carcinomatous meningitis

Has anyone here been diagnosed or know of anyone who has survived this diagnosis? I have a friend who has Her2+ metastatic disease/brain mets who has this diagnosis now and is having neurological deficits.



Thanks,

B.

[michele u]

i wonder if it is the same thing as liptomeningeal cancer?

Anyone hear of this type or been diagnosed with this problem secondary to bain mets or spinal cord mets??

[Barbara H.]

I just went on the web and read about it. It sounds awful and one more thing to worry about.
Barbara H.

[Lolly]

I think I remember that back on the old board someone posted with this diagnosis, but it's been a couple of years ago and I don't remember how it went for her. So sorry your friend has this complication to an already complicated disease. Give her my best wishes.

<3 Lolly

[gdpawel]

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.

Carcinomatous Meningitis (Lepteomeningeal Carcinomatous or Leptomeningeal metastasis) 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.

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. 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.

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.

Diagnosis is most commonly made by lumbar puncture, to look for malignant cells or elevated protein levels in the spinal fluid, although the CSF cytology is persistently negative in about 10% of patients with leptomeningeal carcinomatosis. A MRI of the brain and spine to look for enhancement of meningeal tissue. 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, also head pain, cranial nerve involvement, hearing problems and back pain.

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.

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.

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).

There have been some clinical trials using Temodar (temozolomide) instead of Methotrexate, Ara-C, or combination gemcitabine (Gemzar) plus Thiotepa in treating patients with CM from a solid tumor.

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.

[3sweeties]

I was probably the poster that someone had mentioned before. My cousin's wife unfortunately passed away at the age of 38yrs old last year from that diagnosis. She was her2+ and was then diagnosed with carcinomatous meningitis. She had underwent chemo, mastectmy, radiation and then the mets returned to her spine and went to her brain, she had wbr but she developed the progressive neurological symptoms and at the end could not see, hear or move.
Saying a prayer for your friend because this diagnosis has an extremely poor prognosis.
I wish I had more positive news to give.

A.

[hutchibk]

Thanks for all of the info. Sounds very intimidating, but also sounds like it is not overly common. Prayers and best wishes to all who might be facing this aspect of our journey...

[gdpawel]

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 tumor

John Souglakos; Lambros Vamvakas; Stella Apostolaki; Maria Perraki; Zacharenia Saridaki; Irine Kazakou; Athanasios Pallis; Charalambos Kouroussis; Nikos Androulakis; Kostas Kalbakis; Georgia Millaki; Dimitris Mavroudis; Vassilis Georgoulias

Abstract

Introduction: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse.

Methods: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR.

Results: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007-0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51-101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97-12.84; P = 0.001) were independent predictive factors for CNS relapse.

Conclusion: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs.

Breast Cancer Res. 2006;8(4) ©2006 BioMed Central, Ltd.

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. We 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.

CARCINOMATOUS MENIGITIS: 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

[hutchibk]

Thanks for the additional info! and I would add Tumor markers to that tool box, from personal experience.

[madubois63]

This information was very interesting to read for me now. My dear friend, who's husband posted here for a while, lost her battle to this offshoot of breast cancer. When they first diagnosed it, they gave her a year, and that is what she got. It wasn't a good year either. She spent several months at home in bed unable to move her legs and an arm. The first sign she noticed was trailing vision. She would look at something, then see it a few moments later somewhere else. She mentioned this to her onc and he ignored it. She should have had a brain MRI immediately, but that took some time - I am still angry about that. Tykerb (breaks the brain barrier) was not readily available at the time, and by the time she was able to start treatment, it was too late...She did radiation and a few other things, but I was in the middle of my own fight and didn't understand her diagnosis. Thanks for the info. I hope and pray for a cure for ALL cancers...