Skip to main content

Advertisement

SpringerLink
Log in

Biology and Therapy of Neoplastic Meningitis

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Neoplastic meningitis (NM) occurs in 5% to 8% of cancer patients, commonly as an end-stage process in previously metastatic disease. As newer therapeutics extend patient survival by maintaining long-term control of systemic malignancies, the incidence of NM is likely to rise. This can be expected both because of a change in the natural history of the underlying disease and the generally poor penetrance of many newer anticancer drugs into the central nervous system, thereby creating a sanctuary site for malignant cells. Currently available treatments have provided limited benefit in overall survival in NM, although long-term survival does occur. Because of the morbidity occasionally associated with treatment, prognostic indicators are being analyzed to identify patients who may benefit from systemic and/or intrathecal therapy before making the decision to initiate treatment. Additionally, because of the relative insensitivity of traditional cerebrospinal fluid analysis, new markers of NM are being investigated. This endeavor is being aided by ongoing research into the underlying biology of the metastatic process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Groves MD: Leptomeningeal metastases: still a challenge. In ASCO Educational Book. Edited by Govindan R. Alexandria, VA: American College of Clinical Oncology; 2008:80–87.

    Google Scholar 

  2. Chamberlain MC: Risk of neoplastic meningitis following surgical resection of cerebellar metastases. J Neurooncol 2008, 89:105–107.

    Article  PubMed  Google Scholar 

  3. • Suki D, Abouassi H, Patel AJ, et al.: Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008, 108:248–257. This study addresses the belief that surgical excision of metastatic brain tumors located in the posterior fossa is responsible for an increased incidence of leptomeningeal seeding. The authors found that en bloc resection of brain tumors did not carry an increased risk of NM compared with stereotactic radiosurgery. They did find an increased risk of NM with piecemeal resection compared with both en bloc resection and stereotactic radiosurgery, which held true even after a subgroup analysis accounting for tumor size and other characteristics. This paper importantly points out the need for en bloc resection to be performed whenever feasible.

    Article  PubMed  Google Scholar 

  4. • Suki D, Hatiboglu MA, Patel AJ, et al.: Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis. Neurosurgery 2009, 64:664–674; discussion 674–676. This retrospective study addressed the belief that surgical excision of supratentorial metastatic brain tumors is associated with an increased incidence of NM. The authors found no statistically significant difference between the incidence of NM after en bloc resection versus treatment with stereotactic radiosurgery. There was a statistically significant increase in the incidence of NM after piecemeal resection of metastases compared with either en bloc resection or stereotactic radiosurgery. The results remained statistically significant even after subgroup analysis accounting for tumor size and other characteristics. This paper importantly points out the need for en bloc resection when possible.

    Article  PubMed  Google Scholar 

  5. • Lin C, Turner S, Gurney H, Peduto A: Increased detections of leptomeningeal presentations in men with hormone refractory prostate cancer: an effect of improved systemic therapy? J Med Imaging Radiat Oncol 2008, 52:376–381. This case series illustrates the increasing incidence of NM in malignancies that were previously infrequently associated with leptomeningeal disease. The authors note that before 2004 they had not seen a case of NM in hormone refractory prostate cancer; however, between 2004 and 2006, they identified four patients in their practice. This increase is attributed to the improved survival in hormone refractory prostate cancer owing to newer treatment regimens. This raises the issues of the changing natural history of disease as newer therapies become available and the need for maintaining an awareness to the potential for NM with any underlying malignancy.

    Article  CAS  PubMed  Google Scholar 

  6. Orphanos G, Ardavanis A: Leptomeningeal metastases from prostate cancer: an emerging clinical conundrum. Clin Exp Metastasis 2009 Nov 11 (Epub ahead of print).

  7. Vitaliani R, Spinazzi M, Del Mistro AR, et al.: Subacute onset of deafness and vertigo in a patient with leptomeningeal metastasis from ovarian cancer. Neurol Sci 2009, 30:65–67.

    Article  PubMed  Google Scholar 

  8. Goto Y, Katsumata N, Nakai S, et al.: Leptomeningeal metastasis from ovarian carcinoma successfully treated by the intraventricular administration of methotrexate. Int J Clin Oncol 2008, 13:555–558.

    Article  PubMed  Google Scholar 

  9. Baek WS, Kubba SV: Cauda equina syndrome due to leptomeningeal carcinomatosis of the ovary. Gynecol Oncol 2008, 111:544–545.

    Article  CAS  PubMed  Google Scholar 

  10. Ignatius RT, Wills SM, Nadeau L, et al.: Leptomeningeal carcinomatosis due to squamous cell carcinoma of the uterine cervix associated with HPV-45. J Clin Oncol 2008, 26:154–156.

    Article  PubMed  Google Scholar 

  11. Asensio N, Luis A, Costa I, et al.: Meningeal carcinomatosis and uterine carcinoma: three different clinical settings and review of the literature. Int J Gynecol Cancer 2009, 19:168–172.

    PubMed  Google Scholar 

  12. Oh SY, Lee SJ, Lee J, et al.: Gastric leptomeningeal carcinomatosis: multi-center retrospective analysis of 54 cases. World J Gastroenterol 2009, 15:5086–5090.

    Article  PubMed  Google Scholar 

  13. Raj KP, Sanati H, Mehta RS, Zell JA: Need for a new treatment strategy: leptomeningeal carcinomatosis from gastric cancer. Anticancer Drugs 2009, 20:301–304.

    Article  CAS  PubMed  Google Scholar 

  14. Lee HG, Lee B, Kim SM, et al.: A case of gastric adenocarcinoma presenting as meningeal carcinomatosis. Korean J Intern Med 2007, 22:304–307.

    Article  PubMed  Google Scholar 

  15. Sambasivaiah K, Reddy K, Lakshmi AY, et al.: Gastric cancer with isolated leptomeningeal metastases: a case report. Trop Gastroenterol 2007, 28:39–40.

    CAS  PubMed  Google Scholar 

  16. Groves MD: The pathogenesis of neoplastic meningitis. Curr Oncol Rep 2003, 5:15–23.

    Article  PubMed  Google Scholar 

  17. Wasserstrom WR, Glass JP, Posner JB: Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982, 49:759–772.

    Article  CAS  PubMed  Google Scholar 

  18. Hegde U, Filie A, Little RF, 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, 105:496–502.

    Article  CAS  PubMed  Google Scholar 

  19. Quijano S, López A, Manuel Sancho J, et al.: Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma: improved sensitivity of flow cytometry. J Clin Oncol 2009, 27:1462–1469.

    Article  CAS  PubMed  Google Scholar 

  20. Chamberlain MC: Neoplastic meningitis. Curr Neurol Neurosci Rep 2008, 8:249–258.

    Article  PubMed  Google Scholar 

  21. Chamberlain MC, Glantz M, Groves MD, Wilson WH: Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol 2009, 36:S35–S45.

    Article  PubMed  Google Scholar 

  22. • Groves MD, Hess KR, Puduvalli VK, 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, 94:229–234. This study looks at the possible role of measuring VEGF and SDF-1 levels in CSF in order to detect the presence of NM. VEGF levels were found to be elevated in 15 of 22 patients with positive CSF cytology, as well as in two patients with negative CSF that had evidence of NM on MRI. Overall, the sensitivity of VEGF levels was 67% to 75% and the specificity was 95% to 100%. Based on these results, this test may prove useful as an adjunct in the diagnosis of NM.

    Article  CAS  PubMed  Google Scholar 

  23. • Kleinschmidt-Demasters BK, Damek DM: The imaging and neuropathological effects of bevacizumab (avastin) in patients with leptomeningeal carcinomatosis. J Neurooncol 2009 Jul 16 (Epub ahead of print). The authors present two case reports of patients with non-small cell lung cancer who were being treated with bevacizumab for their systemic disease and developed nonenhancing, biopsy-proven neoplastic meningitis. This paper raises the concern that newer cancer therapies, such as the antiangiogenics, may alter imaging characteristics in NM, making diagnosis more difficult.

  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, 16:1561–1567.

    CAS  PubMed  Google Scholar 

  25. 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, 16:88–92.

    Article  PubMed  Google Scholar 

  26. Fukuoka M, Yano S, Giaccone G, et al.: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003, 21:2237–2246.

    Article  CAS  PubMed  Google Scholar 

  27. Kris MG, Natale RB, Herbst RS, et al.: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003, 290:2149–2158.

    Article  CAS  PubMed  Google Scholar 

  28. • 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, 65:80–84. This retrospective study looks at patients with NSCLC and EGFR mutations who developed NM while responding systemically to treatment with gefitinib. Switching treatment to high-dose gefitinib or erlotinib, thereby effectively increasing CSF concentration of drug, resulted in improvement in 9 of 11 patients. This raises the issue of increasing survival on the incidence of NM, as well as brings to light the effects of newer treatments with poor CSF penetrance increasing the incidence of NM. Of interest is the fact that 82% of the patients responded to a similar treatment modality, suggesting this is a pharmakokinetic issue and not further mutation of the cancer.

    Article  PubMed  Google Scholar 

  29. Katayama T, Shimizu J, Suda K, et al.: Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 2009, 4:1415–1419.

    Article  PubMed  Google Scholar 

  30. Pao W, Miller VA, Politi KA, et al.: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005, 2:e73.

    Article  PubMed  Google Scholar 

  31. Kobayashi S, Boggon TJ, Dayaram T, et al.: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005, 352:786–792.

    Article  CAS  PubMed  Google Scholar 

  32. 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, 17:3110–3116.

    CAS  PubMed  Google Scholar 

  33. Groves MD, Glantz MJ, Chamberlain MC, et al.: A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 2008, 10:208–215.

    Article  CAS  PubMed  Google Scholar 

  34. Bernardi RJ, Bomgaars L, Fox E, et al.: Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis. Cancer Chemother Pharmacol 2008, 62:355–361.

    Article  CAS  PubMed  Google Scholar 

  35. Rebischung C, Hoffmann D, Stefani L, et al.: First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR. Int J Radiat Biol 2008, 84:1123–1129.

    Article  CAS  PubMed  Google Scholar 

  36. 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, 19:832–836.

    Article  CAS  PubMed  Google Scholar 

  37. Gaviani P, Silvani A, Corsini E, et al.: Neoplastic meningitis from breast carcinoma with complete response to liposomal cytarabine: case report. Neurol Sci 2009, 30:251–254.

    Article  PubMed  Google Scholar 

  38. Glas M, Stuplich M, Tschampa H, et al.: Liposomal cytarabine given concomitantly with radiotherapy in a patient with leptomeningeal metastasis from breast cancer. J Neurol 2008, 255:1838–1839.

    Article  CAS  PubMed  Google Scholar 

  39. Passarin MG, Moretto G, Musso AM, et al.: Intrathecal liposomal cytarabine in combination with temozolomide in low-grade oligoastrocytoma with leptomeningeal dissemination. J Neurooncol 2009 Oct 31 (Epub ahead of print).

  40. Chamberlain MC, Kormanik P, Jaeckle KA, Glantz M: 111Indium-diethylenetriamine pentaacetic acid CSF flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases. Neurology 1999, 52:216–217.

    CAS  PubMed  Google Scholar 

  41. Hall WA, Cole BF, et al.: Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer 1995, 75:2919–2931.

    Article  PubMed  Google Scholar 

  42. DeAngelis LM: Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998, 38:245–252.

    Article  CAS  PubMed  Google Scholar 

  43. Brem SS, Bierman PJ, Black P, et al.: Central nervous system cancers: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2005, 3:644–690.

    PubMed  Google Scholar 

  44. Waki F, Ando M, Takashima A, et al.: Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors. J Neurooncol 2009, 93:205–212.

    Article  PubMed  Google Scholar 

  45. • Chamberlain MC, Johnston SK, Glantz MJ: Neoplastic meningitis-related prognostic significance of the Karnofsky performance status. Arch Neurol 2009, 66:74–78. This study addresses the contribution of KPS to prognosis in NM patients. Whereas many retrospective studies note that patients in the low performance group are less likely to be treated with IT chemotherapy, thereby clouding the interpretation, all patients in this study were treated with IT therapy. In addition, the study is control matched with regard to types of cancer and a number of other factors so that the makeup of the two groups differed essentially only by performance status. Based on this, median survival in the low performance status group was less than half of that in the good performance status group (6 weeks vs 15.5 weeks), with no patients in the poor KPS group surviving longer than10 weeks.

    Article  PubMed  Google Scholar 

  46. Bruna J, González L, Miró J, et al.: Leptomeningeal carcinomatosis: prognostic implications of clinical and cerebrospinal fluid features. Cancer 2009, 115:381–389.

    Article  PubMed  Google Scholar 

  47. • Clatot F, Philippin-Lauridant G, Ouvrier MJ, et al.: Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy. J Neurooncol 2009, 95:421–426. This paper addresses prognostic implications of cytologic response to treatment with IT chemotherapy in a cohort of breast cancer patients. The authors propose a treatment paradigm based on treating patients with four cycles of IT chemotherapy regardless of performance status and assessing them for response, then determining whether to continue with aggressive treatment versus supportive care base on the presence or absence of a response. Of interest, four of the 11 patients who responded in their 24 patient cohort would not have been included in treatment based on current NCCN guidelines.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

Dr. Groves has received grant support and honoraria from Schering Plough and Enzon Pharmaceuticals.

No further potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

  1. Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 431, Houston, TX, 77030, USA

    Aaron G. Mammoser & Morris D. Groves

Authors
  1. Aaron G. Mammoser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morris D. Groves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Morris D. Groves.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mammoser, A.G., Groves, M.D. Biology and Therapy of Neoplastic Meningitis. Curr Oncol Rep 12, 41–49 (2010). https://doi.org/10.1007/s11912-009-0079-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-009-0079-2

Keywords

Search

Navigation