View Full Version : Myeloma in the brain

02-10-2009, 05:43 AM
My Freind has just been told that her Myeloma has spread to her brain. The doctors are going to treat her with chemo via a lumber puncture. Can anyone tell me what to expect.

Thank you

03-14-2009, 08:50 PM
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).

Ever since my wife's second CSF tap (when Methotrexate was already being administered), all of her taps were negative for ten consective times. A Whole Body Bone Scan indicated that the skeletal system demonstrated normal uptake and an enhanced brain MRI showed no new areas of abnormal enhancement. Leptomeningeal Carcinomatous (Carcinomatous Meningitis) has a very poor prognosis, however, the cancer cells were eradicted completely from her central nervous system.

Although we used Methotrexate back then, from what I know now about Temador, we definitely would use it instead. And if whole brain radiation (WBR) would be indicated, we would value the Temador chemotherapy instead of going the route of WBR.

01-10-2010, 11:19 PM
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.

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


Just what is the blood-brain barrier?

The blood–brain barrier (BBB), an anatomic structure consisting of endothelial vessel cells, astrocytes and pericytes with tight junctions (TJs) and a number of carrier proteins, controls and limits the passage of molecules to the brain. In the presence of an intact BBB, only small lipophilic molecules (molecular weight [MW] <400 Da) can cross the BBB by diffusion, while the passage of other molecules is regulated by the carrier proteins.

Apart from a few drugs, such as temozolomide, melphalan, carmustine and irinotecan, chemotherapeutic agents, which are large hydrophilic molecules, are unable to cross the BBB, which is furthermore characterized by a high concentration of multidrug resistance efflux pumps, which may be another cause of the low concentration of drugs reaching the site of action.

Recently, Lin et al. underlined the role of astrocytes in preventing chemotherapeutic drugs from reaching metastatic sites in the brain, and observed in murine models that in pathological conditions, astrocytes are activated and come into direct contact with tumor cells, thus confirming the role of the microenvironment in brain metastases (1). This may lead to calcium sequestration, with a *consequent marked reduction in chemotherapy-induced apoptosis.

The role of the BBB in drug resistance has been called into question, since macroscopic intracranial lesions cause BBB disruption due to neoangiogenesis, which produces vessels that lack tight junction molecules and cannot therefore create an effective barrier (2,3).

Nonetheless, BBB disruption may be a characteristic of larger lesions, while the barrier could remain effective in small metastases, as demonstrated by contrast-enhanced images showing enhancement in large intracranial lesions but not in small infiltrative tumors.

Furthermore, the loss of tight junction molecules in the tumor vascular system does not necessarily incur the loss of other biological BBB components, such as detoxification and drug resistance mechanisms, which may remain effective and compromise drug *concentrations in BM (4).

1. Lin Q, Balasubramanian K, Fan D et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 12(9), 748–754(2010).

2. Muldoon LL, Soussain C, Jahnke K et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J. Clin. Oncol. 25(16), 2295–2305(2007).

3. Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna S, Verkman AS. Molecular mechanisms of brain tumor edema. Neuroscience 129(4), 1011–1020(2004).

4. Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol. Rev. 53(4), 569–596(2001).

The Blood-Brain Barrier: Bottleneck in Brain Drug Development [url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539316/

03-26-2011, 01:57 PM
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.

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.

Cancer. 2008 Nov 1;113(9):2524-31.

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

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

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.

Clinical Benefit Rate (CBR) and Disease Control Rate (DCR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. CBR and DCR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether CBR and DCR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR or DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the CBR or DCR are reported suggest that CBR or DCR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient (Curr Opin Investig Drugs. 2010 Dec;11(12):1340-1).

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?


03-26-2011, 01:58 PM
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



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).


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 .19.aspx#

01-19-2012, 02:01 PM
Voraxaze (glucarpidase), an intravenously delivered recombinant enzyme, was approved by the FDA for the treatment of patients with toxic levels of Methotrexate in their blood due to kidney failure.

The drug helps eliminate methotrexate in patients whose kidney function has been compromised by treatment with high doses of the chemotherapy agent. Methotrexate is normally eliminated from the body by the kidneys, but prolonged high doses of the drug used to treat cancer can result in kidney failure.

The injectable treatment can quickly break down the chemotherapy medicine and allow the body to expel it.

According to the FDA, treatment was considered successful if methotrexate levels fell below a critical level within 15 minutes and stayed below the critical level for 8 days. That result was seen in 10 of the 22 patients. The manufacturer of the drug says there was a 95% reduction in methotrexate concentration from pretreatment baseline levels, maintained for up to 8 days, in all evaluable patients.

The agency granted Voraxaze orphan drug status, meant for rare diseases or conditions that affect a very small portion of the population. As incentive for companies to develop such drugs, the orphan designation comes with seven years of marketing exclusivity before a rival medicine could be approved.

Methotrexate is used to treat breast, bone and lung cancer as well as leukemia. In much lower doses, it is commonly used to treat rheumatoid arthritis and other autoimmune diseases.

In addition to kidney failure, Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research said: "Prolonged exposure to high levels of methotrexate can result in kidney and liver damage, severe mouth sores, damage to the lining of the intestine, skin rashes, and death due to low blood counts.

"Voraxaze is an important new treatment option for cancer patients aimed at preventing these toxicities associated with sustained high levels of methotrexate," Pazdur said in a statement.

Common side effects included low blood pressure, headaches, nausea and vomiting.