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Old 02-04-2010, 12:43 PM
gdpawel gdpawel is offline
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Default More Effective Treatment for Leptomeningeal Carcinomatous in Lung Cancer?

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. High dose pulse Tarceva can be effective for central nervous system (CNS) disease, so long as resistance has not developed.

[url]http://cancerfocus.org/forum/showthread.php?t=3920

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.

[url]http://neuro-oncology.oxfordjournals.org/content/12/11/1193.full
[url]http://erj.ersjournals.com/content/37/3/624.abstract
[url]http://neuro-oncology.oxfordjournals.org/content/13/12/1364.abstract

Can Tamoxifen enhance the effect of Tarceva?

http://cancerfocus.org/forum/showthread.php?t=3500

A Pilot Study of Systemically Administered Avastin (bevacizumab) in Patients with Neoplastic Meningitis.

http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2009-0122

Pulsatile High-dose Tarceva (erlotinib)

In a recent, small study on the efficacy of pulsatile high-dose Tarceva (median dose: 1500 mg once weekly) in nine patients with EGFR mutations and disease progression while on standard-dose Tarceva treatment, partial brain metastasis response was obtained in six out of nine patients (67%) with a median time to CNS progression of 2.7 months and an OS of 12 months (1).

The rationale for this study was derived from a previous report in which Clarke et al. demonstrated that a pulsatile Tarceva regimen was effective against leptomeningeal metastases in a patient with EGFR mutation who progressed during standard Tarceva treatment (2).

The Tarceva concentration required to inhibit the growth of EGFR-mutated cells by 50% is 100 nM. The standard dose of 150 mg allows a plasma concentration of 3000 nM of erlotinib, while the concentration reached in the cerebrospinal fluid is less than 1% of the plasma level, which is not sufficient to achieve an anti-tumoral effect against CNS metastases (3).

The administration of a high dose (e.g., 1500 mg) once a week is generally well tolerated and allows a concentration of 130 nM Tarceva to be reached in the cerebrospinal fluid (4). Further prospective studies are therefore required to confirm the efficacy of high-dose pulsatile Tarceva in the treatment of brain metastasis from NSCLC.

1. Grommes C, Oxnard GR, Kris MG et al. 'Pulsatile' high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13(12), 1364–1369(2011).

2. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J. Neurooncol. 99(2), 283–286(2010).

3. Jackman DM, Holmes AJ, Lindeman N et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J. Clin. Oncol. 24(27), 4517–4520(2006).

4. Milton DT, Azzoli CG, Heelan RT et al. A Phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 107(5), 1034–1041(2006).
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Old 02-04-2010, 12:51 PM
gdpawel gdpawel is offline
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Default What is Leptomeningeal Carcinomatous?

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.

Intrathecal Injecton via an Ommaya Reservoir

Intrathecal refers to injecting chemotherapy directly through the meninges, avoiding the blood brain barrier (BBB), into the cerebrospinal fluid (CSF).

An ommaya reservoir, a plastic, dome-shaped device, with a catheter (thin tubing) is implanted in the brain to facilitate the uniform delivery of the intrathecal chemotherapy into the central nervous system (CNS).

Placement of the ommaya reservoir requires a minor surgical procedure by a neurosurgeon, with the patient placed under general anesthesia. The reservoir is placed just under the scalp with the catheter positioned into the cavity of the brain where the CSF is formed.

This enables multiple rounds of chemotherapy in a single access site, so as to increase the comfort and reduce stress and pain associated with repeated injections in a site like the spinal column. They can also use the reservoir to sample CSF for cytology.

The only agents licensed for intrathecal chemotherapy are Methotrexate, Cytarabine (Ara-C) and Hydrocortisone.

With the ommaya reservoir attached inside the brain, frequent spinal CSF analyses can take place. Diagnostic evaluation of the fluid is looked at for chemical, hematological, microbiologic and cytological examination. Chemical analysis includes protein and glucose measurements, which typically would show an abnormally high number of mononuclear cells with elevated protein and low glucose levels (you cannot see this disease).

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.

There are several studies with temozolomide for treatment of brain mets from NSCLC. The results seem to be pretty consistent-10-15% responce rate, about 30% clinical benefit rate and about 8 months overall survival.

Ann Oncol. 2009 Sep 18. Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Siena S, Crinò L, Danova M, Del Prete S, Cascinu S, Salvagni S, Schiavetto I, Vitali M, Bajetta E.

Oncology. 2009;76(2):112-7. Epub 2009 Jan 14.Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study. Kouroussis C, Vamvakas L, Vardakis N, Kotsakis A, Kalykaki A, Kalbakis K, Saridaki Z, Kentepozidis N, Giassas S, Georgoulias V.

Cancer. 2008 Nov 1;113(9):2524-31.Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Addeo R, De Rosa C, Faiola V, Leo L, Cennamo G, Montella L, Guarrasi R, Vincenzi B, Caraglia M, Del Prete S

There is also an interesting case-report from Chicago of a patient with leptomeningeal carcinomatous who responded to gefitinib after progressing on eroltinib.

Nat Clin Pract Oncol. 2006 Jan;3(1):50-7;Gefitinib response of erlotinib-refractory lung cancer involving meninges--role of EGFR mutation. Choong NW, Dietrich S, Seiwert TY, Tretiakova MS, Nallasura V, Davies GC, Lipkowitz S, Husain AN, Salgia R, Ma PC

Note:

What about using a lumbar puncture for assay analysis? The lumbar puncture (spinal tap) is commonly used to look for malignant cells or elevated protein levels in the cerebrospinal fluid. That's how they verified my wife's disease.

Assay lab have only received about a half dozen specimens over the years. Of those, actually only one specimen had sufficient tumor cells for testing. The problem is that it's not safe to take more than a few ml of it, and there are typically not enough cells to test more than one drug, if that.

The yield of tumor cells is too small. Sure, there may be a few tumor cells there, but not of sufficient quantity to be useful for cell culture testing. You can get, at most, several CCs (maybe a tenth of an ounce) of cerebrospinal fluid for testing.

About 500 - 1000 ml of fluid with a tumor cell percentage greater than 30 and the ratio of tumor to reactive cells should be greater than 2:1 with 20,000 units of heparin per liter.

If there would be another site of the disease (lymph node, pleural fluid, ascites), then that could be analyzed. The biology of the disease, in all probability, would be similar to that of the lymph node, pleural fluid, ascites. You can get hundreds to thousands of CCs of pleural fluid or ascites, and the number of tumor cells per CC is typically much greater in these fluids than in cerebrospinal fluid.
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Last edited by gdpawel : 09-24-2012 at 04:25 PM. Reason: additional info
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  #3  
Old 11-15-2010, 05:28 PM
gdpawel gdpawel is offline
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Default Tarceva (erlotinib) for Brain and Leptomeningeal Metastases

Journal of Thoracic Oncology:
November 2009 - Volume 4 - Issue 11 - pp 1415-1419
doi: 10.1097/JTO.0b013e3181b62572

Efficacy of Erlotinib for Brain and Leptomeningeal Metastases in Patients with Lung Adenocarcinoma Who Showed Initial Good Response to Gefitinib

Katayama, Tatsuya MD; Shimizu, Junichi MD; Suda, Kenichi MD; Onozato, Ryoichi MD; Fukui, Takayuki MD; Ito, Simon MD; Hatooka, Shunzo MD; Sueda, Taijiro MD; Hida, Toyoaki MD; Yatabe, Yasushi MD; Mitsudomi, Tetsuya MD

Abstract

Introduction:

The efficacy of high-dose (1250 mg/d) gefitinib for the treatment of leptomeningeal metastasis in a patient with lung cancer harboring a mutation in the epidermal growth factor receptor (EGFR) gene was previously reported. We speculate that erlotinib, instead of high dose of gefitinib, may be also effective for the treatment of central nervous system (CNS) lesions, as trough serum concentration of erlotinib is nine times higher than that of gefitinib.

Patients and Methods:

Patients with lung cancer in whom CNS lesions developed after an initial good response to gefitinib for extra CNS lesions were enrolled in the study. Tumor response, performance status, neurologic symptoms, and survival were retrospectively evaluated.

Results: All seven patients had EGFR mutations in their primary tumors except one patient. The median interval between gefitinib withdrawal and erlotinib administration was 5 days. Three patients showed partial response, three had stable disease, and one had progressive disease. Performance status and symptoms improved in five patients. The overall survival from the initiation of erlotinib treatment ranged from 15 to 530 days (median, 88 days).

Conclusions:

Erlotinib was a reasonable option for the treatment of CNS diseases that appeared after a good initial response of extra CNS disease to gefitinib.

[url]http://journals.lww.com/jto/Fulltext/2009/11000/Efficacy_of_Erlotinib_for_Brain_and_Leptomeningeal

Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis:

[url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409812/?tool=pubmed

Anti-angiogenic activity and VEGF pathway inhibition of Tarceva:

[url]http://cancerfocus.org/forum/showthread.php?t=3738

Response and Resistance in a Non–Small-Cell Lung Cancer Patient With an Epidermal Growth Factor Receptor Mutation and Leptomeningeal Metastases Treated With High-Dose Iressa:

[url]http://jco.ascopubs.org/content/24/27/4517.full
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Old 12-08-2011, 10:27 AM
gdpawel gdpawel is offline
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Default Poor Survival of Leptomeningeal Metastasis from NSCLC by WBRT

Leptomeningeal Metastasis from Non-small Cell Lung Cancer: Survival and the Impact of Whole Brain Radiotherapy

Morris, Patrick G. MD, MSc; Reiner, Anne S. MPH; Szenberg, Olga Rosenvald MD; Clarke, Jennifer L. MD; Panageas, Katherine S. DrPH; Perez, Hector R. MD; Kris, Mark G. MD; Chan, Timothy A. MD, PhD; DeAngelis, Lisa M. MD; Omuro, Antonio M. MD

TAKE-HOME MESSAGE

This large retrospective study highlights the poor prognosis of patients with leptomeningeal disease from NSCLC. Using landmark analyses, the authors suggest that whole brain radiotherapy has limited benefit in terms of survival and that targeted and intrathecal therapies might be more appropriate.

Abstract

Introduction:

Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging. A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes.

Methods:

Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed. Survival was assessed by Kaplan-Meier and landmark analyses by administered treatment to minimize selection bias.

Results:

We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0). No differences in survival were seen between patients who were treated with WBRT (n = 46) and those who were not (n = 59, p = 0.84) in a landmark analysis. In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p = 0.001) in a landmark analysis. The
median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months).

Conclusions:

This retrospective study, the largest published series, demonstrates the poor survival of LM from NSCLC. In this study, survival was not improved by WBRT. The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing
novel agents.

Source: J Thorac Oncol. 2011 Nov 15

[url]http://journals.lww.com/jto/Abstract/publishahead/Leptomeningeal_Metastasis_from_Non_small_Cell_Lung
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Old 03-06-2013, 08:59 PM
gdpawel gdpawel is offline
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Default Valerie Harper diagnosed with terminal brain cancer

Diagnosed with leptomeningeal carcinomatosis, a condition when cancer cells spread into the fluid-filled membrane (called meninges) that surround the brain and brain stem, doctors said she could have as little as three months to live.

There are more and more cases of this disease being reported. Many doctors do not understand this disease. However, I do not feel that it is just one of the terrible trade-offs in treating cancer.

There may be a more effective way to treat the possibilities of future metastasis to the central nervous system. The idea that systemic therapies can be as effective against leptomeningeal metastases has been looked upon for a number of years now, with agents like Temodar and EGFR inhibitors.

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.

A drug like Temodar is small molecule. Empirically, it has been shown to cross the BBB to affect cell death in circulating tumor cells. Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, small molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent.

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

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.

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.

Clinical data suggests that patients benefit both in terms of response and survival from drugs and drug combinations found to be "sensitive" to cancer cells rather than "resistant" to those cells.

The leading edge of research today is determing how a patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. Matching tumor type to drug.
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