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First Published Online September 5, 2008
The Oncologist, Vol. 13, No. 9, 967-977, September 2008; doi:10.1634/theoncologist.2008-0138
© 2008 AlphaMed Press

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Neuro-Oncology

Neoplastic Meningitis

Marc C. Chamberlain

University of Washington, Department of Neurology/Division of Neuro-Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington, USA

Key Words. Neoplastic meningitis • Leptomeningeal metastases

Correspondence: Marc C. Chamberlain, M.D., University of Washington, Department of Neurology/Division of Neuro-Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 825 Eastlake Avenue E, POB 19023, MS G4940, Seattle, Washington 98109-1023, USA. Telephone: 206-288-8280; Fax: 206-288-2000; e-mail: chambemc{at}u.washington.edu

Received June 19, 2008; accepted for publication July 24, 2008; first published online in THE ONCOLOGIST Express on September 5, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Marc C. Chamberlain, Enzon, Mundipharma; Honoraria: Marc C. Chamberlain, Enzon, Mundipharma; Research funding: None; Ownership interest: None; Expert testimony: None; Other: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
After completing this course, the reader should be able to:

  1. Describe the epidemiology of leptomeningeal metastasis.
  2. Participate in the diagnosis of leptomeningeal metastasis.
  3. Engage in the treatment of leptomeningeal metastasis.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
Background. Neoplastic meningitis (NM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with cancer.

Methods. Notwithstanding frequent focal signs and symptoms, NM is a disease affecting the entire neuraxis, and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments.

Results. Central nervous system staging of NM includes contrast-enhanced cranial computerized tomography or magnetic resonance imaging (MR-Gd), contrast-enhanced spine magnetic resonance imaging or computerized tomographic myelography and radionuclide CSF flow study. Treatment of NM incorporates involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (i.e., methotrexate, cytosine, arabinoside, and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery.

Conclusions. Although treatment of NM is palliative with an expected median patient survival of 2 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
Neoplastic meningitis (NM) is the result of seeding of the leptomeninges by malignant cells. NM is not infrequent and is becoming more common as cancer patients live longer [1–5]. NM results in significant morbidity, and the median survival duration is short despite therapy. However, treatment can result in significant palliation of the central nervous system (CNS) and is best approached by a multidisciplinary team.


   EPIDEMIOLOGY
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 Learning Objectives
 Abstract
 Introduction
 Epidemiology
Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
NM is diagnosed in 1%–5% of patients with solid tumors (in which case it is termed carcinomatous meningitis and the main subject of this review), 5%–15% of patients with leukemia (termed leukemic meningitis) and lymphoma (termed lymphomatous meningitis), and 1%–2% of patients with primary brain tumors [5]. Autopsy studies show that 19% of patients with cancer and neurologic signs and symptoms have evidence of meningeal involvement [6]. Adenocarcinoma is the most frequent histology and breast, lung, and melanoma are the most common primaries to metastasize to the leptomeninges [3, 7, 8]. Although small cell lung cancer and melanoma have the highest rates of spread to the leptomeninges (11% and 20%, respectively), because of the higher incidence of breast cancer (with a 5% rate of spread), the latter accounts for most cases in large series of the disorder [1, 7, 9–11]. Carcinomas of unknown primary constitute 1%–7% of all cases of NM [7].

NM usually presents in patients with widely disseminated and progressive systemic cancer (>70%), but it can present after a disease-free interval (20%) and even be the first manifestation of cancer (5%–10%), occasionally in the absence of other evidence of systemic disease [7, 12–14].


   PATHOGENESIS
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 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
Cancer cells reach the meninges by various routes: (a) hematogenous spread, either through the venous plexus of Batson or by arterial dissemination; (b) direct extension from contiguous tumor deposits; and (c) centripetal migration from systemic tumors along perineural or perivascular spaces [15–18].

Once cancer cells have entered the subarachnoid space, they are transported by cerebrospinal fluid (CSF) flow, resulting in disseminated and multifocal neuraxis seeding of the leptomeninges. Tumor infiltration is most prominent at the base of brain, on the dorsal surface of the spinal cord, and, in particular, in the cauda equina [5, 18]. Hydrocephalus or impairment of CSF flow may occur at any level of the neuraxis and is a result of ependymal nodules or tumor deposits obstructing CSF outflow.


   CLINICAL FEATURES
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 
NM classically presents with pleomorphic clinical manifestations encompassing symptoms and signs in three domains of neurological function: (a) the cerebral hemispheres (15% of all patients), (b) the cranial nerves (35%), and (c) the spinal cord and roots (60%). Signs on examination generally exceed the symptoms reported by the patient.

The most common manifestations of cerebral hemisphere dysfunction are headache and mental status changes. Other signs include confusion, cognitive impairment, seizures, and hemiparesis. Diplopia is the most common symptom of cranial nerve dysfunction, with cranial nerve VI being the most frequently affected, followed by cranial nerves III and IV. Trigeminal sensory or motor loss, cochlear dysfunction, and optic neuropathy are also common findings. Spinal signs and symptoms include weakness (lower extremities more often than upper), dermatomal or segmental sensory loss, and pain in the neck, back, or following radicular patterns. Nuchal rigidity is only present in 15% of cases [3, 7, 8, 13, 19].

A high index of suspicion needs to be entertained in order to make the diagnosis of NM. The finding of multifocal neuraxis disease in a patient with known malignancy is strongly suggestive of NM, but it is also common for patients with NM to present with isolated syndromes such as symptoms of raised intracranial pressure, cauda equina syndrome, or cranial neuropathy.

New neurological signs and symptoms may represent progression of NM but must be distinguished from the manifestations of parenchymal disease (30%–40% of patients with NM have coexistent parenchymal brain metastases), from the side effects of chemotherapy or radiation used for treatment, and rarely from paraneoplastic syndromes. At presentation, NM must also be differentiated from chronic meningitis resulting from tuberculosis, fungal infection, or sarcoidosis as well as from metabolic and toxic encephalopathies in the appropriate clinical setting [7, 20].


   DIAGNOSIS
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 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
Staging
 Prognosis
 Treatment
 Conclusions
 References
 
CSF Examination
The most useful laboratory test in the diagnosis of NM is the CSF examination. Abnormalities include increased opening pressure (>200 mm of H2O), increased leukocytes (>4/mm3), elevated protein (>50 mg/dl), and decreased glucose (<60 mg/dl), which, though suggestive of NM, are not diagnostic. The presence of malignant cells in the CSF is diagnostic of NM, but in general, as is true for most cytological analysis, assignment to a particular tumor is not possible [21]. In the author's opinion, a CSF examination is useful in all patients with suspected NM. Demonstrating positive CSF cytology or flow cytometry assists in managing patients with NM. Conversion from positive to negative cytology or cytometry is considered a response and suggests continuation of therapy.

In patients with positive CSF cytology (see below), up to 45% are cytologically negative on initial examination [6]. The yield is increased to 80% with a second CSF examination, but little benefit is obtained from repeat lumbar punctures after two punctures [7]. Of note, a series including lymphomatous and leukemic meningitis by Kaplan et al. [3] observed the frequent dissociation between the CSF cell count and malignant cytology (29% of cytologically positive CSF had concurrent CSF counts <4/mm3). Murray et al. [22] and Rogers et al. [22, 23] showed that CSF levels of protein, glucose, and malignant cells vary at different levels of the neuraxis even if there is no obstruction of the CSF flow. This finding reflects the multifocal nature of neoplastic meningitis and explains why CSF obtained from a site distant to that of the pathologically involved meninges may yield negative cytology.

Of the 90 patients reported by Wasserstrom et al. [7], 5% had positive CSF cytology only from either the ventricles or cisterna magna. In a series of 60 patients with NM, positive lumbar CSF cytology at diagnosis, and no evidence of CSF flow obstruction, ventricular and lumbar cytologies obtained simultaneously were discordant in 30% of cases [24]. The authors observed that, in the presence of spinal signs or symptoms, the lumbar CSF was more likely to be positive and, conversely, in the presence of cranial signs or symptoms, the ventricular CSF was more likely to be positive. Not obtaining CSF from a site of symptomatic or radiographically demonstrated disease was found to correlate with false-negative cytology results in a prospective evaluation of 39 patients, as did withdrawing small CSF volumes (<10.5 ml), delaying processing of specimens, and obtaining fewer than two samples [25]. Even after correcting for these factors, there remains a substantial group of patients with NM and persistently negative CSF cytology. Glass et al. [6] reported on a postmortem study of the value of premortem CSF cytology. They demonstrated that up to 40% of patients with clinically suspected NM proven at the time of autopsy were cytologically negative. This figure increased to >50% in patients with focal NM.

The low sensitivity of CSF cytology makes it difficult not only to diagnose NM, but also to assess the response to treatment. Biochemical markers, immunohistochemistry, and molecular biology techniques applied to CSF have been explored in an attempt to find a reliable biological marker of disease.

Numerous biochemical markers have been evaluated but, in general, their use has been limited by poor sensitivity and specificity. Particular tumor markers such as carcinoembryonic antigen (CEA) from adenocarcinomas and {alpha}-fetoprotein and β-human chorionic gonadotropin from testicular cancers and primary extragonadal CNS tumors can be relatively specific for NM when elevated in CSF in the absence of markedly elevated serum levels [16, 26]. Nonspecific tumor markers such as creatine-kinase BB isoenzyme, tissue polypeptide antigen, β2-microglobulin, β-glucoronidase, lactate dehydrogenase isoenzyme-5, and more recently vascular endothelial growth factor can be strong indirect indicators of NM, but none are sensitive enough to improve the cytological diagnosis [27–31]. The use of these biochemical markers can be helpful as adjunctive diagnostic tests and, when followed serially, to assess response to treatment. Occasionally, in patients with clinically suspected NM and negative CSF cytology, they may support the diagnosis of NM [32].

The use of monoclonal antibodies for immunohistochemical analysis in NM does not significantly increase the sensitivity over that seen with cytology alone [33–35]. However, in the case of leukemia and lymphoma, antibodies against surface markers can be used to distinguish between reactive and neoplastic lymphocytes in the CSF [36].

Cytogenetic studies have also been evaluated in an attempt to improve the diagnostic accuracy of NM. Flow cytometry and DNA single-cell cytometry, techniques that measure the chromosomal content of cells, and fluorescence in situ hybridization, which detects numerical and structural genetic aberrations as a sign of malignancy, can give additional diagnostic information and are especially useful in liquid tumors (leukemia and lymphoma) and appear more sensitive than CSF cytology [37–39]. Polymerase chain reaction can establish a correct diagnosis when cytology is inconclusive, but the genetic alteration of the neoplasia must be known for it to be amplified with this technique, and this is generally not the case, particularly in solid tumors [40].

In cases where there is no manifestation of systemic cancer and CSF examinations remain inconclusive, a meningeal biopsy may be diagnostic. The yield of this test is higher if the biopsy is taken from an enhancing region on magnetic resonance imaging (MRI) (see below) [41].

Neuroradiographic Studies
MRI with gadolinium enhancement (MR-Gd) is the technique of choice to evaluate patients with suspected NM [42–44]. Because NM involves the entire neuraxis, imaging of the entire CNS is required in patients considered for further treatment. T1-weighted sequences, with and without contrast, combined with fat suppression T2-weighted sequences constitute the standard examination [42–45]. MRI has been shown to have a higher sensitivity than cranial contrast-enhanced computed tomography in several series, and is similar to computerized tomographic myelography for the evaluation of the spine, but significantly better tolerated [42, 44–46].

Any irritation of the leptomeninges (i.e., subarachnoid blood) will result in their enhancement on MRI, which is seen as a fine signal-intense layer that follows the gyri and superficial sulci. Subependymal involvement of the ventricles often results in ventricular enhancement. Some changes, such as cranial nerve enhancement on cranial imaging and intradural extramedullary enhancing nodules on spinal MRI (most frequently seen in the cauda equina), can be considered diagnostic of NM in patients with cancer [47]. Lumbar puncture itself rarely can cause a meningeal reaction, leading to dural–arachnoidal enhancement, so imaging should be obtained preferably prior to the procedure [48]. MR-Gd still has a ≥30% incidence of false-negative results, so a normal study does not exclude the diagnosis of NM. On the other hand, in cases with a typical clinical presentation, abnormal MR-Gd alone is adequate to establish the diagnosis of NM [32, 42, 46, 47].

Radionuclide studies, using either 111indium-diethylenetriamine pentaacetic acid or 99Tc macroaggregated albumin, constitute the technique of choice to evaluate CSF flow dynamics [17, 49]. Abnormal CSF circulation has been demonstrated in 30%–70% of patients with NM, with blocks commonly occurring at the skull base, in the spinal canal, and over the cerebral convexities [46, 49, 50]. Patients with interruption of CSF flow demonstrated by radionuclide ventriculography were shown, in three clinical series, to have a shorter survival time than those with normal CSF flow [49, 51, 52]. Involved-field radiotherapy to the site of CSF flow obstruction restores flow in 30% of patients with spinal disease and 50% of patients with intracranial disease [53, 54]. Re-establishment of CSF flow with involved-field radiotherapy followed by intrathecal chemotherapy led to longer survival, lower rates of treatment-related morbidity, and a lower rate of death from progressive NM, compared with the group that had persistent CSF blocks [49, 51].


   STAGING
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
Prognosis
 Treatment
 Conclusions
 References
 
In summary, patients with suspected NM should undergo one or two lumbar punctures, cranial MR-Gd, spinal MR-Gd, and a radioisotope CSF flow study to rule out sites of CSF block. If the cytology remains negative and radiological studies are not definitive, consideration may be given to ventricular or lateral cervical spine CSF analysis based on the suspected site of predominant disease. If the clinical scenario or radiological studies are highly suggestive of NM, treatment is warranted despite persistently negative CSF cytology.


   PROGNOSIS
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
Treatment
 Conclusions
 References
 
The median survival time of untreated patients with NM is 4–6 weeks, and death generally occurs because of progressive neurological dysfunction [7]. Treatment is intended to improve or stabilize the neurological status, maintain the neurological quality of life, and prolong survival. Fixed neurological defects are rarely improved with treatment, but progression of neurological deterioration may be halted in some patients and the median survival time can be increased to 4–6 months [16]. Of the solid tumors, breast cancer responds best, with median survival times of 6 months and 11%–25% 1-year survival rates [26, 55]. Numerous prognostic factors for survival and response have been looked at (age, gender, duration of signs of NM, increased protein or low glucose in CSF, ratio of lumbar/ventricular CEA, etc.), but many remain controversial [55]. It is commonly accepted, however, that patients will do poorly with intensive treatment of NM if they have a poor performance status, multiple fixed neurologic deficits, bulky CNS disease, coexistent carcinomatous encephalopathy, and CSF flow abnormalities demonstrated by radionuclide ventriculography. In general, patients with widely metastatic aggressive cancers that do not respond well to systemic chemotherapies are also less likely to benefit from intensive therapy [56, 57]. What appears clear is that, optimally, NM should be diagnosed in the early stages of disease to prevent progression of disabling neurological deficits, analogous to the clinical situation of epidural spinal cord compression.


   TREATMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
Conclusions
 References
 
The evaluation of treatment of NM is complicated by the lack of standard treatments, the difficulty of determining response to treatment given the suboptimal sensitivity of the diagnostic procedures and the fact that most patients will die of systemic disease, and the fact that most studies are small, nonrandomized, and retrospective. However, it is clear that treatment of NM can provide effective palliation and in some cases result in longer survival. Treatment requires the combination of surgery, radiation, and chemotherapy in most cases. Figure 1 outlines a treatment algorithm for NM.


Figure 1
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  		Figure 1. Treatment algorithm of neoplastic meningitis.

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid.

 
Surgery
Surgery is used in the treatment of NM for the placement of (a) an intraventricular catheter and a subgaleal reservoir for administration of cytotoxic drugs and (b) a ventriculoperitoneal shunt (VPS) in patients with symptomatic hydrocephalus.

Drugs can be instilled into the subarachnoid space by lumbar puncture or via an intraventricular reservoir system. The latter is the preferred approach because it is simpler, more comfortable for the patient, and safer than repeated lumbar punctures. It also results in a more uniform distribution of the drug in the CSF space and produces the most consistent CSF levels. In up to 10% of lumbar punctures, the drug is delivered to the epidural space, even if there is CSF return after placement of the needle, and drug distribution has been shown to be better after drug delivery through a reservoir [58–60].

NM often causes communicating hydrocephalus, leading to symptoms of raised intracranial pressure. Relief of sites of CSF flow obstruction with involved-field radiation should be attempted to avoid the need for CSF shunting. If hydrocephalus persists, a VPS should be placed to relieve the pressure because relief of pressure often results in clinical improvement. Although a theoretical risk, placement of a VPS in a patient with symptomatic hydrocephalus and NM does not appear to result in peritoneal dissemination of cancer [61]. By way of comparison, in patients with medulloblastoma requiring a VPS, there has been no evidence of peritoneal seeding by the medulloblastoma. In patients requiring a VPS for NM-related hydrocephalus, survival is poor, and these patients are considered poor candidates for intra-CSF chemotherapy. If intra-CSF chemotherapy is considered for such patients, intralumbar administration is recommended.

Radiotherapy
Radiotherapy is used in the treatment of NM for (a) palliation of symptoms, such as a cauda equina syndrome; (b) decreasing bulky disease, such as coexistent parenchymal brain metastases; and (c) correction of CSF flow abnormalities demonstrated by radionuclide ventriculography. Patients may have significant symptoms without radiographic evidence of bulky disease and still benefit from radiation. For example, patients with low back pain and leg weakness should be considered for radiation to the cauda equina, and those with cranial neuropathies should be offered whole-brain or base-of-skull radiotherapy [26].

Radiotherapy of bulky disease is indicated because intra-CSF chemotherapy is limited by diffusion to 2–3 mm penetration into tumor nodules. In addition, involved-field radiation can correct CSF flow abnormalities, and this has been shown to improve patient outcome, as discussed above. Whole neuraxis radiation is rarely indicated in the treatment of NM from solid tumors because it is associated with significant systemic toxicity (severe myelosuppression and mucositis among other complications) and is not curative.

Chemotherapy
Chemotherapy is the only treatment modality that can treat the entire neuraxis, and may be administered systemically or intrathecally.

Intrathecal chemotherapy is the mainstay of treatment for NM patients. Retrospective analysis or comparison with historical series suggests that the administration of chemotherapy to the CSF improves the outcome of patients with NM [1, 20, 51, 62, 63]. However, it is noted that most series exclude patients that are too sick to receive any treatment, which may be up to one third of patients with NM [64]. Three agents are routinely used: methotrexate, cytarabine (including liposomal cytarabine or DepoCyt® [Enzon Pharmaceuticals, Fairfield, NJ]) and thiotepa. No difference in response has been seen when comparing single-agent methotrexate with thiotepa or when using multiple-agent (methotrexate, thiotepa, and cytarabine or methotrexate and cytarabine) versus single-agent methotrexate treatment [65–67]. Table 1 outlines the randomized clinical trials conducted for NM whereas Table 2 is an outline of the common treatment regimens for intra-CSF chemotherapy. A sustained-release form of cytarabine (DepoCyt®) results in cytotoxic cytarabine levels in the CSF for ≥10 days, and when given bimonthly and compared with biweekly methotrexate, resulted in a longer time to neurological progression in patients with NM (Table 1) [68, 69]. Furthermore, quality of life and cause of death favored DepoCyt® over methotrexate. These findings were confirmed in a study of lymphomatous meningitis and in an open-label study, suggesting that DepoCyt® should be considered the drug of first choice in the treatment of NM [69, 70]. A pharmacoeconomic assessment of intra-CSF liposomal ara-C (once every 2 weeks) compared with intra-CSF methotrexate (four times every 2 weeks) suggested that the costs of therapy were similar when accounting for professional, pharmacy, and facility fees.


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  		Table 1. Randomized clinical trials

 


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  		Table 2. Regional chemotherapy (intralumbar or intraventricular) for neoplastic meningitis

 
Complications of intrathecal chemotherapy include those related to the ventricular reservoir and those related to the chemotherapy administered. The most frequent complications of ventricular reservoir placement are malposition (rates reported, 3%–12%), obstruction, and infection (usually skin flora). CSF infection occurs in 2%–13% of patients receiving intrathecal chemotherapy. It commonly presents with headache, changes in neurologic status, fever, and malfunction of the reservoir. CSF pleocytosis is commonly encountered. The most frequently isolated organism is Staphylococcus epidermidis. Treatment requires i.v. with or without oral and intraventricular antibiotics. Some authors advocate the routine removal of the ventricular reservoir, whereas others reserve device removal for those cases that do not clear with antibiotic therapy.

Myelosuppression may occur after administration of intrathecal chemotherapies and some recommend that folinic acid rescue (10 mg every 6 hours for 24 hours) be given orally after the administration of methotrexate to mitigate this complication. Chemical aseptic meningitis occurs in nearly half of the patients treated with intrathecal administration and is manifested by fever, headache, nausea, vomiting, meningismus, and photophobia. In the majority of patients, this inflammatory reaction can be treated in the outpatient setting with oral antipyretics, antiemetics, and corticosteroids. Rarely, treatment-related neurotoxicity occurs and may result in symptomatic subacute leukoencephalopathy or myelopathy. However, in patients with NM and prolonged survival, the combination of radiotherapy and chemotherapy frequently results in late leukoencephalopathy, evident on neuroradiographic studies, which is occasionally symptomatic [1, 5, 71–73].

The rationale to give intrathecal chemotherapy is based on the presumption that most chemotherapeutic agents when given systemically have poor CSF penetration and do not reach therapeutic levels. Exceptions to this are systemic high-dose methotrexate, cytarabine, and thiotepa, all of which result in cytotoxic CSF levels. Their systemic administration, however, is limited by systemic toxicity and the difficulty of integrating these regimens into other chemotherapeutic programs being used to manage systemic disease. Some authors argue that intrathecal chemotherapy does not further improve outcome in the treatment of NM, because systemic therapy can obtain access to the subarachnoid deposits through their own vascular supply [64]. In a retrospective comparison of patients treated with systemic chemotherapy and radiation to involved areas, with or without intrathecal chemotherapy, Bokstein et al. [74] did not find significant differences in response rates, the median survival time, or the proportion of long-term survivors among the two groups, but of course, the group that did not receive the intrathecal treatment was spared the complications of this modality. Boogerd et al. [75], in a small, prospective, randomized phase II study of patients with breast cancer and NM, suggested no benefit to intra-CSF chemotherapy when compared with symptomatic therapy, including involved-field radiotherapy and systemic chemotherapy. That study, however, was flawed by poor balancing between known prognostic features affecting survival in patients with NM. Glantz et al. [76] treated 16 patients with high-dose i.v. methotrexate and compared their outcome with that of a reference group of 15 patients treated with intrathecal methotrexate. They found that response rates and survival were significantly better in the group treated with i.v. therapy. Therefore, in patients with methotrexate-sensitive cancers (lymphoma and breast cancer), high-dose methotrexate is a rational treatment for patients with combined brain parenchymal metastases and NM. Similarly, there are case reports suggesting that, in breast cancer patients with combined brain parenchymal metastases and NM, oral capecitabine may be effective as well [77–79]. Finally, a recent report describes two patients with breast cancer in whom NM was controlled with systemic hormonal treatment [80].

Nonetheless, intrathecal administration remains the preferred chemotherapy treatment route for NM at this time. New drugs are being explored to try to improve the efficacy of treatment. These include mafosphamide, diaziquone, topotecan, interferon (IFN)-{alpha}, and temozolomide. Immunotherapy, using interleukin-2 and IFN-{alpha}, 131I-radiolabeled monoclonal antibodies, gene therapy, and retuximab are other modalities that are being explored in clinical trials [81–86].

Supportive Care
Not all patients with NM are candidates for the aggressive treatment outlined above. Most authors agree that combined-modality therapy should be offered to patients with a life expectancy >3 months and a Karnofsky performance status score >60%.

Supportive care should be offered to every patient, regardless of whether they receive NM-directed therapy. These therapies include anticonvulsants for seizure (seen in 10%–15% of patients with NM) control, adequate analgesia with opioid drugs as needed, as well as antidepressants and anxiolytics if necessary. Corticosteroids have a limited use in NM-related neurological symptoms, but can be useful to treat vasogenic edema associated with intraparenchymal or epidural metastases, or for the symptomatic treatment of nausea and vomiting together with routine antiemetics. Decreased attention and somnolence secondary to whole-brain radiation can be treated with psychostimulants [5].


   Conclusions
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
References
 
NM is a complicated disease for a variety of reasons. First, most reports concerning NM treat all subtypes as equivalent with respect to CNS staging, treatment, and outcome. However, clinical trials in oncology are based on the specific tumor histology. Comparing responses in patients with carcinomatous meningitis resulting from breast cancer with patients with non-small cell lung cancer outside investigational new drug trials may be misleading. A general consensus is that breast cancer is inherently more chemosensitive than non-small cell lung cancer or melanoma, and therefore survival following chemotherapy is likely to be different. This observation has been substantiated in patients with systemic metastases, although comparable data regarding CNS metastases, and in particular NM, are meager.

A second feature of NM that complicates therapy is deciding whom to treat. Not all patients necessarily warrant aggressive CNS-directed therapy; however, few guidelines exist directing the appropriate choice of therapy. Based on the prognostic variables determined clinically and by evaluation of the extent of disease, a sizable minority of patients will not be candidates for aggressive NM-directed therapy. Therefore supportive comfort care (radiotherapy to symptomatic disease, antiemetics, and narcotics) is reasonably offered to patients with NM considered poor candidates for aggressive therapy, as seen in Figure 1.

Third, the optimal treatment of NM remains poorly defined. Given these constraints, the treatment of NM today is palliative and rarely curative, with a median patient survival duration of 2–3 months based on data from the four prospective, randomized trials in this disease. However, palliative therapy of NM often affords the patient protection from further neurological deterioration and consequently a better neurologic quality of life. No studies to date have attempted an economic assessment of the treatment of NM, and therefore no information is available regarding a cost–benefit analysis as has been performed for other cancer-directed therapies.

Finally, in patients with NM, the response to treatment is primarily a function of CSF cytology and secondarily of clinical improvement in neurologic signs and symptoms. Aside from CSF cytology and perhaps biochemical markers, no other CSF parameters predict response. Furthermore, because CSF cytology may manifest a rostracaudal disassociation, consecutive negative cytology (defined as a complete response to treatment) requires confirmation by both ventricular and lumbar CSF cytology. In general, only pain-related neurologic symptoms improve with treatment. Neurologic signs such as confusion, cranial nerve deficit(s), ataxia, and segmental weakness minimally improve or stabilize with successful treatment.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Epidemiology
 Pathogenesis
 Clinical Features
 Diagnosis
 Staging
 Prognosis
 Treatment
 Conclusions
 References
 

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