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Treatment Options for Leptomeningeal Metastases of Solid Cancers: Literature Review and Personal Experience

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Gamma Knife Neurosurgery in the Management of Intracranial Disorders II

Part of the book series: Acta Neurochirurgica Supplement ((NEUROCHIRURGICA,volume 128))

Abstract

Leptomeningeal metastases (LM) may complicate the clinical course of any solid cancer or hematological malignancy. Diagnosis of such cases requires a multifaceted approach, including careful evaluation of the clinical history, detailed neurological examination, advanced imaging studies, and related laboratory data analysis. Therapeutic options for management of LM have not been standardized yet. Conventional intrathecal chemotherapy with or without involved-field fractionated radiotherapy has only modest efficacy, and the prognosis of most patients remains grim. Therefore, development of new, more aggressive multimodal treatment strategies is definitely needed. Immune checkpoint inhibitors—in particular, molecular targeted therapy—have demonstrated promising results in selected groups of patients. There may be an important role for stereotactic radiosurgery as well. Because organization of prospective randomized multi-institutional trials on treatment of LM of solid cancers may be problematic, practical guidelines for optimal therapeutic strategies in such cases should be established on the basis of integrated results of small-scale prospective and retrospective studies.

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References

  1. Chamberlain MC. Neoplastic meningitis. Oncologist. 2008;13:967–77.

    Article  Google Scholar 

  2. 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(Suppl 2):S35–45.

    Article  Google Scholar 

  3. Shapiro WR, Johanson CE, Boogerd W. Treatment modalities for leptomeningeal metastases. Semin Oncol. 2009;36(Suppl 2):S46–54.

    Article  CAS  Google Scholar 

  4. Chamberlain M, Soffietti R, Raizer J, Rudà R, Brandsma D, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Junck L, van den Bent M, Wen PY, Jaeckle KA. Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro Oncol. 2014;16:1176–85.

    Google Scholar 

  5. Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ. Leptomeningeal metastasis: clinical experience of 519 cases. Eur J Cancer. 2016;56:107–14.

    Article  Google Scholar 

  6. Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer. 1998;82:733–9.

    Article  CAS  Google Scholar 

  7. Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology. 1979;29:1369–75.

    Article  CAS  Google Scholar 

  8. van Oostenbrugge RJ, Twijnstra A. Presenting features and value of diagnostic procedures in leptomeningeal metastases. Neurology. 1999;53:382–5.

    Article  Google Scholar 

  9. Malkin MG, Posner JB. Cerebrospinal fluid tumor markers for the diagnosis and management of leptomeningeal metastases. Eur J Cancer Clin Oncol. 1987;23:1–4.

    Article  CAS  Google Scholar 

  10. Dearnaley DP, Patel S, Powles TJ, Coombes RC. Carcinoembryonic antigen estimation in cerebrospinal fluid in patients with metastatic breast cancer. Oncodev Biol Med. 1981;2:305–11.

    CAS  PubMed  Google Scholar 

  11. Wasserstrom WR, Schwartz MK, Fleisher M, Posner JB. Cerebrospinal fluid biochemical markers in central nervous system tumors: a review. Ann Clin Lab Sci. 1981;11:239–51.

    CAS  PubMed  Google Scholar 

  12. Kang SJ, Kim KS, Ha YS, Huh SY, Lee JH, Kim JK, Kim MJ. Diagnostic value of cerebrospinal fluid level of carcinoembryonic antigen in patients with leptomeningeal carcinomatous metastasis. J Clin Neurol. 2010;6:33–7.

    Article  Google Scholar 

  13. Groves MD, Hess KR, Puduvalli VK, Colman H, Conrad CA, Gilbert MR, Weinberg J, Cristofanilli M, Yung WK, Liu TJ. 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;94:229–34.

    Google Scholar 

  14. Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, Liu CM, DeAngelis LM, Omuro A. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology. 2013;80:1598–605.

    Article  Google Scholar 

  15. Milojkovic Kerklaan B, Pluim D, Bol M, Hofland I, Westerga J, van Tinteren H, Beijnen JH, Boogerd W, Schellens JH, Brandsma D. EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors. Neuro Oncol. 2016;18:855–62.

    Google Scholar 

  16. Ma C, Lv Y, Jiang R, Li J, Wang B, Sun L. Novel method for the detection and quantification of malignant cells in the CSF of patients with leptomeningeal metastasis of lung cancer. Oncol Lett. 2016;11:619–23.

    Article  CAS  Google Scholar 

  17. Pan Z, Yang G, He H, Zhao G, Yuan T, Li Y, Shi W, Gao P, Dong L, Li Y. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: a prospective and single-arm study. Int J Cancer. 2016;139:1864–72.

    Article  CAS  Google Scholar 

  18. Leal T, Chang JE, Mehta M, Robins HI. Leptomeningeal metastasis: challenges in diagnosis and treatment. Curr Cancer Ther Rev. 2011;7:319–27.

    Article  Google Scholar 

  19. Nagano T, Kotani Y, Kobayashi K, Hatakeyama Y, Hori S, Kasai D, Funada Y, Nishimura H, Kondoh T, Nishimura Y. Long-term outcome after multidisciplinary approach for leptomeningeal carcinomatosis in a non–small cell lung cancer patient with poor performance status. Intern Med. 2011;50:3019–22.

    Article  Google Scholar 

  20. Hermann B, Hültenschmidt B, Sautter-Bihl ML. Radiotherapy of the neuroaxis for palliative treatment of leptomeningeal carcinomatosis. Strahlenther Onkol. 2001;177:195–9.

    Article  CAS  Google Scholar 

  21. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483–91.

    Article  CAS  Google Scholar 

  22. Jo KI, Lim DH, Kim ST, Im YS, Kong DS, Seol HJ, Nam DH, Lee JI. Leptomeningeal seeding in patients with brain metastases treated by Gamma Knife radiosurgery. J Neurooncol. 2012;109:293–9.

    Google Scholar 

  23. Fogarty GB, Hong A, Gondi V, Burmeister B, Jacobsen K, Lo S, Paton E, Shivalingam B, Thompson JF. Debate: adjuvant whole brain radiotherapy or not? More data is the wiser choice. BMC Cancer. 2016;16:372.

    Article  Google Scholar 

  24. Kocher M, Wittig A, Piroth MD, Treuer H, Seegenschmiedt H, Ruge M, Grosu AL, Guckenberger M. Stereotactic radiosurgery for treatment of brain metastases: a report of the DEGRO Working Group on Stereotactic Radiotherapy. Strahlenther Onkol. 2014;190:521–32.

    Article  Google Scholar 

  25. Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, Shaw P, Beyene J, Chang EL. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2015;91:710–7.

    Google Scholar 

  26. Sahgal A, Larson D, Knisely J. Stereotactic radiosurgery alone for brain metastases. Lancet Oncol. 2015;16:249–50.

    Article  Google Scholar 

  27. Bertke MH, Burton EC, Shaughnessy JN. Stereotactic radiosurgery as part of multimodal treatment in a bulky leptomeningeal recurrence of breast cancer. Cureus. 2016;8(3):e523.

    PubMed  PubMed Central  Google Scholar 

  28. Lekovic G, Drazin D, Mak AC, Schwartz MS. CyberKnife radiosurgery and concurrent intrathecal chemotherapy for leptomeningeal metastases: case report of prolonged survival of a HER-2+ breast cancer patient status-post craniospinal irradiation. Cureus. 2016;8(1):e453.

    PubMed  PubMed Central  Google Scholar 

  29. Atalar B, Modlin LA, Choi CY, Adler JR, Gibbs IC, Chang SD, Harsh GR 4th, Li G, Nagpal S, Hanlon A, Soltys SG. Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2013;87:713–8.

    Article  Google Scholar 

  30. Chung SY, Chang JH, Kim HR, Cho BC, Lee CG, Suh CO. Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study. Radiat Oncol J. 2017;35(2):153–62.

    Article  Google Scholar 

  31. Huang AJ, Huang KE, Page BR, Ayala-Peacock DN, Lucas JT Jr, Lesser GJ, Laxton AW, Tatter SB, Chan MD. Risk factors for leptomeningeal carcinomatosis in patients with brain metastases who have previously undergone stereotactic radiosurgery. J Neurooncol. 2014;120:163–9.

    Google Scholar 

  32. Johnson MD, Avkshtol V, Baschnagel AM, Meyer K, Ye H, Grills IS, Chen PY, Maitz A, Olson RE, Pieper DR, Krauss DJ. Surgical resection of brain metastases and the risk of leptomeningeal recurrence in patients treated with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2016;94:537–43.

    Article  Google Scholar 

  33. Lamba N, Muskens IS, DiRisio AC, Meijer L, Briceno V, Edrees H, Aslam B, Minhas S, Verhoeff JJC, Kleynen CE, Smith TR, Mekary RA, Broekman ML. Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis. Radiat Oncol. 2017;12:106.

    Article  Google Scholar 

  34. Ojerholm E, Lee JY, Thawani JP, Miller D, O'Rourke DM, Dorsey JF, Geiger GA, Nagda S, Kolker JD, Lustig RA, Alonso-Basanta M. Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis. J Neurosurg. 2014;121(Suppl):75–83.

    Article  Google Scholar 

  35. Soffietti R, Rudà R, Trakul N, Chang EL. Point/counterpoint: is stereotactic radiosurgery needed following resection of brain metastasis? Neuro Oncol. 2016;18:12–5.

    Google Scholar 

  36. Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, Greenspoon J, Parney IF, Laack NNI, Ashman JB, Bahary JP, Hadjipanayis CG, Urbanic JJ, Barker FG 2nd, Farace E, Khuntia D, Giannini C, Buckner JC, Galanis E, Roberge D. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:1049–60.

    Google Scholar 

  37. Asher AL, Burri SH, Wiggins WF, Kelly RP, Boltes MO, Mehrlich M, Norton HJ, Fraser RW. A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys. 2014;88:899–906.

    Article  Google Scholar 

  38. Doré M, Martin S, Delpon G, Clément K, Campion L, Thillays F. Stereotactic radiotherapy following surgery for brain metastasis: predictive factors for local control and radionecrosis. Cancer Radiother. 2017;21:4–9.

    Article  Google Scholar 

  39. Patel KR, Burri SH, Asher AL, Crocker IR, Fraser RW, Zhang C, Chen Z, Kandula S, Zhong J, Press RH, Olson JJ, Oyesiku NM, Wait SD, Curran WJ, Shu HK, Prabhu RS. Comparing preoperative with postoperative stereotactic radiosurgery for resectable brain metastases: a multi-institutional analysis. Neurosurgery. 2016;79:279–85.

    Article  Google Scholar 

  40. Patel KR, Burri SH, Boselli D, Symanowski JT, Asher AL, Sumrall A, Fraser RW, Press RH, Zhong J, Cassidy RJ, Olson JJ, Curran WJ, Shu HG, Crocker IR, Prabhu RS. Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi-institutional analysis. J Neurooncol. 2017;131:611–8.

    Google Scholar 

  41. Smalley KS, Fedorenko IV, Kenchappa RS, Sahebjam S, Forsyth PA. Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer. 2016;139:1195–201.

    Article  CAS  Google Scholar 

  42. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–83.

    Google Scholar 

  43. Bot I, Blank CU, Brandsma D. Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. J Neurol. 2012;259:1976–8.

    Article  CAS  Google Scholar 

  44. Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, Horita N, Segawa Y, Hamada N, Takata I, Yamane H, Kamei H, Kiura K, Tanimoto M. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012;77:134–9.

    Article  Google Scholar 

  45. Deng Y, Feng W, Wu J, Chen Z, Tang Y, Zhang H, Liang J, Xian H, Zhang S. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol. 2014;2:116–20.

    Article  CAS  Google Scholar 

  46. Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, Sakamori Y, Nagai H, Kim YH, Katsura T, Mishima M. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non–small cell lung cancer. Cancer Chemother Pharmacol. 2012;70:399–405.

    Article  CAS  Google Scholar 

  47. Bui N, Woodward B, Johnson A, Husain H. Novel treatment strategies for brain metastases in non-small-cell lung cancer. Curr Treat Options in Oncol. 2016;17:25.

    Article  Google Scholar 

  48. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol. 2000;18:2349–51.

    Article  CAS  Google Scholar 

  49. Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs. 2007;18:23–8.

    Google Scholar 

  50. Zagouri F, Sergentanis TN, Bartsch R, Berghoff AS, Chrysikos D, de Azambuja E, Dimopoulos MA, Preusser M. 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;139:13–22.

    Article  CAS  Google Scholar 

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Correspondence to Takeshi Kondoh .

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Kondoh, T., Sonoda, T. (2021). Treatment Options for Leptomeningeal Metastases of Solid Cancers: Literature Review and Personal Experience. In: Chernov, M.F., Hayashi, M., Chen, C.C., McCutcheon, I.E. (eds) Gamma Knife Neurosurgery in the Management of Intracranial Disorders II. Acta Neurochirurgica Supplement, vol 128. Springer, Cham. https://doi.org/10.1007/978-3-030-69217-9_8

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  • DOI: https://doi.org/10.1007/978-3-030-69217-9_8

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