- Breast Unit, Department of Medical Oncology, Centre Oscar Lambret and Department of Neuro Oncology, Roger Salengro Hospital, University Hospital, Lille, France
- Neurology, Mazarin and Radiation Oncology, Pitié Salpétrière Hospital, University Pierre et Marie Curie, Paris VI, Paris, France
- Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Research Cancer Center, Seattle, WA, USA
Correspondence Address:
Marc C. Chamberlain
Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Research Cancer Center, Seattle, WA, USA
DOI:10.4103/2152-7806.111304
Copyright: © 2013 Le Rhun E This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Rhun EL, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 02-May-2013;4:
How to cite this URL: Rhun EL, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 02-May-2013;4:. Available from: http://sni.wpengine.com/surgicalint_articles/carcinomatous-meningitis-leptomeningeal-metastases-in-solid-tumors/
Abstract
Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.
Keywords: Diagnostic tools, leptomeningeal metastases, monoclonal antibody, neoplastic meningitis, solid tumors, tyrosine kinase inhibitors, targeted therapy
INTRODUCTION
Leptomeningeal metastases (LM) result from metastatic infiltration of the leptomeninges by malignant cells originating from an extrameningeal primary tumor site that may be extraneural (most common) or intraneural (less common). Cerebrospinal fluid (CSF) dissemination of cancer is an important issue in neuro-oncology because its incidence is increasing and the clinical consequences are profound. Over the past decades, important advances have been made in earlier diagnosis of the disease but these advances have not been accompanied by substantial therapeutic progress. Patients usually present with pleomorphic and subtle neurological signs affecting the central nervous system (CNS), sometimes difficult to differentiate from those due to brain metastases or adverse effects of cancer treatment. Entire neuraxis magnetic resonance imaging (MRI) is required for diagnosis, but the identification of neoplastic cell by CSF cytological study is the key feature determining LM. The specificity and the sensitivity of MRI and CSF analyses remain poor. Diagnosis notwithstanding the availability of CNS imaging and CSF cytology remains a challenge. New methods for corroborating a diagnosis of LM are under development. Additionally, several prognostic factors have been identified to assist in determining whom to treat with LM-directed therapy. Early detection of LM, before the installation of fixed deficits, is needed to improve the prognosis. Without specific LM-treatment, median survival is limited to several weeks. With combined treatments, the median survival of patients with LM averages several months. Specific treatment of LM typically combines systemic and intrathecal (IT) chemotherapy and site-specific radiotherapy. Choice of intra-CSF chemotherapy may vary according to the site of origination of the primary tumor. New agents are now under evaluation. This review focuses on LM originating from solid tumors excluding leptomeningeal dissemination of hematological malignancies (e.g., leukemia and lymphoma) or primary brain tumors.
EPIDEMIOLOGY
The incidence of clinically diagnosed LM in patients with solid tumors is approximately 5% but the incidence of undiagnosed or asymptomatic LM may be 20% or more with many solid tumors as illustrated in autopsy series.[
Treatment of systemic cancer metastatic to the CNS appears to influence the incidence of LM accounting in part for the apparent increase incidence of LM. Among these factors, surgical resection of parenchymal cerebellar metastases has purportedly resulted in subsequent development of LM.[
Another important factor contributing to an increased incidence of LM is more effective systemic therapy, both adjuvant and salvage, leading to a prolongation of survival and late metastatic spread to the CNS. The use of newer targeted therapies with poor CNS penetration such as trastuzumab (Herceptin used for her2/neu positive cancers) and rituximab (Rituxan used for B-cell malignancies) is another factor that contributes to an increased incidence of LM.[
The meninges and CSF compartment are indeed a pharmacological sanctuary for many cytotoxic agents that poorly cross an intact blood–CSF barrier. In this situation, tumor cells in the subarachnoid space are not adequately treated by systemic cytotoxic therapy and may consequently escape cytotoxic effects of systemic therapy and proliferate as previously observed in acute leukemia prior to the introduction of CNS-directed therapy.
A combination of these factors probably explains the considerable increase in the actuarial incidence of LM in small cell lung cancer (SCLC) over time, from 0.5% at diagnosis to 25% after 3 years of survival and the observation that isolated meningeal involvement is no longer an exceptional site of relapse after chemotherapy for breast cancer, particularly when taxanes or trastuzumab are used, both of which penetrate poorly into the CSF.[
PATHOPHYSIOLOGY AND PATHOLOGY
Cancer cells may invade the meninges through different pathways, depending on histology of the primary tumor.[
Hematogenous spread
Hematogenous spread to the arachnoid via the arterial circulation, is probably the most common route of metastasis resulting in LM, but appears less common in solid tumors compared with hematological malignancies.[
Endoneural/perineural and perivascular lymphatic spread
Vertebral and paravertebral metastases (particularly from breast and lung cancers) as well as head and neck cancers may spread centripetally along peripheral or cranial nerves[
Direct spread from the brain parenchyma
Direct spread from metastases located in the brain parenchyma that is in close opposition to the CSF space has been described. These tumors appear to breach the subarachnoid or ventricular spaces and diffuse widely in the CSF, although a peritumoral fibrotic reaction at the site of invasion often circumscribes this type of metastasis. This manner of spread is particularly relevant with respect to primary brain tumors.[
Choroid plexus
Metastases to the choroid plexus and subependyma has been described with subsequent CSF dissemination though is considered an uncommon mechanism of cancer spread.[
De novo tumors
Primary tumors arising in the meninges such as melanoma and some soft tissue sarcomas (e.g., malignant peripheral nerve sheath tumors) may secondarily spread to the CSF and disseminate.
Iatrogenic spread
During invasive procedures or neurosurgery as mentioned earlier, CSF tumor spread may result through an ependymal or pial breach.[
Once malignant cells enter the CSF, cancer cells disseminate by extension along the meningeal surface and by convective CSF flow to distant parts of the CNS where random implantation and growth occurs forming secondary leptomeningeal metastatic deposits. While a diffuse covering of the leptomeninges is particularly frequent in hematological malignancies, plaque-like deposits with invasion of the Virchow–Robin spaces and nodular formations are more characteristics of solid tumors. The areas of predilection for circulating cancer cell settlement are characterized by slow CSF flow and gravity-dependent effects (basilar cisterns, posterior fossa, and lumbar cistern).[
PATHOLOGY
Gross
Gross inspection of brain, spinal cord, and spinal roots may be normal. More often, however, the leptomeninges are abnormal manifesting thickening and fibrosis that may be diffuse or localized in one or several distinct area(s) of the CNS, particularly in regions with relative CSF flow stasis, as stated earlier.[
Microscopic
Characteristically there is diffuse or multifocal infiltration of arachnoid membranes by cancer cells, often filling the subarachnoid and Virchow–Robin spaces, and sometimes invading the underlying neuraxis, vessels, and nerve surfaces. Cranial and spinal nerve demyelination and axonal degeneration are occasionally observed without any tumor infiltration. Microscopic examination may also reveal infarction of infiltrated areas.[
The physical–chemical characteristics of the blood–CSF-barrier comprised of ependymal and leptomeningeal (brain/spine) parts, differs from those of the blood–brain barrier (between blood and brain parenchyma).[
PATHOPHYSIOLOGY OF SIGNS AND SYMPTOMS
Several mechanisms, often combined, are incriminated, which result in the symptom complex characteristic of LM.
Hydrocephalus and increased intracranial pressure
Tumor infiltration of the base of the brain, Sylvian fissures, and arachnoid villi as well as reactive fibrosis and inflammation may impair or block CSF outflow and lead to hydrocephalus and increased intracranial pressure. However, when the site of obstruction is located near the sagittal sinus or basilar cisterns, intracranial pressure may be elevated in the absence of obvious hydrocephalus.[
Compression and invasion
Focal neurological symptoms and signs, and increased intracranial pressure may result from compression or invasion of the brain and spinal cord, as well as cranial and peripheral nerve roots.[
Ischemia
Invasion, compression, or spasm of blood vessels located on the brain convexity or in the Virchow-Robin spaces may interfere with the blood supply and oxygenation of neurons and may produce transient attacks, strokes, and perhaps encephalopathy secondary to a global decrease in cerebral blood flow.[
Metabolic competition
Some patients develop a diffuse encephalopathy of unknown origin and it has been suggested that tumor cells and neurons may be in competition for metabolites such as glucose leading to relative metabolite deprivation of the underlying neurons.[
Blood–CSF barrier disruption
A disruption of the blood–CSF barrier is rarely a consequence of direct invasion by LM but more commonly due to the development of tumoral angiogenesis with associated leaky fenestrated LM-related neovasculature that develops when LM-related tumors reach a threshold diameter (nodules) or thickness (layers).[
DIAGNOSIS OF LM
The diagnosis of LM may be ascertained according to the National Comprehensive Cancer Network (NCCN) guidelines.[
Clinical features
Patients most often present with pleomorphic and multifocal neurological symptoms and signs related to the specific region of the CNS involved by malignant cells. Symptoms and signs are classically divided into three domains of neurological function: Cerebral hemisphere, cranial nerve and spinal cord, and exiting nerve roots.[
Pleomorphic and multifocal neurological symptoms and signs are strongly suggestive of the diagnosis of LM in patients with known cancer, but patients may also present with isolated and subtle neurologic symptoms. Neurologic dysfunction due to LM should be distinguished from those due to parenchymal brain metastases, complications of antineoplastic treatments, other causes of chronic meningitis (tuberculosis, fungal infections, sarcoidosis) as well as metabolic and toxic encephalopathies or concurrent diseases.[
Imaging diagnosis
Because LM involves the entire neuraxis, imaging of the entire CNS is required. MRI with gadolinium enhancement is the radiologic technique of choice.[
The standard examination should include at the cerebral level, axial T1-weighted images without contrast, fluid attenuation inversion recovery (FLAIR) sequences and 3D axial T1-weighted sequences with contrast. The spine is best evaluated with sagittal T1-weighted sequences with and without contrast and sagittal fat suppression T2-weighted sequences, combined with axial T1-weighted images with contrast of regions of interest. Contrast enhanced T1-weighted and FLAIR sequences are the most sensitive to detect LM.[
Any irritation of the leptomeninges, such as subarachnoid blood, infection, inflammation can result in enhancement on MRI. Lumbar puncture itself can cause a meningeal reaction, leading to leptomeningeal enhancement. MRI should be obtained preferably prior the lumbar puncture.[
The sensitivity of MRI varied from 20% to 91%.[
CT is of limited value in the diagnosis of LM.[
Radionuclide studies using 111Indium-diethylene-triamine pentaacetic or 99Tc macro-aggregated albumin represent the techniques of choice for the evaluation of CSF flow interruption. In patients with LM, CSF flow blocks may be present in 30-70% of patients, mostly occurring at the skull base, within the spine and over the cerebral convexities.[
CSF examination
Abnormalities of the standard CSF analysis are observed in more than 90% of the cases of LM.[
Several simple procedures can improve the sensitivity of the CSF cytological analysis including submission of a nonhemorrhagic CSF specimen. In a series of patients with LM demonstrated by positive lumbar CSF cytology and without any evidence of CSF flow obstruction, ventricular and lumbar cytology obtained simultaneously were discordant in 30% of cases.[
A variety of biomarkers of LM have been suggested to assist in achieving an earlier diagnosis of LM and to evaluate effectiveness of treatment. These biomarkers may be nonspecific, such as β-glucuronidase, lactate dehydrogenase, beta2-microglobulin, carcinoembryonic antigen or alternatively organ specific such as CA 15-3, CA 125, CA 19-9, CA724, AFP, NSE, Cyfra 21-1, and EGFR. CSF release of tumor biomarkers markers has been demonstrated in many patients with LM, however, there was no clear correlation with the type of carcinoma or response to treatment observed.[
At present there is neither agreement regarding CSF biomarker cutoff levels nor has there been standardization of CSF sampling and processing. Due to inconsistencies in laboratory methodology, there is considerable variations in sensitivity and specificity of these assays that represent serious challenges for utilizing biomarkers in the management of LM.[
EVALUATION AND RESPONSE TO TREATMENT
No standardized criteria to evaluate the response to treatment of LM have been defined or universally agreed upon. New clinical signs and symptoms must be distinguished from manifestations of parenchymal disease, from side-effects of intra-CSF treatment, systemic treatment or radiation, from co-medications, from neurological or extraneurological concurrent disease, and more rarely from paraneoplastic syndromes.[
As mentioned earlier, CSF cytological analysis remains the gold standard for the identification of malignant cells in the CSF. The sensitivity of a first CSF examination varied from 45% to 55%, and usually, two successive CSF samples are required to adequately assess cytology. The majority of clinical trials in LM have utilized a combination of CSF cytology (conversion from positive to negative) and clinical response (improved or stable) to determine success of LM-directed treatment. At present there are no agreed upon radiographic criteria to determine response to treatment in LM. Consequently, new consensual response criteria are needed in LM so as to better adjudicate outcome and to permit more uniform conduct of clinical trials with novel agents.
SURVIVAL AND PROGNOSTIC FACTORS
The median overall survival (OS) of untreated patients with LM is 4-6 weeks.[
The aim of LM-directed treatment is to improve or stabilize the neurological status, maintain neurological quality of life, and prolong survival. Nonetheless, deciding which patients to treat with LM remains challenging. The NCCN CNS guidelines (version 1.2012) have attempted to distinguish between patients reasonably considered for treatment vs. those patients in whom supportive care is most appropriate [
Based on the literature, the type of primary cancer is known to be the major prognostic factor with regard to OS in LM.[
In addition to tumor histology, multivariate analysis confirms the association between OS and the performance status (PS), the age at LM diagnosis and the treatment modality (administration of systemic therapy).[
In a recent study of patients with lung cancer and LM, multivariate analysis confirmed that PS, the treatment modality (especially systemic therapy), clinical improvement after intra-CSF chemotherapy were all significantly associated with a better OS.[
TREATMENT
The goals of treatment include palliating neurologic symptoms and whenever possible stabilizing or improving patient neurologic function as well as prolonging survival. Since the prognosis of LM varies noticeably depending upon the primary tumor type and extent of both neurologic and systemic disease, parameters separating poor-risk from good-risk patients are helpful to determine the appropriate therapeutic approach for an individual patient. The poor-risk and good-risk patients categories are illustrated in
Symptomatic
Patients with low PS, quality of life interfering fixed neurologic deficits or encephalopathy due to extensive LM-brain infiltration, and uncontrolled systemic disease with limited therapeutic options have a poor prognosis even with active LM-directed treatment. A palliative approach should be considered in such poor prognosis patients.[
Treatment of LM-related pain that may include headache, back, or radicular pain, frequently necessitates using opioid analgesics. In addition, neuropathic pain often requires tricyclic antidepressants (such as amitriptyline or nortrptyline) or antiepileptic drugs (such as gabapentin, pregabalin, carbamazepine, and lamotrigine). Corticosteroids may also improve radicular pain. Focal irradiation of symptomatic sites is often quite efficient in relieving pain. Seizures are managed with anticonvulsant drugs (AEDs) but prophylactic administration of AEDs is not recommended in patients who have never had seizures. Headaches related to edema or increased intracranial pressure can sometimes be managed with steroids, even if the contribution of steroids in the treatment of LM is modest as compared with their efficacy in brain parenchymal metastases. In instances of hydrocephalus secondary to CSF block, a course of steroids during whole brain or skull-base radiotherapy is sometimes useful but CSF shunting is often required in this situation.[
Surgery
The main surgical intervention in LM is ventriculoperitoneal shunting (VPS) for symptomatic hydrocephalus and placement of a ventricular (rarely lumbar) access device (e.g., an Ommaya or Rickham reservoir) to facilitate administration of intra-CSF chemotherapy. When both a VPS and Ommaya ventricular access device are needed, an on–off valve may be placed but this necessitates that the patient can tolerate having the VPS placed in the off position so as to permit drug installation into the ventricles and time for ventricular transit and distribution into the nonventricular CSF compartments.[
When a ventricular access device is placed, confirmation postimplantation of correct intraventricular (IVent) placement requires a brain CT or alternatively a radio-isotope CSF flow study before intra-CSF drug administration.[
Radiation therapy
Craniospinal axis irradiation (CSI) is the only method of radiotherapy that treats the entire neuraxis and that may be reasonably considered as a single modality of treatment for LM. However, in the majority of adults CSI is rarely considered as most patients have previously had some region of the neuraxis irradiated and as well have poor bone marrow reserve as a consequence of prior exposure to cytotoxic chemotherapy. Consequently, CSI and treatment-associated toxicities of myelosuppression and enteritis is deemed too toxic for routine use in adults with solid tumor-related LM. The role of alternative methods of CSI such as tomotherapy and proton radiotherapy, which could permit improved precision in radiation dosing and targeted volumes and consequently less hematological toxicity, has not been formally evaluated and may be an option in the future.
The majority of patients with LM receive involved-field radiotherapy to sites of symptomatic disease, bulky disease observed on MRI and to sites of CSF flow block defined by radioisotope ventriculography. Irradiation permits tumor masses not treated by intra-CSF chemotherapy (due to limited diffusion of intra-CSF chemotherapy) to receive palliative radiotherapy.[
Major side effects secondary to involved-field RT alone are uncommon aside from radiation-associated fatigue. However, major effects such as myelosuppression, mucositis, esophagitis, and leukoencephalopathy have been reported with more extensive radiation fields. Leukoencephalopathy (asymptomatic more often than symptomatic) may be a delayed consequence in patients treated by concomitant WBRT and methotrexate (MTX) (either systemic or intra-CSF). Ongoing clinical trials evaluating the safety of concomitant WBRT and intra-CSF liposomal cytarabine (ara-C) will define if this is a common problem with chemoradiation or unique to MTX when combined with radiotherapy.
Other types of RT consisting of intra-CSF administration of radioisotopes[
Chemotherapy
Chemotherapy is the only modality aside from CSI allowing simultaneous treatment of the entire neuraxis.[
Intra-CSF chemotherapy
Intra-CSF (intralumbar or IT and IVent) chemotherapy is the mainstay of treatment for LM, although its superiority compared with systemic treatment has not been established in randomized trials and its efficacy consequently is uncertain [
The normal blood–brain and blood–CSF barriers limit penetration into the CNS of most systemically administered anticancer agents. Consequently, CSF exposure to most cytotoxic agents is less than 5% of the plasma concentration. The blood–CSF barrier in LM is compromised but the disruption is partial, varies from one region to another such that with few exceptions (e.g., high-dose MTX discussed later for breast cancer-associated LM) is rarely a primary treatment of LM.
The goal of intra-CSF chemotherapy is therefore to bypass the blood–CSF barrier, maximizing drug exposure in the CSF while reducing systemic toxicity. With this approach, a higher drug concentration can be achieved using a smaller dose, because the distribution volume of CSF is lower than that of the plasma (140 vs. 3500 ml).[
Lumbar intrathecal or intraventricular route of administration
IT treatment can be delivered by repeated spinal punctures. Position affects ventricular drug levels after intralumbar administration and patients should remain flat for at least 1-hour following treatment.[
IVent administration of intra-CSF drug via an Ommaya or Rickham reservoir offers several advantages compared with IT therapy.[
Techniques of intra-CSF administration
Even in asymptomatic patients, it is critical to avoid any variation in CSF volume in these fragile patients recognized to be on the edge of their CSF ventricular “pressure-volume” compliance curve. If the total CSF volume is increased, severe intracranial hypertension can occur. Thus equivalent volume of CSF should be removed (so called isovolumetric withdrawal) prior chemotherapy administration. During the withdrawal of a large volume of CSF from the ventricles, a transient retro-orbital or frontal headache may result. The headache is often improved with administration of intra-CSF chemotherapy if given in 5-10 ml volume. No prospective trials in adults with LM have proven any benefit to concomitant use intra-CSF glucocorticoids (hydrocortisone) in combination with intra-CSF chemotherapy.
Drugs available for intra-CSF treatment
Currently, MTX, liposomal ara-C, and less often thiotepa are used in daily practice. Unfortunately, these drugs are not effective against many of the most frequent solid cancers associated with LM, particularly melanoma and lung cancer. New agents including monoclonal antibodies are currently being investigated in clinical trials and are discussed later.
Methotrexate
Therapeutic CSF concentrations, at 1 μM or more during 48-72 h, are obtained with a 12 mg IT dose of MTX in adults and in children aged older than 2 years.[
MTX is eliminated from the CSF by CSF/venous resorption and subsequent delivery into the systemic circulation. Consequently factors that interfere with CSF resorption increase intra-CSF MTX-related neurotoxicity. Similarly renal insufficiency resulting in delayed excretion of MTX or the presence of pleural or peritoneal effusions that create a “third space effect” and thereby accumulation of MTX, can increase systemic MTX toxicity resulting in myelosuppression or mucositis. The coadministration of drugs that displace MTX from albumin such as aspirin, phenytoin, sulfonamides, and tetracycline, may also increase MTX toxicity. Neurologic complications of intra-CSF MTX include aseptic meningitis, acute encephalopathy, transverse myelopathy, and delayed leukoencephalopathy.[
An accidental overdose of intra-CSF MTX may result in significant morbidity or death. Standard recommendations in such clinical situations include immediate drainage of CSF via lumbar puncture, ventriculostomy with ventriculo-lumbar perfusion, systemic steroids, and systemic leucovorin administration. A potentially useful antidote, the carboxypeptidase-G2 (CPDG2) has been reported. Pharmacokinetic studies showed a 400-fold decrease in CSF MTX concentrations within 5 minutes of CPDG2 administration.[
Cytosine arabinoside (Cytarabine)
ara-C is initially administered at a dosage of 25-100 mg twice weekly and used in a similar manner to that of MTX with a 4-week induction, followed by 4 weeks of consolidation and subsequent maintenance. The half-life of ara-C is much longer in the CSF than in serum because of the low levels of CSF cytidine deaminase, the main catabolic enzyme of ara-C. The rapid deamination observed in the systemic circulation causes minimal systemic toxicities. A concentration times time regimen of intra-CSF ara-C has also been reported.[
In solid tumor-related LM, a randomized trial comparing intra-CSF liposomal ara-C to MTX found that liposomal ara-C increased median time to neurologic progression (58 vs. 30 days, P = 0.0068) but did not affect median survival (105 vs. 78 days, not significant) [
Liposomal ara-C has shown similar rate (28%) of response compared with other intra-CSF drugs in nonrandomized series.[
Thiotepa
Thiotepa, the only alkylating agent (that by definition has a cell cycle nonspecific mechanism of action) used for intra-CSF chemotherapy, has the shortest half-life (approximately 20 minutes) of all agents used for intra-CSF chemotherapy and shows complete CSF clearance within 4 hours. It is often used as a second-line agent for breast cancer patients who do not respond to or cannot tolerate intra-CSF MTX. Thiotepa unlike other intra-CSF administered drugs rapidly crosses brain capillaries and consequently may result in meaningful systemic serum levels and associated myelosuppression. Because of the short half-life and rapid transcapillary movement, it has been argued that there is no pharmacological advantage to intra-CSF thiotepa. Nonetheless, the efficacy and toxicity of intra-CSF thiotepa has been prospectively compared with intra-CSF MTX in a randomized trial of adults with LM and demonstrated statistically significant differences in median survival (14 weeks with intra-CSF thiotepa vs. 16 weeks with intra-CSF MTX), a CSF cytological clearance rate of 30% and patients on the thiotepa arm experienced fewer neurological toxicities.[
Combination (multi-agent) intra-CSF chemotherapy
There is no evidence that has demonstrated using an intra-CSF drug combination in LM from solid tumors that shows any superiority to that of a single agent regimen. In addition, increased toxicity and decreased tolerance to treatment has been demonstrated with multi-agent intra-CSF chemotherapy.[
Systemic chemotherapy
In contrast with hematologic neoplasms, the benefit of intra-CSF chemotherapy in LM from solid tumors remains modest. These disappointing results are due to several factors, including intrinsic chemoresistance, limited choice of intra-CSF chemotherapeutic agents, and the poor accessibility of bulky nodules to intra-CSF chemotherapy.[
Siegal reviewed intra-CSF vs. systemic chemotherapy in LM from solid tumors.[
The choice of the most appropriate systemic chemotherapy should be based not only on the chemosensitivity profile of the primary tumor and potential of secondary (acquired) resistance but also upon the ability of drug to achieve effective concentrations in the CSF, features that reflect the chemical properties (lipophilic, low protein-binding, low molecular weight agents) of the systemic agent. Alternatively, high-dose systemic chemotherapy (e.g., MTX) has been administered and shown to be effective for lymphoma and breast cancer-related LM.[
Temozolomide, an alkylating chemotherapy that crosses the blood–brain barrier has been recently evaluated in a phase II trial in first line treatment of LM secondary to breast cancer and NSCLC.[
High-dose methotrexate
High-dose IV methotrexate (HD IV MTX) with leucovorin rescue is an alternative to intra-CSF treatment. It has been prescribed up to 8 g/m2, and its efficacy in this indication has been evaluated in small retrospective studies.[
High-dose cytarabine
Therapeutic CSF levels can be achieved by administering ara-C 3 g/m2 every 12 hours[
NEW THERAPEUTIC APPROACHES
Investigational intra-CSF therapies
Innovative intra-CSF chemotherapy regimens
Considerable effort has been invested in evaluating new intra-CSF chemotherapeutic drugs such as diaziquone (AZQ),[
In addition to DepoCyt, intra-CSF administration of MTX encapsulated in liposomes is being developed, but careful evaluation of the potential toxicity of liposomal MTX will be needed. Intra-CSF instillation of a microcrystalline preparation of busulfan (Spartaject) has been studied in clinical trials though again with limited clinical efficacy aside from chronic myelogenous leukemia-related LM.[
Intra-CSF etoposide has been evaluated in two feasibility studies and one phase II study.[
Topotecan is a topoisomerase I inhibitor that shows antitumor activity against a wide variety of adult and childhood solid tumors. Experimental studies have shown that IVent administration of 1/100th of the systemic dose of topotecan could provide a 450-fold greater CSF exposure. A phase I study of IT topotecan in patients with LM has shown a response in 3 out of 13 children with LM secondary to primary brain tumors.[
Biological modifiers
Transduction inhibitors,[
Intra-CSF IL-2 has been evaluated in patients with LM secondary to melanoma.[
Monoclonal antibodies
General comments
A major challenge with biological response modifiers for use in patients with LM, is the poor CSF penetration after systemic administration as illustrated by trastuzumab (humanized monoclonal antibody targeting HER2/neu) and SU5416 (inhibitor of the tyrosine kinase activity of the VEGF receptor).[
Clinical trials using I[
Trastuzumab
LM remain relatively rare (3-5%) in the HER 2/neu positive breast cancer patients as compared with parenchymal brain metastases (approximately 30%).[
A toxicology study with weekly intra-CSF administration of trastuzumab was performed in monkeys with a good tolerance profile at CSF concentrations that exceeded those reported in patients after systemic administration.[
Intra-CSF trastuzumab has been administered at varying doses (5-100 mg) with clinical and cytological success reported in case studies of patients with LM and HER-2/neu positive breast cancer.[
Intra-CSF trastuzumab has also been administered to two patients in association with intra-CSF MTX and ara-C.[
Investigational systemic treatment
Breast cancer
Capecitabine
Capecitabine, an oral prodrug of 5-fluorouracil, has induced encouraging long-lasting responses and stabilization in a limited number of patients with LM from breast cancer but the role in patients with LM is uncertain given the paucity of patients reported to date.[
Hormonal treatment
Similar to capecitabine, hormonal agents such as tamoxifen, letrozole, anastrozole, and megestrol have occasionally been useful in breast cancer LM but like capecitabine these reports are usually comprised of a single patient and it is difficult to draw any conclusions as to effectiveness of either hormonal agents or capecitabine in breast cancer-related LM.[
Nonsmall cell lung cancer
Chemotherapy
Previous reports that suggest systemic chemotherapy improves survival for patients with LM have primarily been of of chemoresponsive cancers, such as breast cancer or hematologic malignancies. Recently, Park reported that administration of systemic chemotherapy after diagnosis of LM in NSCLC patients was a significant prognostic factor.[
Targeted therapies/epidermal growth factor inhibitors
The epidermal growth factor (EGFR) TKI erlotinib and gefitinib show activity in NSCLC, especially in women, nonsmokers, patients of Asian ethnicity, those with adenocarcinoma, and patients with specific activating mutations of the EGFR.
Several studies have suggested that a subset of patients with LM secondary to NSCLC may benefit with long lasting remission (11-12 months) from erlotinib and gefitinib at normal or higher dose if an EGFR mutation is present.[
Two recent and a large retrospective series have demonstrated particularly encouraging results with the use of these agents. In the US series, the median survival of the nine patients with LM and known EGFR mutations (all of whom received TKI at some point) was 14 months (range, 1-28 months).[
Whether erlotinib should be prescribed in LM at standard dose or high-dose is not clear.[
Long-lasting meningeal responses have been reported with erlotinib after a prior progression under gefitinib, and vice versa.[
In conclusion, among new generation chemotherapeutic agents, EGFR TKI may be a valuable option in patients with LM particularly in patients with activating EGFR mutations or favorable clinical factors for EGFR TKI responsiveness.
Bevacizumab
CSF levels and CSF/serum indices of (VEGF) have been measured in several studies and were significantly higher in patients with LM, supporting the hypothesis that angiogenesis contributes to LM. VEGF was also negatively correlated with survival in these patients.[
Bevacizumab is a monoclonal antibody targeting the VEGF ligand. This angiogenic inhibitor is widely prescribed in metastatic colorectal cancer and NSCLC. Retrospective data suggests that bevacizumab is safe in CNS metastases and not associated with an increased risk of intratumoral or intracranial hemorrhage particularly when intracranial lesions are asymptomatic and are of comparatively small volume.[
Intra-CSF bevacizumab is currently being evaluated in LM.[
Melanoma
Patients with LM from melanoma have a poor prognosis, with a median survival less than 2 months.[
Clinical results from the development of immunotherapy agents such as the anti-CTLA4 monoclonal antibody ipilimumab and targeted therapies targeting mutated BRAF such as vemurafenib and dabrafenib suggest that these agents may play a role in the multidisciplinary management of melanoma patients with parenchymal brain metastases.[
TOXICITY AND COMPLICATIONS OF LM-DIRECTED TREATMENT
Most series of patients treated for LM describe a global complication rate of 70% (all grades of toxicity) with severe complications in 15-20% of cases, and treatment-related deaths in less than 5% of patients.[
It remains challenging to differentiate neurologic side-effects secondary to LM-directed treatment from underlying disease progression and from other associated co-morbidities. Elements of prior or concurrent treatment (whole brain radiotherapy, intra-CSF chemotherapy, HD MTX, or HD ara-C) appear to increase intra-CSF drug (MTX and liposomal ara-C) toxicities, regardless of the route (lumbar or ventricular) of administration.[
CONCLUSION
The incidence of CNS metastasis including LM likely will continue to increase in the future due to an improvement of OS of the patients with cancer that is reflective of more effective systemic treatments often with limited penetration into the CNS. Consequently an early diagnosis based upon clinical suspicion is needed to improve the quality of life and the OS of the patients with LM as once neurologic deficits are established rarely reverse with treatment. Available diagnostic tools for LM (CSF cytology and neuraxis imaging) lack both specificity and sensitivity, but new methods of CSF biomarkers are being actively evaluated. Nonetheless prognosis of LM remains poor with a median OS of 3 months and less than 15% of all patients surviving 1 year following diagnosis. At present, LM is treated with combined modality therapy often using some combination of systemic chemotherapy, CNS directed radiotherapy and intra-CSF chemotherapy. Novel targeted agents increasingly are being studied in the treatment of LM and may prove promising in the future. New clinical trials of LM based on a tumor-specific histology are needed to establish the role of these new approaches. Equally important in the management of LM is establishing a common method of assessing response to LM-directed treatment that would improve new trial design and enable cross trial comparisons.
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