawel's Avatar
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    Who Needs Taxol?

    In the last decade, the incidence of central nervous system (CNS) metastasis has increased. The very first reference I found of this was a NCI observational study in 1995 that reported experience in their clinic where recurrent systemic disease occurred in all patients for which they received dose-intense Paclitaxel (Taxol) therapy. Brain metastasis was the only site of disease recurrence. The cerebellum was involved in two out of three patients, presenting with headache, dizziness, unsteady gait, nausea and vomiting (all the things that happened to my wife in 1998, after her adjunct Taxol treatment in 1997).

    This is what led me to research this further and found out about the rarity of ovarian cancer cells metastasizing to the brain. Ovarian cancer uncommonly involves the nervous system. Brain metastasis was a "rare" complication of ovarian cancer with only 67 well-documented cases in medical literature, until 1994. A multi-institutional study of 4027 ovarian cancer patients over 30 years identified only 32 cases while an autopsy study of ovarian cancer reported an incidence of 0.9%. Even more "rare" is the occurrance of Carcinomatous Meningitis. Until 1994, there have been only 14 cases reported. This presentation is similar to metastases from other solid tumors (breast, lung). (1)

    In 2002, I came across a study by Christos Kosmas, M.D., consultant medical oncologist, Department of Medicine and Medical Oncology Unit at Helena-Venizelou Hospital, Athens, Greece entitled, "Carcinomatous Meningitis: Taxane-Induced," which found what is called "dissemination after taxane-based (Taxol) chemotherapy." The study conclusions stated that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectively to non-taxane-treated patients. (2)

    A commentary by Dr. Lawrence N. Shulman, Vice Chair for Clinical Services and Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, in the September, 2002 issue of The American Journal of Oncology Review, describes the complete lack of progress in the chemotherapeutic treatment of metastatic breast cancer since 1970. Dr. Shulman noted that a retrospective comparision of a well-characterized "standard-dose" database with a less well-characterized "high-dose" database suggested that there was increased early mortality for "high-dose" therapy. (3)

    An editorial by Drs. V. Valero and G.N. Hortobagyi in the March 15, 2003 issue of the Journal of Clinical Oncology, reviewed all of the large, prospective, randomized trials published comparing taxane-based chemotherapy regimens. They conclude that none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at two years or less, or precisely the same results which were being obtained over thirty years ago. (4)

    In 2004, as reported at the 27th Annual San Antonio Breast Cancer Symposium, using a technique that quantifies circulating tumor cells, German investigators from Friedrich-Schiller University in Jena, have shown that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding could help explain the fact that complete pathologic responses do not correlate well with improvements in survival.

    In the study, according to Katharina Pachmann, M.D., professor of experimental oncology and hematology, breast cancer patients undergoing neoadjuvant chemotherapy gave blood samples in which epithelial antigen-positive cells were isolated. Such cells are detected in most breast cancer patients but are rarely found in normal subjects. The investigators measured the levels of cirulating tumor cells before and during primary chemotherapy with several different cytotoxic agents.

    Paclitaxel (taxol) produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells. In three different paclitaxel-containing regimens, circulating cell numbers massively increased, whereas tumor size decreased. These cells remained in the circulation for at least five months after surgery.

    The tumor shrinks, but more cells are found in the circulation. This corresponds with a high pathologic complete response during paclitaxel treatment, but in the end, this is not reflected in improved survival. These cells are alive in the circulation. What this study has shown, so far, that in three different paclitaxel (taxol) containing regimens, as the tumor collapses (a clinical response, not cure), it produces the greatest release of circulating tumor cells. The study has not looked at any other combination regimens. (5)

    The results of these kinds of study are coming out slowly and quietly (now that Taxol is off-patent) and indicate that taxol containing regimens didn't prolong survival over other more conventional and less expensive cytotoxic drugs. Even before the advent of the CellSearch technique, it had been observed in various "cell death" assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from taxane therapy, even in cases where the majority of the cells are being killed by taxanes. It may indeed give clincial response (tumor shrinkage), sometimes impressive, however, these are mostly short-lived and relapses after a response to taxanes (Taxol) are often dramatic. (6)

    With these cells being alive in the circulation, it may mean that a patient with invasive breast cancer without lymph node involvement (where systemic treatment "may" benefit), or a patient with invasive breast cancer that involves lymph nodes (where systemic treatment is "usually" recommended), would need additional (anti-estrogen) treatment, such as Tamoxifen (it may be given alone or in addition to chemotherapy, if given).

    It has been shown that Tamoxifen treatment will reduce circulating tumor cells in some patients, but not all. So they develop a drug called Herceptin. Why? It has been shown that Herceptin treatment will reduce circulating tumor cells in patients with HER2-negative tumors, but less pronounced in HER2-positive tumors.

    Does Herceptin really work on these circulating tumor cells? A study from the Dana Farber Cancer Institute identified central nervous system metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

    Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. (7)

    In 2006, another report that CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen. Central Nervous System Relapse in Patients With Breast Cancer Is Associated With Advanced Stages, With CK-19 mRNA-positive Circulating Occult Tumor Cells and With Her2/neu-positive tumors.

    During the past years it has been frequently observed that patients with breast cancer treated with a taxane-containing chemotherapy regimen, either in the adjuvant setting or in the metastatic setting, presenting central nervous system (CNS) involvement as the only evidence of disease progression. More studies were therefore interested to evaluate the incidence of CNS metastases in patients with early and advanced breast cancer treated with a taxane-containing chemotherapy regimen and to identify predictive factors for CNS relapse.

    Recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen. There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab (Herceptin).

    In the present study it was also possible to confirm the initial clinical observation that breast cancer patients who receive a taxane-containing chemotherapy regimen have a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen.

    The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS.

    Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

    Furthermore, the detection of cytokeratin 19 (CK-19) and of mRNA-positive circulating tumor cells (CTCs) in the peripheral blood and the bone marrow of patients with breast cancer is correlated with increased incidence of relapse.

    The aforementioned data suggest that taxanes may not penetrate well into the CNS, and therefore the CNS may represent tumor 'sanctuary' sites for taxane-containing chemotherapy regimens. A difference in the incidence of CNS relapses between patients with breast cancer and other solid tumors treated with taxanes was observed. (8)

    The percentage of patients that must respond to a drug before it is approved by the FDA varies from as high as 80% to as low as 20%. Thereafter, it is used routinely for all patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean it will help all patients with the same diagnosis. The response rate for Taxol for FDA approval was 30%.

    Taxol (Paclitaxel) is known as a taxane type of chemotherapy drug. Taxol is given into a vein, but in order for the body to absorb the drug, it must first be dissolved in a solution. The compound wouldn't dissolve very much in any solution. It was discovered that something Taxol would dissove in the might work in a reasonably safe intravenous solution in humans. It was an elixir made of castor oil and marketed as Cremophor EL. It was the only answer. However, this castor-oil carrier is suspected as the culprit behind the misery which includes nausea, vomiting, joint pain, appetite loss, brittle hair and tingling sensations in hands and feet (neuropathy). (9)

    The American Cancer Society has mentioned that the solution can cause dangerous allergic reactions in many people, so patients "must" first take other drugs like steroids and antihistamines in "hopes" to prevent a bad reaction. The solution can also leach chemicals from regular plastic tubes used to deliver medication, so Taxol must be given through special tubing.

    A new drug for breast cancer (Abraxane) is a new form of Taxol (Paclitaxel). Abraxane does not need to be dissolved in the castor oil solution and does not require special equipment to be given to patients. However, more of the women on Abraxane had numbness and tingling in their hands and feet. And more suffered nausea and vomiting, diarrhea, muscle and joint pain and anemia.

    Taxol (Paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients. Side effects of Taxol (Paclitaxel) include severe allergic reactions, cardiovascular problems (such as changes in blood pressure), infections developing from white blood cell deficiencies, complete hair loss (apolecia), joint and muscle pain, irritation at the Taxol and other chemotherapy drugs injection site, low red blood cell count, mouth or lip sore, numbness or burning in the hands and feet, and stomach upset/diarrhea. (10)There is a molecular basis for the peripheral pain caused by Taxol. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling, researchers at Yale School of Medicine reported in a study published in the Proceedings of the National Academy of Sciences. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms. These serious side effects limit the drug's effectiveness. Peripheral pain becomes worse with continued use and increased dosages lead to persistent and irreversible pain.

    The binding protein is called neuronal calcium sensor (NCS-1). When paclitaxel (taxol) binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme (calpain) that degrades proteins, especially NCS-1. Calcium signals are needed for nerves to be stimulated and to respond and the loss of NCS-1 makes it more difficult to generate any calcium signals. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses. (11)Sources:

    (1) National Cancer Institute
    (2) American Journal Clinical Oncology 2002;63:6-15
    (3) Am J Oncology Rev 1(3):169-170, '02
    (4) J Clin Oncol 21(6): 959-962, '03
    (5) Oncol News Int'l, Vol 14, #5, May '05
    (6) Cell Function Analysis
    (7) Cancer 2003 Jun 15;97(12):2972-7
    (8) Breast Cancer Res. 2006;8(4)2006 BioMed Central, Ltd.
    (9) Office of Research, Florida State University
    (10) Bionumerik
    (11) PNAS 104: 11103-11108 June 20, 2007

  4. #4
    Top User gdpawel's Avatar
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    Re: Carcinomatous Meningitis

    I've been reading about clinical trials using Temodar (Temozolomide) instead of methotrexate, or Ara-C, or combination gemcitabine plus thiotepa in treating patients with carcinomatous meningitis (leptomeningeal carcinomatous).

    http://www.cancer.gov/search/ViewCli...ersion=patient

    http://clinicaltrials.gov/ct/show/NCT00005812?order=11

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    Carcinomatous Meningitis

    gdpawel,

    I have a relative, who is a breast cancer patient, that has just been diagnosed with Carcinomatous Meningitis. Thank you for all the information you provided in your postings. Since it was last year since these postings, has there been any findings or breakthroughs on the treatment of CM? Any information would be extremely helpful. Thanks
    mpd

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    Hi,

    My dad is 78 and is fighting since July 2008 with lung cancer. Last month, we found out the cancer had spread to his brain and to the meninges. He started brain radiation and is finishing next week. His condition right now is stable, but he seems to be very tired right now, don't know if it's the meningitis or the radiation.

    Since we don't hear about carcinomatosis meningitis very often, I'll keep you posted on his journey and his treatment here. It's very frustrating to look for info about a subject and not find anything.

    Well, my father is dealing with 3 brain mets and the meningitis. He is finishing brain radiation, after that he'll have another spinal tap to see how the tumor is doing... If it's still there, he'll have interthecal chemo, four shots in two weeks. Straight after radio ends, he'll be starting Tarceva. He was tested for it and he is a perfect match, the only thing is that oncologists don't know how does Tarceva works on the meningitis. It's very efective in the nervous system but it's unclear if it works in the meninges.
    So, I'll keep you guys posted on how things are going and if I have some news.
    Love,
    Roberta

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    Hi, as promissed, I'm keeping you posted about my father's treatment.
    Last Friday he had his first intrathecal chemo shot and is having the second one tomorrow. He is reacting well, until now had no side effects and is showing a slighty better mental consition, less confused.
    His last lumbar puncture showed 5% of neopasic cells in his liquor. Prior to the radiation therapy the count was 12%. The oncolgist is planning on 6 rounds of chemo to clear it for now. He already started taking tarceva for the lymph nodes and brain mets.

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    Hello!
    My father, who was suffering from carcinomatous meningitis due to lung cancer passed away today. He actually died from a lung emboli caused by tombosis in his legs. Because of that, the meningitis didn't run its whole course.
    I know it's very hard to find information on that topic so I'm posting everything that happened to him here, so it can give some answers to anyone in the same situation.

    He was diagnosed with carcinomatous meningitis on September 21st 2009. He also had three brain mets. The next day, he started radiation for both the brain mets and the meningitis. He did 15 sessions total and endured it well, feeling very tired towards the final sessions. His brain mets were gone and the neoplasic cell count in the liquor went from 12% to 5% with the radiation.

    Two weeks after that, he began interthecal chemo. He did 4 shots of it and started taking Tarceva together with it (he was a match). The chemo was unable to clear the liquor and he started to have a quicker mental deterioration. He was unable to walk without help and felt very tired all the time. But, his mind was right and he was very lucid.

    Last week, he had some problems in his liver due to medication he was taking and was admited in the hospital again (he did all the chemo at the hospital due to his difficulty to walk). Today, they found out the trombosis and he ended up dieing from the emboli (he couldn't take any mediaction to treat it because of the brain mets).

    What I know about the meningitis: The treatment has some level of response, he would still be alive today if it wasn't for the other complications.

    A physiotherapy is usefull to keep the pacient moving, and not attached to bed (that causes trombosis). It's also good for their self esteem.

    I don't know if I would do the intratechal chemo. It didn't show much result. The Tarceva works. When they took the Tarceva away (because of the liver problems) his mind deteriorated really fast.

    Well, this is my experience. Every case is diffent. Feel free to contact me at robertacastello@hotmail.com if you want to share stories or know anything about my case.

    I wish you all my best.

    XX
    Roberta

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    Top User gdpawel's Avatar
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    More effective treatment for Leptomeningeal Carcinomatous?

    A small molecule drug may be able to penetrate the blood-brain barrier (BBB). Small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain.

    What may be another alternative is high doses of two small molecule EGFR pathway drugs, Tarceva (erlotnib) and Iressa (gefitinib), given together. It might cross the blood-brain barrier and some patients may get a long-lived remission with these drugs.

    High-dose tamoxifen could then be given continuously as a potentiator and an anti-angiogenic effect. This suggestion comes from cell function analysis.

    There has been clinical trials with molecularly-targeted Iressa for Leptomeningeal Carcinomatous from NSCLC.

    Iressa and Tarceva are very similar drugs, small molecule inhibitors of tyrosine kinase, a key intermediary in the EGF cascade pathway. They act on multiple receptors in the cancerous cells.

    EGF is epidermal growth factor. EGF is a receptor on many normal tissues/cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called EGFR (epidermal growth factor receptor).

    It then activates signalling pathways withing the cell (a cascade of biochemical events). One type of enzyme which is involved in the pathway is called tyrosine kinase.

    Targeted treatments like Iressa and Tarceva take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer.

    So, in different tumors, either Iressa or Tarceva might get inside the cells, better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

    I'm sure that Tarceva or Iressa would be more tolerable than Methotrexate, a mean and nasty drug. And you don't have to take Tarceva intrathecally.
    Gregory D. Pawelski

 
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