ABSTRACT
Leptomeningeal metastasis occurs in ~5% of all patients with cancer and is the third most common metastatic complication of the central nervous system. Staging of leptomeningeal metastasis includes contrast-enhanced brain and spine magnetic resonance imaging and radionuclide cerebrospinal fluid (CSF) flow study. Treatment, when clinically indicated, often requires administration of involved-field radiotherapy to bulky or symptomatic disease sites as well as intra-CSF and systemic chemotherapy. The use of high-dose systemic therapy may benefit selected patients with breast- or lymphoma-related leptomeningeal metastasis and obviate the need for intra-CSF chemotherapy. Intra-CSF drug therapy primarily utilizes one of three chemotherapeutic agents (e.g., methotrexate, cytosine arabinoside, and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Beginning to be utilized are novel intra-CSF agents, such as the targeted monoclonal antibodies rituximab (anti-CD20 for B-cell lymphoma-related leptomeningeal metastasis) and trastuzumab (anti-Her2/neu for breast cancer-related leptomeningeal metastasis). Although treatment of leptomeningeal metastasis is palliative with median patient survival of 2 to 3 months, treatment may afford stabilization and protection from further neurologic deterioration in patients with leptomeningeal metastasis.
KEYWORDS
Leptomeningeal metastases - intra-CSF chemotherapy
REFERENCES
1
Jaeckle K A.
Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment.
Semin Oncol.
2006;
33(3)
312-323
2
Pace A, Fabi A.
Chemotherapy in neoplastic meningitis.
Crit Rev Oncol Hematol.
2006;
60(3)
194-200
3
Kaplan J G, DeSouza T G, Farkash A et al..
Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias.
J Neurooncol.
1990;
9(3)
225-229
4
Siegal T, Lossos A, Pfeffer M R.
Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy.
Neurology.
1994;
44(8)
1463-1469
5
Blaney S M, Poplack D G.
Neoplastic meningitis: diagnosis and treatment considerations.
Med Oncol.
2000;
17(3)
151-162
6
Glass J P, Melamed M, Chernik N L, Posner J B.
Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology.
Neurology.
1979;
29(10)
1369-1375
7
Wasserstrom W R, Glass J P, Posner J B.
Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients.
Cancer.
1982;
49(4)
759-772
8
Rosen S T, Aisner J, Makuch R W et al..
Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience.
Medicine (Baltimore).
1982;
61(1)
45-53
9
Amer M H, Al-Sarraf M, Baker L H, Vaitkevicius V K.
Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival.
Cancer.
1978;
42(2)
660-668
10
van Oostenbrugge R J, Twijnstra A.
Presenting features and value of diagnostic procedures in leptomeningeal metastases.
Neurology.
1999;
53(2)
382-385
11
Balm M, Hammack J.
Leptomeningeal carcinomatosis. Presenting features and prognostic factors.
Arch Neurol.
1996;
53(7)
626-632
12
Sorensen S C, Eagan R T, Scott M.
Meningeal carcinomatosis in patients with primary breast or lung cancer.
Mayo Clin Proc.
1984;
59(2)
91-94
13
Gonzalez-Vitale J C, Garcia-Bunuel R.
Meningeal carcinomatosis.
Cancer.
1976;
37(6)
2906-2911
14
Gleissner B, Chamberlain M C.
Neoplastic meningitis.
Lancet Neurol.
2006;
5(5)
443-452
15
Boyle R, Thomas M, Adams J H.
Diffuse involvement of the leptomeninges by tumour—a clinical and pathological study of 63 cases.
Postgrad Med J.
1980;
56(653)
149-158
16
Wolfgang G, Marcus D, Ulrike S.
Leptomeningeal carcinomatosis; clinical syndrome in different primaries.
J Neurooncol.
1998;
38
103-110
17
Kölmel H W.
Cytology of neoplastic meningosis.
J Neurooncol.
1998;
38(2-3)
121-125
18
Murray J J, Greco F A, Wolff S N, Hainsworth J D.
Neoplastic meningitis. Marked variations of cerebrospinal fluid composition in the absence of extradural block.
Am J Med.
1983;
75(2)
289-294
19
Rogers L R, Duchesneau P M, Nunez C et al..
Comparison of cisternal and lumbar CSF examination in leptomeningeal metastasis.
Neurology.
1992;
42(6)
1239-1241
20
Chamberlain M C, Kormanik P A, Glantz M J.
A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases.
Neuro-oncol.
2001;
3(1)
42-45
21
Glantz M J, Cole B F, Glantz L K et al..
Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results.
Cancer.
1998;
82(4)
733-739
22
Groves M D, Hess K R, Puduvalli V K et al..
Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma.
J Neurooncol.
2009;
94(2)
229-234
23
Chamberlain M C.
Cytologically negative carcinomatous meningitis: usefulness of CSF biochemical markers.
Neurology.
1998;
50(4)
1173-1175
24
Hovestadt A, Henzen-Logmans S C, Vecht C J.
Immunohistochemical analysis of the cerebrospinal fluid for carcinomatous and lymphomatous leptomeningitis.
Br J Cancer.
1990;
62(4)
653-654
25
van Oostenbrugge R J, Hopman A H, Ramaekers F C, Twijnstra A.
In situ hybridization: a possible diagnostic aid in leptomeningeal metastasis.
J Neurooncol.
1998;
38(2-3)
127-133
26
Quijano S, López A, Manuel Sancho J Spanish Group for the Study of CNS Disease in NHL et al.
Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin's lymphoma: improved sensitivity of flow cytometry.
J Clin Oncol.
2009;
27(9)
1462-1469
27
Bromberg J EC, Breems D A, Kraan J et al..
CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies.
Neurology.
2007;
68(20)
1674-1679
28
Hegde U, Filie A, Little R F et al..
High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology.
Blood.
2005;
105(2)
496-502
29
Cheng T M, O'Neill B P, Scheithauer B W, Piepgras D G.
Chronic meningitis: the role of meningeal or cortical biopsy.
Neurosurgery.
1994;
34(4)
590-595
discussion 596
30
Chamberlain M C, Sandy A D, Press G A.
Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain.
Neurology.
1990;
40(3 Pt 1)
435-438
31
Schumacher M, Orszagh M.
Imaging techniques in neoplastic meningiosis.
J Neurooncol.
1998;
38(2-3)
111-120
32
Chamberlain M C.
Comparative spine imaging in leptomeningeal metastases.
J Neurooncol.
1995;
23(3)
233-238
33
Freilich R J, Krol G, DeAngelis L M.
Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis.
Ann Neurol.
1995;
38(1)
51-57
34
Mittl Jr R L, Yousem D M.
Frequency of unexplained meningeal enhancement in the brain after lumbar puncture.
AJNR Am J Neuroradiol.
1994;
15(4)
633-638
35
Chamberlain M C.
Radioisotope CSF flow studies in leptomeningeal metastases.
J Neurooncol.
1998;
38(2-3)
135-140
36
Glantz M J, Hall W A, Cole B F et al..
Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status.
Cancer.
1995;
75(12)
2919-2931
37
Grossman S A, Trump C L, Chen D C, Thompson G, Camargo E E.
Cerebrospinal flow abnormalities in patients with neoplastic meningitis. An evaluation using 111indium-DTPA ventriculography.
Am J Med.
1982;
73
641-647
38
Chamberlain M C, Kormanik P A.
Prognostic significance of 111indium-DTPA CSF flow studies in leptomeningeal metastases.
Neurology.
1996;
46(6)
1674-1677
39
Mason W P, Yeh S D, DeAngelis L M.
111Indium-diethylenetriamine pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases.
Neurology.
1998;
50(2)
438-444
40
Chamberlain M C, Corey-Bloom J.
Leptomeningeal metastases: 111indium-DTPA CSF flow studies.
Neurology.
1991;
41(11)
1765-1769
41
Chamberlain M C, Kormanik P, Jaeckle K A, Glantz M.
111Indium-diethylenetriamine pentaacetic acid CSF flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases.
Neurology.
1999;
52(1)
216-217
42
Chamberlain M C, Kormanik P A.
Prognostic significance of coexistent bulky metastatic central nervous system disease in patients with leptomeningeal metastases.
Arch Neurol.
1997;
54(11)
1364-1368
43
Chamberlain M C.
Neoplastic meningitis-related encephalopathy: prognostic significance.
Neurology.
2004;
63
2159-2161
44
Chamberlain M C.
Neoplastic meningitis: deciding who to treat.
Expert Rev Neurother.
2004;
4
89-96
45
Brem S S, Bierman P J, Black P et al..
Central nervous system cancers.
J Natl Compr Canc Netw.
2008;
6(5)
456-504
46
Shapiro W R, Young D F, Mehta B M.
Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections.
N Engl J Med.
1975;
293(4)
161-166
47
Grossman S A, Finkelstein D M, Ruckdeschel J C, Trump D L, Moynihan T, Ettinger D S. Eastern Cooperative Oncology Group .
Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis.
J Clin Oncol.
1993;
11(3)
561-569
48
Glantz M J, Jaeckle K A, Chamberlain M C et al..
A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.
Clin Cancer Res.
1999;
5(11)
3394-3402
49
Glantz M J, LaFollette S, Jaeckle K A et al..
Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.
J Clin Oncol.
1999;
17(10)
3110-3116
50
Shapiro W R, Schmid M, Glantz M, Miller J J.
A randomized phase III/IV study to determine benefit and safety of cytarabine liposome injection for treatment of neoplastic meningitis.
J Clin Oncol.
2006;
24(Suppl)
1528 (Abstract)
51
Chamberlain M C.
A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis.
Cancer.
2002;
94(10)
2675-2680
52
Chamberlain M C, Wei-Tsao D D, Groshen S.
Phase 2 trial of intra-CSF etoposide in the treatment of neoplastic meningitis.
Cancer.
2006;
106(9)
2021-2027
53
Groves M D, Glantz M J, Chamberlain M C et al..
A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies.
Neuro-oncol.
2008;
10(2)
208-215
54
Chamberlain M C, Johnston S K, Van Horn A, Glantz M J.
Recurrent lymphomatous meningitis treated with intra-CSF rituximab and liposomal ara-C.
J Neurooncol.
2009;
91(3)
271-277
55
Rubenstein J L, Fridlyand J, Abrey L et al..
Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.
J Clin Oncol.
2007;
25(11)
1350-1356
56
Mir O, Ropert S, Alexandre J, Lemare F, Goldwasser F.
High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer.
Ann Oncol.
2008;
19(11)
1978-1980
57
Allison D, Glantz M.
Intra-CSF Trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors.
Neurology.
2009;
72(11, Suppl 3)
A30
58
Chamberlain M C.
Risk of neoplastic meningitis following surgical resection of cerebellar metastases.
J Neurooncol.
2008;
89(1)
105-107
59
Berweiler U, Krone A, Tonn J C.
Reservoir systems for intraventricular chemotherapy.
J Neurooncol.
1998;
38(2-3)
141-143
60
Sandberg D I, Bilsky M H, Souweidane M M, Bzdil J, Gutin P H.
Ommaya reservoirs for the treatment of leptomeningeal metastases.
Neurosurgery.
2000;
47(1)
49-54
discussion 54-55
61
Glantz M J, Van Horn A, Fisher R, Chamberlain M C.
Route of intra-CSF chemotherapy administration and efficacy of therapy in neoplastic meningitis.
Cancer.
2010;
116(8)
1947-1952
62
Siegal T.
Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy?.
J Neurooncol.
1998;
38(2-3)
151-157
63
Boogerd W, van den Bent M J, Koehler P J et al..
The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.
Eur J Cancer.
2004;
40(18)
2726-2733
64
Hitchins R N, Bell D R, Woods R L, Levi J A.
A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis.
J Clin Oncol.
1987;
5(10)
1655-1662
65
Chamberlain M C, Kormanik P A, Barba D.
Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases.
J Neurosurg.
1997;
87(5)
694-699
66
Siegal T, Pfeffer M R, Steiner I.
Antibiotic therapy for infected Ommaya reservoir systems.
Neurosurgery.
1988;
22(1 Pt 1)
97-100
67
Kerr J Z, Berg S, Blaney S M.
Intrathecal chemotherapy.
Crit Rev Oncol Hematol.
2001;
37(3)
227-236
68
Stapleton S, Blaney S M.
New agents for intrathecal administration.
Cancer Invest.
2006;
24(5)
528-534
69
Glantz M J, Cole B F, Recht L et al..
High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?.
J Clin Oncol.
1998;
16(4)
1561-1567
70
Bokstein F, Lossos A, Siegal T.
Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy.
Cancer.
1998;
82(9)
1756-1763
71
Sampson J H, Archer G E, Villavicencio A T et al..
Treatment of neoplastic meningitis with intrathecal temozolomide.
Clin Cancer Res.
1999;
5(5)
1183-1188
72
Bernardi R J, Bomgaars L, Fox E et al..
Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.
Cancer Chemother Pharmacol.
2008;
62(2)
355-361
73
Herrlinger U, Weller M, Schabet M.
New aspects of immunotherapy of leptomeningeal metastasis.
J Neurooncol.
1998;
38(2-3)
233-239
74
Coakham H B, Kemshead J T.
Treatment of neoplastic meningitis by targeted radiation using (131)I-radiolabelled monoclonal antibodies. Results of responses and long term follow-up in 40 patients.
J Neurooncol.
1998;
38(2-3)
225-232
75
Chamberlain M C, Kormanik P R.
Carcinomatous meningitis secondary to breast cancer: predictors of response to combined modality therapy.
J Neurooncol.
1997;
35(1)
55-64
76
Chamberlain M C, Kormanik P.
Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy.
Arch Neurol.
1998;
55(4)
506-512
77
Chamberlain M C, Johnston S K, Glantz M J.
Neoplastic meningitis-related prognostic significance of the Karnofsky performance status.
Arch Neurol.
2009;
66(1)
74-78
78
Chamberlain M C, Johnston S K.
Neoplastic meningitis: survival as a function of cerebrospinal fluid cytology.
Cancer.
2009;
115(9)
1941-1946
79
Garcia-Marco J A, Panizo C, Garcia E S et al..
Efficacy and safety of liposomal cytarabine in lymphoma patients with central nervous system involvement from lymphoma.
Cancer.
2009;
115(9)
1892-1898
80
Jaeckle K A, Batchelor T, O'Day S J et al..
An open label trial of sustained-release cytarabine (DepoCyt) for the intrathecal treatment of solid tumor neoplastic meningitis.
J Neurooncol.
2002;
57(3)
231-239
Marc C ChamberlainM.D.
Department of Neurology and Neurological Surgery, Division of Neuro-Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance
825 Eastlake Avenue E, POB 19023, MS G4940, Seattle, WA 98109-1023
eMail: chambemc@u.washington.edu