Volume 21, Issue 1, Pages 25-66 (February 2003)

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Leptomeningeal metastases

Article Outline

• Frequency

• Leptomeningeal metastasis in extraneural solid tumors

• Leptomeningeal metastasis in hematologic malignancies

• Leptomeningeal metastasis and primary brain tumors

• Primary leptomeningeal diseases

• Primary leptomeningeal lymphoma

• Nonlymphomatous leptomeningeal processes

• Pathophysiology

• Clinical presentation

• Diagnosis

• Imaging

• Cerebrospinal fluid studies

• Biopsy

• Adjunctive studies

• Staging

• Treatment

• Symptomatic treatment

• Chemotherapy

• Methotrexate

• Cytosine arabinoside

• Thio-TEPA

• Other drugs

• Intathecal combination therapy

• Experimental therapies

• Immunotherapy

• Targeted toxins

• Summary

• References

• Copyright

Metastases to the nervous system are an increasingly common complication of cancer, and can involve the brain parenchyma, dura, skull, epidural space, peripheral nerves, and leptomeninges (pia and arachnoid membranes). Leptomeningeal metastasis (LM) is defined as the appearance of tumor cells in the leptomeninges or cerebrospinal fluid (CSF) distant from the site of a primary tumor [1]. LM is also know as carcinomatous meningitis, neoplastic meningitis, neoplastic meningosis, leukemic meningitis (for leukemia), lymphomatous meningitis (for lymphoma), and meningeal carcinomatosis (for carcinoma) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. LM was first described in 1870 in a patient with lung cancer, and was thought to be a rare condition, usually diagnosed at autopsy [12]. By the 1970s, the condition was increasingly diagnosed due to increased suspicion and improved diagnostic tests [8], [13]. As treatments for systemic cancers improve and as patients live longer, there is a higher risk of central nervous system (CNS) metastases, including LM. LM has a devastating impact on the prognosis and quality of life for affected patients. Neurologic dysfunction may severely impair the ability of a patient to function independently. Advances in diagnostics, chemotherapy, radiotherapy, and surgery have made it possible to partially alleviate symptoms and to improve the quality of life. Further advances in modalities that may allow earlier diagnosis of LM and the development of more effective therapeutics may offer future patients with LM an improved quality of life and longer duration of survival.

Frequency

The incidence of LM is increasing, primarily due to two factors. Patients with cancer are surviving longer and, thus, there is a greater likelihood of LM during the course of their illness [14], [15], [16], [17]. Better ascertainment with improved noninvasive neuroimaging techniques and, perhaps, more aggressive diagnostic evaluation has led to higher frequency of successful diagnosis. Meningeal involvement may be the first manifestation of a systemic carcinoma in 5% to 11% of patients who develop LM and maybe the sole site of relapse in patients successfully treated for cancer [18], [19], [20]. In patients with known cancer the frequency of LM is estimated at 5% to 70%, and is highly dependent on the type of primary cancer, prior treatment regimen, and duration of illness (Table 1). Leptomeningeal involvement occurs in 5% to 8% of solid tumors [21], 5% to 29% of non-Hodgkin's lymphomas (NHL) [22], [23], [24], and 11% to 70% of leukemias [25], [26]. The incidence is especially high in patients with lymphoma, leukemia, and breast cancer. In an autopsy series of patients with cancer and neurologic involvement, 19% had leptomeningeal metastases [27]. Some primary brain tumors have a high incidence of leptomeningeal dissemination at the time of presentation, including malignant astrocytoma (14% [28]) and medulloblastoma (32% [29]) [30], [31], [32]. The diagnosis of LM should be strongly considered in any patient with a history of cancer and multifocal neurologic deficits.

Table 1.

Frequency of leptomeningeal metastasis by primary malignancies


		Frequencya
	Non-CNS solid malignancies
	Lung-SCLC>NSCLC	15%>1%
	Breast	5%
	Skin-melanoma	5%
	Gastrointestinal	1%
	Head and neck	1%
	Carcinoid	rare
	Genitourinary—renal cell	rare
	Gynecologic—ovary, fallopian tubes	rare
	Prostate	rare
	Sarcoma	rare
	Thyroid	rare
	Unknown primary	rare
	Hematologic malignancies
	Leukemia	5–15%
	Lymphoma	6%
	Plasma cell tumors	rare
	Primary CNS malignancies
	PCNSL	42%
	Neuroblastoma	40%
	Medulloblastoma	32%
	Glioma	14%
	Choroid plexus carcinoma	rare
	Epidermoid cyst	rare
	Esthesioneuroblastoma	rare
	Germinoma	rare
	JPA	rare
	Pineoblastoma	rare
	Pituitary adenoma	rare
	Teratoma	rare

Abbreviations: ALL, acute lymphocytic leukemia; CNS, central nervous system; JPA, juvenile pilocytic astrocytoma; NSCLC, nonsmall-cell lung cancer; PCNSL, primary CNS lymphoma; SCLC, small-cell lung cancer.

Adapted from Jeyapalan SA, Batchelor TT. Diagnostic evaluation of neurologic metastases. Cancer Invest 2000;18:381–94; with permission [28], [29], [61], [114], [246].

Leptomeningeal metastasis in extraneural solid tumors

The most common solid tumors that metastasize to the leptomeninges in terms of overall frequencies are breast adenocarcinoma (11% to 64%), lung adenocarcinoma (14% to 29%), and melanoma (6% to 18%) [6], [10], [27]. In patients with a specific cancer, melanoma has the highest frequency of LM (23%) [33] followed by small-cell lung cancer (9% to 25%) [34] and breast cancer (5%) [35], [36]. Metastases from the gastrointestinal system are usually from gastric adenocarcinoma [37], but cases from cancer of the gallbladder [38] and biliary ducts have also been reported [39].

Other tumors that less commonly metastasize to the leptomeninges are listed in Table 1. As therapy for these malignancies improve and as patients survive longer, the frequency of LM will likely increase.

Leptomeningeal metastasis in hematologic malignancies

Hematologic cancers frequently invade the CSF space, especially certain subtypes of NHL [40] and the leukemias [41], [42]. Lymphoma tends to infiltrate the leptomeninges with focal extension into the cerebral parenchyma, especially the optic chiasm, tuber cinereum, and the hypothalamus. Infiltration of the spinal and cranial nerve roots occurs in approximately one-third of cases. Histologically, large-cell lymphomas (diffuse and immunoblastic) more commonly involve the leptomeninges than the small-cell varieties. Cutaneous T-cell lymphomas may also involve the leptomeninges in advanced stages [43], [44].

Meningeal involvement is common with acute lymphoblastic leukemia (ALL) at presentation, and successful treatment for leukemia has led to an increased frequency of leptomeningeal relapse. Since initiation of CNS prophylaxis in children with leukemia, the incidence of leptomeningeal relapse has decreased significantly [45], [46], [47]. In contrast, in adults with ALL, CNS prophylaxis is not generally effective, but combination therapies may prove to be beneficial [48], [49]. Leptomeningeal involvement occurs in 20% to 50% of acute myelocytic leukemia [45], but is rare in chronic myelogenous leukemia [50], [51]. Disseminated plasma cell tumors frequently involve the vertebral bodies from where they can spread into the leptomeninges or grow as masses causing spinal cord compression [52].

Leptomeningeal metastasis and primary brain tumors

Some primary brain tumors have a propensity to involve the leptomeninges, especially neuroepithelial neoplasms (medulloblastoma [53], ependymoma, and choroid plexus carcinoma [54]). Leptomeningeal involvement by glioma and oligodendroglioma is more frequent than is generally realized [55], [56], [57], [58]. Even low-grade astrocytomas may disseminate to the leptomeninges [59]. Other primary brain tumors that may involve the leptomeninges include pituitary tumors [60], neuroblastoma [61], [62], juvenile pilocytic astrocytoma [63], [64], [65], neurocytoma/gangliocytoma [66], esthesioneuroblastoma [67], and intracranial epidermoid cyst [68] (Table 1).

Primary CNS lymphoma (PCNSL) is a rare type of NHL that is confined to the CNS. The incidence is 0.43/100,000 persons-years and is increasing, especially in immunocompromised and elderly individuals [69], [70], [71]. In PCNSL, up to 42% of patients develop LM [72].

Primary leptomeningeal diseases

Primary leptomeningeal lymphoma

Primary leptomeningeal lymphoma (lymphoma isolated to the leptomeninges without parenchymal or systemic involvement) occurs in up to 7% of all PCNSL cases [70], [73], [74], [75], [76], [77]. Primary leptomeningeal lymphoma is predominantly a T-cell lymphoma in contrast to PCNSL, which is predominantly a B-cell lymphoma [69], [75]. This unique form must be distinguished from the much more common secondary involvement of the leptomeninges by PCNSL or systemic NHL.

Nonlymphomatous leptomeningeal processes

There are a number of reports of primary nonlymphomatous tumors affecting the leptomeninges, and these include glioma [58], [78], [79], [80], [81], oligodendroglioma [55], [82], [83], ganglioglioma [84], neuroblastoma [85], meningioma [86], melanoma [87], [88], [89], [90], sarcoma [91], [92], meningioangiomatosis [93], [94], fibrosarcoma [95], and malignant histiocytosis [96] (see box 1). Uncommon, nonmalignant lesions of leptomeninges include fibroma [97], myelomatosis [98], posttraumatic cysts [99], [100], heterotopia (more common in children) [101], [102], fibrosis (due to multiple etiologies) [103], and melanocytosis [104].

Box 1

Primary leptomeningeal diseases

Neoplastic

PLML

Glioma

Oligodendroglioma

Meningioangiomatosis (benign)

Melanocytic lesions

Malignant histiocytosis

Neuroblastoma

Sarcomas

Nonneoplastic

Myelomatosis

Infectious—chronic meningitis, TB, viral, ADEM

Inflammatory—sarcoid, granulomatosis

Subarachnoid hemorrhage

Posttraumatic cysts

Heterotopia

Fibrosis

Abbreviations: ADEM, acute disseminated encephalomyelitis; PLML, primary leptomeningeal lymphoma; TB, tuberculosis.

Pathophysiology

The CNS may be a sanctuary for malignant cells, in part, due to the blood–brain barrier (BBB), which limits penetration of most forms of systemic chemotherapy. There are several possible mechanisms of spread of a primary tumor to the leptomeninges: (1) hematogenous, (2) direct extension, (3) transport through the valveless venous plexus, (4) extension along nerves, (5) perineural/perivasular lymphatics, (6) escape from choroid plexus or subependymal metastases, and (7) iatrogenic (see box 2). The histologic type of the primary tumor is the main determinant of the frequency and pattern of spread. In some cases the primary cancer may be small or latent, and thus undetectable by current methods. Hematogenous spread is the most common mechanism of LM because the CNS is highly vascularized and receives 20% of the cardiac output [7], [105]. The leptomeninges are highly vascularized, and the CSF contains high concentrations of oxygen and glucose to support tumor cells without the need for angiogenesis [9]. Direct extension from parenchymal or parameningeal tumor is related to proximity of the tumor to the leptomeninges or ependyma [106]. Venous spread usually occurs from vertebral and paravertebral metastases, especially from prostate cancer [107], but also by perivenous spread from bone marrow metastases [24]. Uncommon routes of spread are from peripheral nerve metastases [108] via the endoneural route, and perineural/perivascular lymphatics to the leptomeninges [16], [34], [109]. Subependymal, choroid plexus, or perivascular microscopic metastases also provide possible routes for CSF dissemination [7]. In two studies, 33% to 75% of patients with LM had synchronous brain metastases [10], [27]. There is potential for a spread to leptomeninges during intracranial surgery or by other invasive procedures when the ependymal or dural layers are breached [110], [111], [112].

Box 2

Potential mechanisms of leptomeningeal dissemination

Hematogenous

Via arachnoid vessels

Direct extension

From primary CNS tumors in epidural, subdural, orintraparenchymal locations

From vertebral/paravertebral metastases of non-CNS tumors

Venous

From Batson's plexus and perivenous spread of bonemarrow metastases

Nerve

Metastases to nerve that spread along the nerve or nervesheath to the SAS

Perineural/perivascular lymphatics

From tumor deposits on nerve or adjacent tissue

Subependymal/choroid plexus

Metastases that form deposits close to ventricular systemand then breach the ependymal layer

latrogenic

Spread into CSF during surgery for parenchymal metastases

Abbreviations: CNS, central nervous system; SAS, subarachnoid space.

The major mechanism of dissemination once the tumor cells reach the leptomeninges is via exfoliation into the CSF space. CSF is made in the choroid plexus of the ventricular system and flows caudally through the third ventricle, cerebral aqueduct, and fourth ventricle, and through the foramina of Luschka and Magendie to eventually cover the brain, spinal cord, and exiting nerves. The CSF is absorbed into the venous system through the arachnoid granulations. Cells that have penetrated into the CSF can form secondary deposits in the leptomeninges throughout the neuraxis. These deposits include: (1) plaque-like deposits in leptomeninges with invasion of Virchow-Robin spaces, (2) thin diffuse coating of the meninges, (3) nodular deposits on nerve roots, frequently without shedding into CSF (Fig. 1, Fig. 2). The first and third mechanisms are common in solid tumors, and the second occurs most frequently in lymphoma and leukemia.

LM can cause symptoms by direct compression of brain structures (by meningeal nodules causing focal symptoms), irritation of adjacent brain (seizures), blocking of CSF pathways (leading to hydrocephalus and raised intracranial pressure), ischemia, or stroke (by constriction of pial arteries) [113], cranial and peripheral nerve palsies (by direct nerve involvement), metabolic derangements (by decreasing available glucose for brain by rapidly growing tumor cells), and by causing meningeal fibrosis [103]. The most frequently involved regions are the basilar cisterns and the cauda equina where slow CSF flow and gravity promote deposition of cells [106]. On gross pathologic examination, the pia-arachnoid membranes appear gray, fibrotic, and thickened, and plaque-like or nodular deposits may be seen (Fig. 1). On microscopy a mononuclear infiltrate and fibroblastic reaction are often present in the meninges or parenchyma adjacent to tumor cells (Fig. 2). A minority of cases does show diffuse involvement of the leptomeninges. More often LM is multifocal, emphasizing the importance of adequate CSF sampling and complete craniospinal imaging to obtain a definitive diagnosis.

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Fig. 1. Gross pathology of LM. (A) Gross autopsy photograph showing a macroscopic subarachnoid deposit (arrow) and diffuse haziness of the leptomeninges surrounding the cortical surface of the cerebrum from leptomeningeal metastases due to breast cancer. (B) Gross autopsy picture showing a macroscopic nodular subarachnoid tumor deposit (arrow) from a metastatic melanoma. (Courtesy of Dr. Umberto De Girolami, Department of Neuropathology, Brigham and Women's Hospital, Boston, MA.)

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Fig. 2. Histopathology of LM. (A) Section of midbrain showing intraventricular carcinoma (arrow) with partial obstruction of the CSF pathway (H&E, ×7). (B) Cytology showing carcinomatous cells in the CSF (H&E). There are numerous pleomorphic and hyperchromatic abnormal cells floating in the CSF and adjacent leptomeninges. (C) Photomicrograph showing infiltration of the leptomeninges by metastatic melanoma and minimal reaction in adjacent brain (b) (H&E, ×100). (D) Photomicrograph showing perivascular (arrow) and leptomeningeal infiltration by tumor cells from a patient with PCNSL (H&E, ×100). (Courtesy of Dr. Umberto De Girolami, Department of Neuropathology, Brigham and Women's Hospital, Boston, MA.)

Clinical presentation

The clinical hallmark of LM is the presence of multifocal neurologic symptoms and signs. LM can be the first presentation of an occult cancer, and should be suspected in patients with a history of cancer and multifocal neurologic symptoms. Patients with LM can have varied clinical manifestations (Table 2). LM may present clinically as low-grade meningitis, suggestive of an infectious process. A detailed history and physical examination in addition to a high degree of suspicion is needed to initiate the proper workup to make an early diagnosis. Often, LM causes progressive neurologic dysfunction in an unremitting manner.

Table 2.

Signs and symptoms of leptomeningeal metastases


		Incidencea
	Focal
	CN [common (III, IV, or VI), VII, VIII]	9–22%
	Radiculopathy/back pain	1–14%
	Myelopathy	2–6%
	Cauda equina syndrome	2–3%
	Mononeuritis	rare
	Mental neuropathy	rare
	Bilateral internuclear ophthalmoplegia	rare
	Urinary and fecal retention	rare
	Stroke	rare
	Nonfocal
	Headache	10–31%
	Sensory	30%
	Nausea/vomiting	15%
	Weakness	3–36%
	Visual—diplopia, blurred vision, papilledema	2–32%
	Ataxia	3–15%
	Meningismus	2–13%
	Encephalopathy	2–10%
	Seizure	1–5%
	Fever	rare
	Others (DI, stroke, myoclonus, apnea, diencephalic syndrome)	rare

Abbreviations: CN, cranial neuropathy; DI, diabetes insipidis.

Adapted from Jeyapalan SA, Batchelor TT. Diagnostic evaluation of neurologic metastases. Cancer Invest 2000;18:381–94; with permission.

Most patients present with nonspecific, nonlocalizing symptoms that may be related to elevated intracranial pressure. The most common symptom is pain (80%) and patients may report a diffuse headache (25%) [114] or pain in a spinal, radicular, or meningeal pattern (>50%) [115]. Nonlocalizing symptoms can include a variety of systemic symptoms and global neurologic dysfunction [116]. Localizing symptoms include cranial neuropathies [114], [117], [118], mononeuritis [119], radiculopathy [120], urinary incontinence [121], and visual disturbance [122].

Uncommonly, patients may present with ischemic symptoms or strokes, which may be due to tumor emboli [123], a hypercoaguable state, or narrowing/blocking of cerebral arteries by perivascular tumor deposits [124]. When there are parenchymal signs such as aphasia or hemiparesis, the possibility of cerebral metastases should be considered. In patients with coma, nonconvulsive status epilepticus should be excluded [125]. Rarely, LM may produce central hypoventilation [126], diencephalic syndrome [127], or diabetes insipidus [10]. Some patients may have minimal symptoms and no findings on physical exam, and yet magnetic resonance imaging (MRI) can identify LM [128], so a high index of suspicion is critical for early diagnosis.

Diagnosis

The diagnosis of LM rests on finding malignant cells on CSF examination or on characteristic gadolinium-enhanced MRI findings in the appropriate clinical context. The diagnosis should ideally be based on a combination of CSF studies and neuroimaging. Despite the high sensitivity of MRI, these studies are nonspecific and only suggestive. In cases where there is no identifiable primary cancer, CSF should be collected for cytopathology to categorize the type of cancer, as this may influence the treatment regimen. Even in the absence of CSF or MRI findings, if there is clinical evidence of a progressive neurologic disease consistent with LM, close clinical follow-up, serial neuroimaging, and repeat CSF studies are warranted [5], [129], [130]. Up to 40% of patients with LM at autopsy had a negative CSF cytopathologic analysis as part of the premortem evaluation [27].

The National Comprehensive Cancer Network (NCCN) [5], [130] recommended work-up for LM is shown in Fig. 3. The work-up should include MRI with and without gadolinium of the brain and spine, followed by evaluation of CSF for cell count, chemistry, and cytopathology if a lumbar puncture can be safely performed. A CSF flow scan is recommended to further define the extent of the disease and to determine whether other therapies should be considered.

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Fig. 3. NCCN practice guidelines for carcinomatous/lymphomatous meningitis. (A) Shows the initial work-up and treatment pathways for LM, and (B) shows how CSF flow studies may be used to help guide treatment and assess response. aInitiation of chemotherapy should not be delayed for flow study. [Adapted from the National Comprehensive Cancer Network (NCCN) guidelines (version 1.2001, 2/14/2002) with permission of NCCN. These guidelines are a work in progress that will be refined as often as new significant data becomes available. The NCCN guidelines are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way] [130].

Imaging

Radiologic imaging has facilitated the ability to diagnose LM, especially with MRI and CSF flow studies. MRI may demonstrate enhancement of the leptomeninges, ventricular surface, cranial nerves, or spinal roots (Fig. 4, Fig. 5, Fig. 6). The enhancement may be linear or nodular, and in the appropriate setting is diagnostic of LM. Clinicians should be aware of enhancement artifacts due to intracranial hypotension (recent lumbar puncture), infection, recent craniotomy, recent head trauma, and seizures [131]. In general, MRI is more sensitive than CT and as sensitive as CSF cytology but not as specific [132], [133]. In a retrospective study of 41 cases of LM, gadolinium-enhanced MRI was positive in all cases when it was performed (25/25), and pial enhancement and nodularity was the most common finding (67%). In this study, CT was normal or misleading in two-thirds of patients [134].

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Fig. 4. MRI features of intracranial leptomeningeal metastases. T1-weighted, contrast-enhanced axial (A) and coronal (B) MR images showing enhancing, nodular lesions along the midbrain (A, arrows) and brainstem and cervical spinal cord (B, arrow) in a patient with leptomeningeal metastases from esophageal cancer. (Reproduced and adapted with permission from Jeyapalan and Batchelor [133], by courtesy of Marcel Dekker, Inc., New York, 2000.)

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Fig. 5. MRI features of spinal leptomeningeal metastases. T1-weighted, contrast-enhanced spine MR images showing enhancing nodular lesions (arrows) along the spine in a patient with leptomeningeal metastases from a systemic cancer.

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Fig. 6. MRI of synchronous parenchymal and leptomeningeal metastases. T1-weighted, contrast-enhanced axial (A–C) and coronal (D) MR images showing enhancing, nodular lesions in the periventricular parenchyma (B, small arrow) and leptomeninges (A–D, big arrows) in a patient with brain and leptomeningeal metastases from breast cancer. (Courtesy of Dr. Liangge Hsu, Department of Neuroradiology, Brigham and Women's Hospital, Boston, MA.)

The recognition of various patterns of meningeal enhancement may help in differentiating between infectious and carcinomatous meningitis. Infectious meningitis usually presents with leptomeningeal enhancement, while carcinomatous meningitis presents with pachymeningeal enhancement [135]. Another study of 61 patients with known cancer compared MRI with CSF cytology and concluded that CSF cytology was 75% sensitive and 100% specific compared with gadolinium-enhanced MRI, which was 76% sensitive and 77% specific [136]. Novel MRI sequences that better image the subarachnoid space may provide insight into the pathogenesis of LM, and may increase the sensitivity of LM detection in the future [137].

Other studies may prove useful when MRI or cytology is nondiagnostic. MRI may demonstrate communicating hydrocephalus due to obstruction of CSF resorption [138]. CSF flow studies using Indium-111-DTPA are more sensitive in demonstrating interruption of CSF flow when compared to conventional neuroimaging [139], [140], [141], [142], [143], [144]. Subarachnoid CSF block occurs in up to 70% of patients with LM from solid tumors, and is a poor prognostic sign. It is critical to diagnose this early because it impacts on the immediate management of the patient (Fig. 3).

Cerebrospinal fluid studies

All patients in whom LM is considered should have MRI of the brain and spine to exclude large parenchymal masses and obstructive hydrocephalus before undergoing lumbar puncture, due to potential for brain herniation. CSF findings include increased protein (most cases), reduced glucose (25% to 30%), lymphocytic pleocytosis (50%), and elevated opening pressure (50%) [114], [129].

•Routine studies—opening pressure, cell count, protein, glucose

•Cytology

•Flow cytometry—cell surface markers, deoxyribonucleic acid, ribonucleic acid

•Immunocytochemistry

•Tumor markers

•Polymerase chain reaction

CSF eosinophilia without another cause is highly suggestive of leptomeningeal metastases [9], [145]. However, not all of these findings are present in any one case, and multiple lumbar punctures may be needed to make a definitive diagnosis. There are numerous ancillary CSF studies that may be of assistance in the diagnosis of specific cancers when the primary is known, but most of these tests are still considered experimental (Table 3). For an initial evaluation without a known primary cancer, standard infectious studies should be obtained to rule out other etiologies of leptomeningeal enhancement and CSF pleocytosis, especially if the cytology is not diagnostic.

Table 3.

Cerebrospinal fluid tumor markers in leptomeningeal metastasis


	Marker	Tumor
	Alkaline phosphatase	Lung cancer [247]
	AFP	Teratocarcinoma, yolk sac tumor, ECC, endodermal sinus tumor [248]
	Beta 2-microglobulin	Lymphoma, infection, other tumors [249]
	Beta-glucuronidase	Nonspecific [157]
	CEA	Colon, ovarian, breast, bladder, lung [250], [251]
	CA-125	Ovarian cancer [252]
	CA-15-3	Breast cancer [253]
	CA 19-9	Adenocarcinoma, biliary disease [254]
	Creatine kinase BB	Small cell lung cancer [249]
	Enolase isoenzymes	Leukemia [255]
	Ferritin	Nonspecific [256]
	GFAP	Glioma [257]
	Glucosephosphate isomerase	Lung cancer [258]
	HCG subunit (HCG)	Choriocarcinoma, ECC, germ cell tumor
	5-HIAA	Carcinoid [259]
	HMFG1 mAb	Nonspecific [260]
	HPAP (pALP)	Germinoma [247]
	IgM	Myeloma [261]
	LDH isoenzymes	Carcinoma, non-specific [161]
	MBP	Nonspecific [262]
	Matrix metalloproteinase	Nonspecific [263]
	Melanin	Melanoma [264]
	Neuropeptides	Pituitary adenoma [60]
	PSA	Prostate cancer [265]
	Tissue polypeptide antigen	Breast cancer [266]
	VEGF	Nonspecific [267]

Abbreviations: AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; ECC, embryonal cell carcinoma; GFAP, glial fibrillary acid protein; HCG, human chorionic gonadotropin; HIAA, hydroxyindoleacetic acid; HMFG, high molecular weight, epithelial-associated glycoprotein antigen; HPAP, human placental alkaline phosphatase; IgM, immunoglobulin M; LDH, lactate dehydrogenase; mAb, monoclonal antibody; MBP, myelin basic protein; PSA, prostate-specific antigen; VEGF, vascular endothelial growth factor.

Many CSF specimens contain so few malignant cells that definitive pathologic diagnosis is difficult, especially with metastases from solid tumors, which release fewer cells into CSF than lymphomas and leukemias [24], [146]. Also, distinguishing leukemia or lymphoma from inflammatory disorders can be difficult, but finding a monoclonal cell population with flow cytometry is diagnostic. False-negative findings are common, but false-positives are rare [27]. Generally, high volume (5 to 10 mL) and serial lumbar punctures are needed to make a diagnosis, and if disease is localized to certain regions of the leptomeninges, then a CSF sampling close to the site of pathology (ie, lumbar, cisternal, or lateral cervical samples) may increase the yield [2], [27], [147]. Cytology specimens should be processed immediately to preserve cell morphology. Cytology after three lumbar punctures is positive in 74% to 91% of LM cases, but solid tumors may be associated with fewer positive results [13], [14], [17], [130], [148], [149]. Cytology may be supplemented by flow cytometry, immunohistochemical studies, protein studies, and polymerase chain reaction (PCR) [150] (see below and Table 3). Flow cytometry may be especially useful for patients with lymphoma and leukemia, as it may allow detection of monoclonal cell populations, and aneuploid and hyperdiploid cells [151].

If cytology is nondiagnostic, then CSF markers may facilitate detection of LM [152], [153], [154] (Table 3). However, these markers are limited by poor sensitivity and specificity when used independently. These markers can be detected by enzyme assays [lactate dehydrogenase (LDH), beta-glucuronidase] and immunoassays [alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, beta 2-microglobulin] [155]. Many other markers that may be detectable in CSF from patients with LM from a variety of primary tumors are shown in Table 3. The sensitivity of CSF CEA determination in the diagnosis of leptomeningeal cancer was only 31%, with a specificity of 90% [156]. CSF beta-glucuronidase levels are often elevated in LM, but are not specific, and can also be seen in acute and chronic infectious meningitis [157], [158], [159]. Elevated CSF LDH levels occur in patients with stroke, meningitis, head injury, and primary CNS tumors, but this marker in CSF has been useful in detecting LM and for following the course of disease in some cases [160], [161]. Simultaneous serum tumor marker levels should be done to exclude high serum concentrations as the cause for a positive CSF sample. Immunocytochemistry can also be useful in distinguishing chronic aseptic meningitis versus leptomeningeal carcinomatosis in the appropriate clinical context when abnormal cells are seen on routine CSF examination [162], [163], [164]. PCR-based methods are more sensitive than conventional cytology if there is a clearly identified marker, such as detecting clonal immunoglobulin heavy chain (IgH) gene rearrangements in patients with lymphoma [165], [166], [167]. Several reports of specific gene products have been successful, such as PCR for tumor-derived K-ras DNA [168] and reverse transcriptase PCR (RTPCR) for CEA mRNA to detect lung adenocarcinoma [169]. Telomerase expression in CSF was 64% sensitive and 90% specific in detecting LM [170], [171]. The sensitivities and specificities of these markers and other novel markers will have to be confirmed in prospective studies prior to broad clinical usage.

Biopsy

When cytology is nondiagnostic and disease is identified on imaging without an identified primary cancer, then a leptomeningeal and/or brain biopsy is indicated for accurate diagnosis of a neoplastic or a nonneoplastic process.

Adjunctive studies

Electromyography/nerve conduction studies may be useful in distinguishing a radiculopathy from a peripheral neuropathy, and may point to a more extensive and diffuse process [120]. If the CSF is negative, and there are findings on electromyography/nerve conduction studies, then a nerve biopsy could be performed to exclude direct nerve infiltration. Myelography may be necessary in patients with contraindications for MRI, and typical findings include thickening and nodularity of the nerve roots, extradural mass effect, or CSF flow block. Other serum and imaging studies may be done to rule out diseases that mimic LM (shown in box 3).

Box 3

Differential diagnosis of leptomeningeal metastasis

Bacterial/viral meningitis [268], [269]

Castleman's disease [270]

Enhancing meningeal blood vessels [271]

Granulomatous angiitis [272]

Histiocytosis [273]

Lyme disease [274]

Multiple sclerosis [275]

Neurocystercosis [276]

Opportunistic infections (TB [277] and cryptococcus [278])

Paraneoplastic encephalomyelitis [21], [279], [280]

Post LP changes [281]

Relapsing polychondritis [282]

Rheumatoid nodules [283], [284]

Sarcoidosis [285], [286], [287], [288], [289]

Vasculitis [9], [124], [290]

Wegener's granulomatosis [291], [292]

Abbreviations: LP, lumbar puncture; TB, tuberculosis.

Staging

In patients with LM, workup for a primary tumor (in patients without a prior history of cancer) and for extraneural recurrence (in patients with a history of cancer) should be done to assess extent of systemic disease. Staging may include MRI of brain and spine, chest and abdominal imaging, and serum tumor markers (if indicated). When lymphoma is being considered, a bone scan, gallium scan, bone marrow biopsy, and ophthalmologic exam are also indicated. In most cases, the patient has a known systemic cancer. In rare cases where no primary tumor is identified the neoplasm may represent a primary leptomeningeal malignancy (see box 1) [172].

Treatment

Treatment of LM is currently palliative for most patients, with an expected median survival of less than 6 months. An important treatment goal is stabilization and protection from further neurologic deterioration in patients with LM. Treatment of LM due to solid tumors is less successful than that due to leukemia and lymphoma. The main modality of treatment for LM has been intrathecal (IT) chemotherapy, with focal external beam radiotherapy to sites of symptomatic and bulky disease or to the entire neuraxis. This is usually combined with optimal treatment of any systemic disease. The specific treatment depends on the tumor type, extent of disease, and clinical condition of the patient. Because of the high incidence of LM in certain hematologic malignancies these are sometimes treated prophylactically for prevention of LM. In children with ALL, IT methotrexate (MTX) prophylaxis without cranial irradiation was effective with only a 4% CNS relapse rate [173]. Prophylactic brain radiotherapy (RT) reduces the incidence of brain metastases in patients with small-cell lung cancer, but does not prevent leptomeningeal relapse [174].

Despite few randomized studies for patients with LM there does seem to be a notable benefit of therapies in patients who have received and responded to treatment. The prognosis for patients with LM is better in leukemias and lymphomas, because of the relative sensitivity of these malignancies to chemotherapy. The prognosis is generally poor in patients with solid tumors, with median survival ranging from 1–4 months after diagnosis [10]. In most treatment studies median survival is approximately 6 months [24], [175], [176], [177], [178], [179], [180]. Treated patients that are refractory have a median survival of 2 months. A subset of patients, especially those with leukemia, lymphoma, and breast cancer, may achieve survival greater than a year with a reasonably good quality of life. In a multivariate analysis of 58 breast cancer patients with LM, poor prognostic markers included age greater than 55, presence of lung metastases, cranial nerve involvement, reduced CSF glucose level, and elevated CSF protein level [175].

In the absence of factors contraindicating treatment, all patients with LM are candidates for treatment with chemotherapy or radiation. The respective weight of systemic chemotherapy, intrathecal chemotherapy, and radiation therapy remains unclear. This may depend upon the stage and the nature of the primary tumor. Overall, meaningful palliation is achieved in 50% to 90% patients who receive treatment, including reduction of pain and improvement in neurologic deficits [10], [24], [175], [178].

The NCCN guidelines [5], [130] recommend a CSF flow scan to exclude obstruction of CSF flow pathways prior to treatment (Fig. 3). If CSF blockage is present, then the patient should receive RT to sites of obstruction. If repeat flow scans after RT demonstrate restored CSF flow then IT chemotherapy can be administered. If significant flow abnormalities remain, then the patient should be treated as a poor-risk patient. Again, the usual goal of treatment is palliative, that is, alleviation of neurologic symptoms or prevention of neurologic symptoms. Prevention of neurologic deterioration is a worthy goal considering the symptoms and signs of LM are usually debilitating and have a negative impact on the quality of life for patients. Patients generally die from systemic rather than neurologic complications of their neoplasm. Once the diagnosis has been established, the patient's overall status should be carefully assessed to determine how aggressively the patient should be treated (Fig. 3). The NCCN guidelines recommend stratifying patients into “poor risk” and “good risk” based on Karnofsky performance status, degree of neurologic deficits, extent of systemic disease, and available treatment options. Because some patients fall between these two groupings, clinical judgment and the patient's wishes should dictate management.

Serial cytologic examination of CSF is the most definitive method for evaluation of response to treatment in patients with LM. As a general guideline, serial CSF samples should be obtained according to the NCCN recommendations (Fig. 3) [5], [130]. Clinical status is a critical parameter to follow, and strongly influences treatment decisions. The patient's clinical and CSF status should be assessed every 1 to 3 months. For patients with progressive disease or persistently positive CSF, the patient can be retreated for another 4 weeks with the same chemotherapy and reassessed, another IT agent can be tried, or supportive care measures can be instituted.

Symptomatic treatment

Symptomatic treatment includes corticosteriods, CSF shunting, anticonvulsants, or radiotherapy. Some tumors (breast cancer, leukemia, lymphoma) are responsive to steroids, which can reduce edema and inflammation quickly and lead to significant clinical improvement. The usual dose of steroids is 16 mg of dexamethasone per day, except in patients who are deteriorating rapidly, in which case higher doses may be needed. After more definitive treatment is administered, steroids may be gradually tapered. Ventriculo-peritoneal shunting is needed for patients with symptomatic hydrocephalus. An Ommaya reservoir can also be placed at the time of shunting for subsequent use in patients who will receive IT chemotherapy. Anticonvulsants should be administered to any patients with LM who have experienced a seizure. Radiotherapy may also be used for nonsurgical symptomatic relief. Focal RT is effective in treating bulky disease identified on imaging and also for symptom relief in patients with cranial nerve palsies and associated pain. The dose of radiation is usually 2400 to 3000 cGy administered over 2 weeks [181]. Patients in the poor-risk group (Fig. 3) are usually offered supportive care measures, including analgesics for pain control.

The symptomatic treatments mentioned above are not without risk. Steroids carry a host of complications that are well known [182]. Ventriculo-peritoneal shunting and Ommaya placement carry the risk of shunt malfunction, infection, and disruption of CSF flow [183]. Complications of radiation include radiation necrosis, myelosuppression, and leukoencephalopathy [184], [185], [186], [187], [188].

Chemotherapy

Patients in the good-risk group (Fig. 3) may be candidates for more aggressive measures such as chemotherapy. Chemotherapy can be administered via intravenous or IT routes. IT chemotherapy may be given by lumbar puncture or by injection into an Ommaya reservoir and ventricular catheter. The latter requires a surgical procedure, and carries a small risk of infection. However, the Ommaya reservoir offers advantages in ease of delivery, more uniform distribution of drug, and more reliable delivery of drug to CSF [13]. In either case, it is important to confirm the patency of the CSF pathways before treatment (Fig. 3) [140]. CSF blocks or abnormal resorption of CSF may predict inhomogeneous distribution of chemotherapy, and has been shown by radioisotope studies to correlate with poorer outcome [140], [141], [142], [144]. CSF blockage may limit the distribution of the drug to all sites of disease, and can cause local neurotoxicity due to high concentrations [189], [190].

Although some have questioned the utility of IT therapy in nonlymphomatous LM [191], other studies suggest that it can be an effective modality. Initial studies of patients with LM from solid tumors have shown that IT chemotherapy confers a small survival advantage compared to radiation alone [175], [176], [179], [192]. Several agents have been shown to be effective in LM and depend on whether the primary tumor is chemosensitive or chemoresistant (see box 4). In patients with breast cancer and lymphoma, which are generally chemosensitive, IT chemotherapy may result in clearance of malignant cells from CSF [193]. However, in patients with melanoma and nonsmall-cell lung cancer, relatively chemoresistant tumors, results are not as good [191], [194]. Bulky leptomeningeal involvement (visible on MRI) may be resistant to IT chemotherapy because the drug only penetrates a few millimeters into adjacent tissue [195]. Due to the fact that LM usually occurs in patients at the time of progression or relapse, another concern is that the tumor may be relatively resistant to treatment at this point in the disease.

Box 4

Treatment options for leptomeningeal metastasis

Symptomatic

Steroids: for edema

Shunt: for hydrocephalus

Radiotherapy: to sites of symptomatic and bulky disease

AEDs: for seizures

Analgesics: for pain management

IT Chemotherapy

Methotrexate

10–12 mg 2×/week

Cytosine arabinoside

50 mg 2×/week

Liposomal cytosine arabinoside

2×/month

Thiotepa

10 mg 2×/wk

Optimal treatment of systemic disease

Experimental

New IT agents:

Studies in progress (see text)

Immunotherapy:

Based on known molecular characterization of neoplasm with and without toxins

Gene Therapy:

Using virus-engineered or genetically modified cells

Abbreviations: AED, antiepileptic drugs; ICP, intracranial pressure; IT, intrathecal.

Patients with lymphoreticular neoplasms often experience complete responses only to relapse if systemic disease is poorly controlled. Solid tumors often achieve clinical stabilization for a short time. Success of therapy is also dependent upon pretreatment CNS extent of disease [196].

According to the NCCN guidelines, IT chemotherapy should be administered in phases: induction, consolidation, and maintenance (Fig. 3B). After induction therapy, the patient should be reassessed clinically and with repeat CSF cytology. If the patient is clinically stable or improving, and cytology is negative then the patient should receive consolidation with the same chemotherapy followed by maintenance therapy. If the patient is deteriorating, then a different chemotherapy agent or symptomatic treatment should be started. In a randomized study of a liposomal form of Ara-C (DepoCyt) [197], the protocol stipulated two cycles of induction followed by four cycles of consolidation over 3 months. In the rare case of a patient with sustained remission, it is unclear how long IT chemotherapy should be given.

Methotrexate

Methotrexate is the agent most commonly used for intrathecal administration. It has a broad range of activity including activity against leukemias, lymphomas, and breast cancer, and to a lesser extent, other solid tumors [198]. MTX is an antimetabolite that interferes with DNA synthesis by inhibiting dihydrofolate reductase. MTX, administered as an intravenous infusion, poorly penetrates the intact BBB, but in patients with LM there is compromise of the BBB and cytotoxic levels of the drug can be achieved in the CSF [199]. Complete responses of central nervous system lymphoma have been repeated with intravenous MTX alone (Fig. 7). The regimen is administered as a 10 mg to 12 mg IT dose twice weekly. This regimen results in therapeutic concentrations (>10−6 molar) in CSF for 48 hours [200] with very little systemic reabsorption, thus reducing side effects. Leucovorin rescue (10 mg every 12 hours for six doses) is commonly used after each IT injection to prevent myelosuppression and mucositis [201].

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Fig. 7. MRI showing positive response to Treatment of PCNSL. T1-weighted, contrast-enhanced axial MR images showing PCNSL on initial presentation as enhancing lesions located in periventricular and intraventricular regions (A, B, arrows). (C) and (D) show resolution of lesions after treatment with high-dose intravenous methotrexate.

In solid tumors, IT MTX may be beneficial as monotherapy or as part of a combination regimen [71], [197], [202], [203]. In a study of 90 patients with LM, half of the patients treated with IT MTX experienced improvement or stabilization of neurologic symptoms for more than a month, and median survival was 5.8 months after diagnosis with minimal toxicity [10]. In a study of 98 patients with LM treated with RT and IT MTX, median survival was 8 months (range 1 to over 87) in patients with lymphoma and 3 months (range 1 to 40) in breast carcinoma patients [178]. In another study of 24 patients with LM treated with either RT alone (8 patients) or with combined therapy consisting of RT plus IT MTX (16 patients), only one patient with lung carcinoma was stabilized clinically in the RT-alone group while 7 of 16 patients (six were patients with breast cancer) in the combined therapy group improved clinically [202].

Complications of IT MTX include aseptic meningitis, leukoencephalopathy, mucositis, myelosuppression, encephalopathy, and opportunistic infections. Aseptic meningitis may be reduced by concomitant IT hydrocortisone [204]. High levels of MTX can cause seizures, and transverse myelopathy is rare [205]. The major delayed complication is leukoencephalopathy [206], which usually occurs in patients treated for >6 months and in those patients who have received a cumulative IT MTX dose of 140 mg [207], [208].

Cytosine arabinoside

Cytarabine (ara-C) is a synthetic pyrimidine nucleoside that is used commonly for leukemic and lymphomatous meningitis. It has limited activity against most solid tumors. Although ara-C has a short half-life (less than 4 hours) in serum, it is longer (less than 24 hours) in CSF due to low levels of cytidine deaminase, which inactivates ara-C [13]. Ara-C is given at a dose of 50 mg to 90 mg IT two to three times a week. IT ara-C has relatively little systemic toxicity due to rapid deamination of drug reaching the serum. High-dose systemic ara-C (3 g/m2 every 12 hours) penetrates well into the CNS, and is sometimes used in patients with leukemia or lymphoma who have both systemic and CNS disease [209].

Liposomal cytarabine (DepoCyt) [210] is a slow-release formulation of ara-C for IT use. This formulation maintains cytotoxic concentrations (>0.1 μg/mL) for up to 2 weeks, thus, it only needs to be administered every 2 weeks [211]. In a randomized trial of 28 patients with lymphomatous meningitis treated with either DepoCyt (every 2 weeks) or ara-C (twice a week) for 1 month, there was a higher response rate in the DepoCyt-treated versus the ara-C treated patients (71% versus 15%). The patients treated with DepoCyt also had delayed time to neurologic progression and improvement in Karnofsky performance status compared to those treated with ara-C [212].

Another randomized trial of 61 patients compared IT DepoCyt to IT MTX in patients with LM from solid tumors. There was a trend favoring DepoCyt with respect to cytologic response (26% versus 20%, P=0.76) and median survival (105 days versus 78 days, P=0.15), and a statistically significant delay in time to neurologic progression (58 days versus 30 days, P=0.007). An important advantage of DepoCyt is the fact that the treatment schedule entails 75% fewer outpatient clinic visits. The main side effect of DepoCyt was arachnoiditis. Concomitant administration of oral dexamethasone (4 mg BID×5 days) significantly reduced the incidence of arachnoiditis [197], [212].

Complications associated with IT ara-C include transverse myelopathy, aseptic meningitis, encephalopathy, headaches, and seizures [213], [214].

Thio-TEPA

Thio-TEPA (N, N′, N″-triethylenethiophosphoramide) is an alkylating agent with activity against leukemia and breast cancer. It is a second-line IT agent for patients who either do not respond or cannot tolerate IT MTX or IT ara-C. The IT dose is 10 mg twice weekly, but it has limited use due to a half-life of less than 1 hour in the CSF [215]. In a series of 14 patients with LM from malignant glioma who received treatment with IT thio-TEPA, the median survival was 10 months without significant neurotoxicity or myelopathy [216]. A randomized prospective trial of IT MTX versus IT thio-TEPA found that the efficacy and overall toxicities of intraventricular methotrexate and thiotepa were similar, and that neither reversed fixed neurologic deficits [176]. Complications of IT thio-TEPA include neurotoxicity and myelosuppression [217].

Other drugs

Intrathecal administration of 5-fluoro-2′-deoxyuridine was associated with a decreased CSF cell count in 16 of the 23 patients with LM and conversion of positive CSF cytology to negative in 6 of the 23 patients without apparent neurotoxicity [218]. However, this remains an experimental treatment for LM. Other drugs under investigation for IT administration in patients with LM are listed below [219].

•Busulfan [293]

•Dacarbazine [219], [294], [295]

•Diaziquone [295], [296]

•Fluorouracil [297], [298]

•Hydroxypercyclophosphamide [299], [300]

•Mafosfamide [301], [302]

•Melphalan [303]

•Neocarzinostatin [216]

•Nitrosureas (nimustine, ranimustine) [297], [304], [305]

•Topotecan [219]

•Trimetrexate (amifolate agent) [306]

Intathecal combination therapy

Early trials of IT combination therapy (MTX and thio-TEPA) for LM were disappointing due to increased toxicity and lack of efficacy [217]. In a study of 25 patients with LM treated weekly with concurrent IT thio-TEPA (10 mg), IT MTX (10 mg), and radiation therapy, 22/25 patients were clinically improved or stable, and malignant cells were cleared from the cerebrospinal fluid in 76% of the patients. Myelosuppression was the dose-limiting toxicity, while neurotoxicity occurred in three patients [217]. In another study, 22 patients with LM from a variety of malignancies were treated with biweekly combination intraventricular chemotherapy using MTX, ara-C, and thio-TEPA. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Myelosuppression was the major toxicity, and occurred in 17 of 22 patients (77%). No patient achieved a complete response, although nine patients (41%) had partial responses lasting 4 to 24 weeks. Median survival for the entire group was 10 weeks (range 6 to 24 weeks). The authors of the latter study concluded that simultaneous triple-drug IT therapy caused unacceptable myelosuppression without increasing response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy [220].

In another study, 23 patients with LM from a variety of malignancies were treated with intra-Ommaya injections of MTX, hydrocortisone, ara-C, and thio-TEPA. Whole-brain irradiation was also administered to most patients who had not previously received it. Most patients in this study demonstrated improvement of CSF parameters, and 50% of the subjects experienced neurologic improvement. However, 10/20 patients had neurologic complications, leading the authors to conclude that this regimen was associated with higher toxicity than less intense regimens [221].

In another study, 44 patients with LM (mostly from small-cell lung cancer, 29% and breast carcinoma, 25%) were treated in a prospective randomized trial with intrathecal MTX (15 mg) or MTX plus ara-C. Overall response rate was 55%, and the response rate to combined MTX/Ara-C was not significantly better than MTX alone (45% versus 61%; P>0.1) [222].

All of these studies suggest that combination dosing and schedules play a critical role in the balance between cytotoxicity versus neurotoxicity. Further investigation is necessary to achieve a more favorable balance in this relationship. However, at the present time there is no compelling evidence that combination IT chemotherapy is superior to IT monotherapy.

Experimental therapies

Immunotherapy

Novel immunotherapeutic approaches to LM include the IT administration of monoclonal antibodies [222], [223], [224], [225], cytokines [interleukin-2 (IL-2), interferon-alpha (IFN-alpha)], and lymphokine-activated killer cells (LAK cells). In one study, 52 patients with LM were treated with IT-radiolabeled monoclonal antibodies directed against tumor antigens. Fifty percent of the patients survived for at least 1 year, and the mean survival of responders was 39 months and nonresponders 4 months [226]. Immunotherapy with IT IL-2 in patients failing conventional treatment for LM showed improvement in cytokine parameters in 11 patients [227], [228]. The neurotoxicity of this therapy, mainly increased intracranial pressure, was considerable but manageable [229], [230], [231]. Combination therapy with intraventricular IL-2 and LAK cells was effective in reducing the clinical symptoms and signs, and in eliminating the malignant cells from the CSF in two patients with LM [232].

Targeted toxins

Targeted toxins represent a unique form of therapy that have two components—a carrier molecule with high specificity for tumor-associated antigens, and a potent protein toxin [233]. In a pilot study of eight patients with LM, four of eight subjects treated with intraventricular monoclonal immunotoxin 454A12-rRA—a chemically linked conjugate of a monoclonal antibody against the human transferrin receptor (454A12)—and a protein toxin—recombinant ricin A chain (rRA)—had greater than 50% reduction in their lumbar CSF tumor cell counts, but seven of eight patients progressed. Side effects included transient headache, nausea, vomiting, lethargy, and mental status changes that required treatment with corticosteroids and CSF drainage [234]. Although encouraging, further human studies and randomized trails are needed to establish their true efficacy in humans.

New therapies for LM that are currently under investigation include monoclonal antibodies to tumor antigens [235], [236], signal transduction inhibitors [237], [238], and viral-mediated gene therapy [239], [240], [241]. Systemic chemotherapy combined with techniques to disrupt the BBB is another promising approach [242] for chemosensitive cancers.

Summary

LM is an increasingly common neurologic complication of cancer with variable clinical manifestations. Although there are no curative treatments, currently available therapies can preserve neurologic function and potentially improve quality of life. Further research into the mechanisms of leptomeningeal metastasis will elucidate molecular and cellular pathways that may allow identification of potential targets to interrupt this process early or to prevent this complication. Animal models are needed to further define the pathophysiology of LM and to provide an experimental system to test novel treatments [242], [243], [244], [245].

There is an urgent need to develop new drug-based or radiation-based treatments for patients with LM. Randomized clinical trials are the appropriate study design to determine the efficacy of new treatments for LM. However, surrogate markers for response must be developed to facilitate the identification of effective regimens. Survival is not the optimal end point for such studies as most patients who develop this complication already have advanced, incurable cancer. Prevention of or delay in neurologic progression is one objective that has been utilized in recent randomized trials in patients with LM, and this end point deserves further attention.

Although the development of LM represents a poor prognostic marker in patients with cancer it is important for physicians to recognize the symptoms and signs of the disease and establish the diagnosis as early in the disease course as possible. This may provide an opportunity for effective intervention that can improve quality of life, prevent further neurologic deterioration and, for a subset of patients, improve survival.

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Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA

Corresponding author: Brain Tumor Center, Cox 315, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114

PII: S0733-8619(02)00032-4

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