Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of leptomeningeal metastases (carcinomatous meningitis)

Alexis Demopoulos, MD
Paul Brown, MD
Section Editor
Lisa M DeAngelis, MD, FAAN, FANA
Deputy Editors
April F Eichler, MD, MPH
Diane MF Savarese, MD


Cancer arising outside the central nervous system (CNS) can metastasize to any intracranial structure, including the membranes covering the brain. These membranes consist of the dura mater, and the arachnoid and pia mater, the latter two together are called the leptomeninges. The subarachnoid space lies between the arachnoid and pia mater and contains the cerebrospinal fluid (CSF) and arteries supplying the brain parenchyma. When tumor invades the leptomeninges, tumor cells can be disseminated via the CSF and spread throughout the subarachnoid space, causing multifocal signs and symptoms.

The treatment of leptomeningeal metastases from solid tumors is reviewed here. The pathophysiology, clinical manifestations, and diagnosis of leptomeningeal metastases, and leptomeningeal involvement in hematologic malignancies, especially large cell lymphomas and acute leukemias, are discussed separately. (See "Clinical features and diagnosis of leptomeningeal metastases from solid tumors" and "Clinical presentation and diagnosis of secondary central nervous system lymphoma", section on 'Leptomeningeal metastasis' and "Involvement of the central nervous system with acute myeloid leukemia".)


The goals of treatment include stabilizing or improving neurologic function, prolonging survival and if these are not possible, palliating symptoms. However, the prognosis varies considerably, depending upon the tumor type and extent of both neurologic and systemic disease; these factors can help determine the appropriate therapeutic approach for an individual patient. The key parameters separating poor-risk from good-risk patients are summarized in the table (table 1).

Poor-risk patients — Patients with a low Karnofsky performance status (KPS) (table 2), multiple, serious, fixed neurologic deficits, and extensive systemic cancer with limited therapeutic options have a poor prognosis even with active treatment. Management of leptomeningeal metastases in this setting focuses on alleviating symptoms. A palliative approach should also be considered for patients with leptomeningeal gliomatosis and those with encephalopathy due to extensive brain infiltration (carcinomatous encephalitis), since the prognosis is poor even with combined modality therapy [1,2].

The palliative regimen can include the following components:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 19, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Chamberlain MC. Combined-modality treatment of leptomeningeal gliomatosis. Neurosurgery 2003; 52:324.
  2. Chamberlain MC, Tsao-Wei D, Groshen S. Neoplastic meningitis-related encephalopathy: prognostic significance. Neurology 2004; 63:2159.
  3. Omuro AM, Lallana EC, Bilsky MH, DeAngelis LM. Ventriculoperitoneal shunt in patients with leptomeningeal metastasis. Neurology 2005; 64:1625.
  4. Lee SH, Kong DS, Seol HJ, et al. Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis. J Neurooncol 2011; 104:545.
  5. Rickert CH. Abdominal metastases of pediatric brain tumors via ventriculo-peritoneal shunts. Childs Nerv Syst 1998; 14:10.
  6. Grossman SA, Trump DL, Chen DC, et al. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. An evaluation using 111indium-DTPA ventriculography. Am J Med 1982; 73:641.
  7. Chamberlain MC, Corey-Bloom J. Leptomeningeal metastases: 111indium-DTPA CSF flow studies. Neurology 1991; 41:1765.
  8. Glantz MJ, Hall WA, Cole BF, et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer 1995; 75:2919.
  9. Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 1998; 82:733.
  10. van Oostenbrugge RJ, Hopman AH, Arends JW, et al. Treatment of leptomeningeal metastases evaluated by interphase cytogenetics. J Clin Oncol 2000; 18:2053.
  11. Nayak L, Fleisher M, Gonzalez-Espinoza R, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 2013; 80:1598.
  12. Chang EL, Maor MH. Standard and novel radiotherapeutic approaches to neoplastic meningitis. Curr Oncol Rep 2003; 5:24.
  13. Grossman SA, Reinhard CS, Loats HL. The intracerebral penetration of intraventricularly administered methotrexate: a quantitative autoradiographic study. J Neurooncol 1989; 7:319.
  14. Burch PA, Grossman SA, Reinhard CS. Spinal cord penetration of intrathecally administered cytarabine and methotrexate: a quantitative autoradiographic study. J Natl Cancer Inst 1988; 80:1211.
  15. Larson SM, Schall GL, Di Chiro G. The influence of previous lumbar puncture and pneumoencephalography on the incidence of unsuccessful radioisotope cisternography. J Nucl Med 1971; 12:555.
  16. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975; 293:161.
  17. Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987; 5:1655.
  18. Glantz MJ, Van Horn A, Fisher R, Chamberlain MC. Route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis. Cancer 2010; 116:1947.
  19. Zairi F, Le Rhun E, Bertrand N, et al. Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumor: a single centre experience in 112 patients. J Neurooncol 2015; 124:317.
  20. Sandberg DI, Bilsky MH, Souweidane MM, et al. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery 2000; 47:49.
  21. Sullivan MP, Moon TE, Trueworthy R, et al. Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Blood 1977; 50:471.
  22. Siegal T, Lossos A, Pfeffer MR. Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology 1994; 44:1463.
  23. Grossman SA, Finkelstein DM, Ruckdeschel JC, et al. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol 1993; 11:561.
  24. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998; 16:1561.
  25. Pfeffer MR, Wygoda M, Siegal T. Leptomeningeal metastases--treatment results in 98 consecutive patients. Isr J Med Sci 1988; 24:611.
  26. Sause WT, Crowley J, Eyre HJ, et al. Whole brain irradiation and intrathecal methotrexate in the treatment of solid tumor leptomeningeal metastases--a Southwest Oncology Group study. J Neurooncol 1988; 6:107.
  27. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982; 49:759.
  28. Rubin R, Owens E, Rall D. Transport of methotrexate by the choroid plexus. Cancer Res 1968; 28:689.
  29. Fulton DS, Levin VA, Gutin PH, et al. Intrathecal cytosine arabinoside for the treatment of meningeal metastases from malignant brain tumors and systemic tumors. Cancer Chemother Pharmacol 1982; 8:285.
  30. Esteva FJ, Soh LT, Holmes FA, et al. Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer. Cancer Chemother Pharmacol 2000; 46:382.
  31. Glantz MJ, Jaeckle KA, Chamberlain MC, 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; 5:3394.
  32. Cole BF, Glantz MJ, Jaeckle KA, et al. Quality-of-life-adjusted survival comparison of sustained-release cytosine arabinoside versus intrathecal methotrexate for treatment of solid tumor neoplastic meningitis. Cancer 2003; 97:3053.
  33. Jaeckle KA, Phuphanich S, Bent MJ, et al. Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001; 84:157.
  34. Fusco JP, Castañón E, Carranza OE, et al. Neurological and cytological response as potential early predictors of time-to-progression and overall survival in patients with leptomeningeal carcinomatosis treated with intrathecal liposomal cytarabine: a retrospective cohort study. J Neurooncol 2013; 115:429.
  35. Gutin PH, Levi JA, Wiernik PH, Walker MD. Treatment of malignant meningeal disease with intrathecal thioTEPA: a phase II study. Cancer Treat Rep 1977; 61:885.
  36. Comte A, Jdid W, Guilhaume MN, et al. Survival of breast cancer patients with meningeal carcinomatosis treated by intrathecal thiotepa. J Neurooncol 2013; 115:445.
  37. Le Rhun E, Taillibert S, Devos P, et al. Salvage intracerebrospinal fluid thiotepa in breast cancer-related leptomeningeal metastases: a retrospective case series. Anticancer Drugs 2013; 24:1093.
  38. Fisher PG, Kadan-Lottick NS, Korones DN. Intrathecal thiotepa: reappraisal of an established therapy. J Pediatr Hematol Oncol 2002; 24:274.
  39. Chamberlain MC, Kormanik P. Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy. Arch Neurol 1998; 55:506.
  40. Kim DY, Lee KW, Yun T, et al. Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone. Jpn J Clin Oncol 2003; 33:608.
  41. Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer 2004; 40:2726.
  42. Tetef ML, Margolin KA, Doroshow JH, et al. Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol 2000; 46:19.
  43. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98:231.
  44. Slevin ML, Piall EM, Aherne GW, et al. Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983; 1:546.
  45. Lopez JA, Nassif E, Vannicola P, et al. Central nervous system pharmacokinetics of high-dose cytosine arabinoside. J Neurooncol 1985; 3:119.
  46. Frick J, Ritch PS, Hansen RM, Anderson T. Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside. J Clin Oncol 1984; 2:365.
  47. Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. Cancer Treat Rep 1986; 70:1059.
  48. Giglio P, Tremont-Lukats IW, Groves MD. Response of neoplastic meningitis from solid tumors to oral capecitabine. J Neurooncol 2003; 65:167.
  49. Rogers LR, Remer SE, Tejwani S. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol 2004; 6:63.
  50. Shigekawa T, Takeuchi H, Misumi M, et al. Successful treatment of leptomeningeal metastases from breast cancer using the combination of trastuzumab and capecitabine: a case report. Breast Cancer 2009; 16:88.
  51. Ekenel M, Hormigo AM, Peak S, et al. Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007; 85:223.
  52. Tham YL, Hinckley L, Teh BS, Elledge R. Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Clin Breast Cancer 2006; 7:164.
  53. Vincent A, Lesser G, Brown D, et al. Prolonged regression of metastatic leptomeningeal breast cancer that has failed conventional therapy: a case report and review of the literature. J Breast Cancer 2013; 16:122.
  54. Yi HG, Kim HJ, Kim YJ, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer 2009; 65:80.
  55. Kanaji N, Bandoh S, Nagamura N, et al. Significance of an epidermal growth factor receptor mutation in cerebrospinal fluid for carcinomatous meningitis. Intern Med 2007; 46:1651.
  56. Sakai M, Ishikawa S, Ito H, et al. Carcinomatous meningitis from non-small-cell lung cancer responding to gefitinib. Int J Clin Oncol 2006; 11:243.
  57. Hashimoto N, Imaizumi K, Honda T, et al. Successful re-treatment with gefitinib for carcinomatous meningitis as disease recurrence of non-small-cell lung cancer. Lung Cancer 2006; 53:387.
  58. So T, Inoue M, Chikaishi Y, et al. Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: report of two cases. Surg Today 2009; 39:598.
  59. Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 2006; 24:4517.
  60. Dhruva N, Socinski MA. Carcinomatous meningitis in non-small-cell lung cancer: response to high-dose erlotinib. J Clin Oncol 2009; 27:e31.
  61. Clarke JL, Pao W, Wu N, et al. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010; 99:283.
  62. Cessot A, Blanchet B, Goldwasser F. Erlotinib treatment of meningeal carcinomatosis in lung cancer: more is better. Ann Oncol 2014; 25:2093.
  63. Kawamura T, Hata A, Takeshita J, et al. High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs. Cancer Chemother Pharmacol 2015; 75:1261.
  64. Yang JC, Kim D-W, Kim S-W, et al. Osimertinib activity in patients with leptomeningeal metastases from non-small cell lung cancer: Updated results from BLOOM, a phase I study (absstract). J Clin Oncol 34, 2016 (suppl; abstr 9002). Abstract available online at http://meetinglibrary.asco.org/content/169604-176 (Accessed on June 14, 2016).
  65. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015; 33:1881.
  66. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014; 15:1119.
  67. Gainor JF, Chi AS, Logan J, et al. Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib. J Thorac Oncol 2016; 11:256.
  68. Gainor JF, Sherman CA, Willoughby K, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol 2015; 10:232.
  69. Ou SH, Sommers KR, Azada MC, Garon EB. Alectinib induces a durable (>15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis. Oncologist 2015; 20:224.
  70. Slavc I, Schuller E, Falger J, et al. Feasibility of long-term intraventricular therapy with mafosfamide (n = 26) and etoposide (n = 11): experience in 26 children with disseminated malignant brain tumors. J Neurooncol 2003; 64:239.
  71. Fleischhack G, Reif S, Hasan C, et al. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. Br J Cancer 2001; 84:1453.
  72. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 2006; 106:2021.
  73. Champagne MA, Silver HK. Intrathecal dacarbazine treatment of leptomeningeal malignant melanoma. J Natl Cancer Inst 1992; 84:1203.
  74. Kochi M, Kuratsu J, Mihara Y, et al. Neurotoxicity and pharmacokinetics of intrathecal perfusion of ACNU in dogs. Cancer Res 1990; 50:3119.
  75. Gururangan S, Petros WP, Poussaint TY, et al. Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004). Clin Cancer Res 2006; 12:1540.
  76. Friedman HS, Archer GE, McLendon RE, et al. Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats. Cancer Res 1994; 54:4710.
  77. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 2008; 10:208.
  78. Laufman LR, Forsthoefel KF. Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer 2001; 2:235.
  79. Stemmler HJ, Schmitt M, Harbeck N, et al. Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Oncol Rep 2006; 15:1373.
  80. Platini C, Long J, Walter S. Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 2006; 7:778.
  81. Stemmler HJ, Mengele K, Schmitt M, et al. Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report. Anticancer Drugs 2008; 19:832.
  82. Oliveira M, Braga S, Passos-Coelho JL, et al. Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat 2011; 127:841.
  83. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat 2013; 139:13.
  84. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999; 25:103.
  85. Glantz MJ, LaFollette S, Jaeckle KA, 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; 17:3110.
  86. Morikawa A, Jordan L, Rozner R, et al. Characteristics and Outcomes of Patients With Breast Cancer With Leptomeningeal Metastasis. Clin Breast Cancer 2017; 17:23.
  87. Sanson M, Cartalat-Carel S, Taillibert S, et al. Initial chemotherapy in gliomatosis cerebri. Neurology 2004; 63:270.
  88. Louis E, Keime-Guibert F, Delattre JY, Sanson M. Dramatic response to chemotherapy in oligodendroglial gliomatosis cerebri. Neurology 2003; 60:151.
  89. DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998; 38:245.