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Leptomeningeal metastases: the future is now

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Abstract

Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed. This is to provide context for how the field of LM management may evolve in the near term. The future directions currently undergoing investigation for diagnostic, response assessment, and therapeutic purposes are highlighted. This is done within the context of the pathophysiology of the disease. Specifically the role of CSF circulating tumor cells and cell free circulating tumor DNA in diagnosis and response assement are reviewed. Novel therapeutic approaches across a range of modalities are discussed. Numerous ongoing studies which have the potential to alter the management of LM are referenced.

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References

  1. Thakkar JP, Kumthekar P, Dixit KS, Stupp R, Lukas RV (2020) Leptomeningeal metastasis from solid tumors. J Neurol Sci 411:116706

    Article  PubMed  Google Scholar 

  2. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM (2010) Leptomeningeal metastases in the MRI era. Neurology 74(18):1449–1454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ (2016) Leptomeningeal metastasis: clinical experience of 519 cases. Eur J Cancer 56:107–114

    Article  PubMed  Google Scholar 

  4. Glass JP, Melamed M, Chernik NL, Posner JB (1979) Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 29(10):1369–1375

    Article  CAS  PubMed  Google Scholar 

  5. Lamba N, Wen PY, Aizer AA (2021) Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol 23(9):1447–1456

    Article  PubMed  Google Scholar 

  6. Le Ruhn E, Weller M, Brandsma D et al (2017) EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up of patients with leptomeningeal metastasis from solid tumors. Ann Oncol 28(Suppl_4):iv84–iv99

    Google Scholar 

  7. Chamberlain M, Junck L, Brandsma D et al (2017) Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol 19(4):484–492

    PubMed  Google Scholar 

  8. Nevel KS, DiStefano N, Lin X et al (2020) A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer. Neuro Oncol 22(5):675–683

    Article  CAS  PubMed  Google Scholar 

  9. Le Ruhn E, Devos P, Boulanger T et al (2019) The RANO leptomeningeal metastasis group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro Oncol 21(5):648–658

    Article  Google Scholar 

  10. Chamberlian MS, Kormanik PA, Glantz MJ (2001) A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro Oncol 3(1):42–45

    Google Scholar 

  11. Weller M, Le Ruhn E (2020) 40. An update on the development of a new tool to assess response in leptomeningeal metastasis. Neuro Oncol Adv 2(Suppl2):ii7

    Article  Google Scholar 

  12. Boire A, Brandsma D, Brastianos PK et al (2019) Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications. Neuro Oncol 21(5):571–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Van Bussel MTJ, Pluim D, Milojkovic Kerklaan B et al (2020) Circulating epithelial cell analysis in CSF in patients with leptomeningeal metastases. Neurology 94(5):e521–e528

    Article  PubMed  Google Scholar 

  14. Angus L, Deger T, Jager A, et al (2021) Detection of aneuploidy in cerebrospinal fluid from patients with breast cancer can improve diagnosis of leptomeningeal metastases. Clin Cancer Res. [EPub ahead of print]

  15. Sperduto PW, Mesko S, Li J et al (2020) Survival in patients with brain metastases: summary report of the updated diagnosis-specific graded prognostic assessment and definition of the eligibility quotient. J Clin Oncol 38(32):3773–3784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Murakami Y, Ichikawa M, Bakhit M et al (2018) Palliative shunt surgery for patients with leptomeningeal metastases. Clin Neurol Neurosurg 168:175–178

    Article  PubMed  Google Scholar 

  17. Lee SH, Kong DS, Seol HJ, Nam DH, Lee JI (2011) Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis. J Neurooncol 104(2):545–551

    Article  PubMed  Google Scholar 

  18. Jung TY, Chung WK, Oh IJ (2014) The prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases. Clin Neurol Neurosurg 119:80–83

    Article  PubMed  Google Scholar 

  19. Yang JCH, Kim SW, Kim DW et al (2020) Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the BLOOM study. J Clin Oncol 38(6):538–547

    Article  CAS  PubMed  Google Scholar 

  20. Park S, Lee MH, Seong M et al (2020) A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 31(10):1397–1404

    Article  CAS  PubMed  Google Scholar 

  21. Morikawa A, de Stanchina E, Pentsova E et al (2019) Phase I study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases. Clin Cancer Res 25(13):3784–3792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lassman AB, Abrey LE, Shah GD et al (2006) Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol 78(3):255–260

    Article  CAS  PubMed  Google Scholar 

  23. Mrugala MM, Kim B, Sharma A et al (2019) Phase II study of systemic high-dose methotrexate and intrathecal liposomal cytarabine for treatment of leptomeningeal carcinomatosis from breast cancer. Clin Breast Cancer 19(5):311–316

    Article  CAS  PubMed  Google Scholar 

  24. Kumthekar P, Grimm SA, Avram MJ et al (2013) Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases. J Neurooncol 112(2):247–255

    Article  CAS  PubMed  Google Scholar 

  25. Burger MC, Wagner M, Franz K et al (2018) Ventriculoperitoneal shunts equipped with on-off valves for intraventricular therapies in patients with communicating hydrocephalus due to leptomeningeal metastases. J Clin Med 7(8):216

    Article  PubMed Central  Google Scholar 

  26. Groves MD, Glantz MJ, Chamberlain MC et al (2008) A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 10(2):208–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blaney SM, Heideman R, Berg S et al (2003) Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 21(1):143–147

    Article  CAS  PubMed  Google Scholar 

  28. Chamberlain MC, Tsao-Wei DD, Groshen S et al (2006) Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 106(9):2021–2027

    Article  CAS  PubMed  Google Scholar 

  29. Fan C, Zhao Q, Li L et al (2021) Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating tyrosine kinase inhibitor-failed leptoeningeal metastases from EGFR-mutant NSCLC, a prospective, open-label, single-arm phase 1/2 clinical trial (Unique identifier: ChiCTR1800016615). J Thorac Oncol 16(8):1359–1368

    Article  CAS  PubMed  Google Scholar 

  30. Glantz MJ, Jaeckle KA, Chamberlain MC et al (1999) A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5(11):3394–3402

    CAS  PubMed  Google Scholar 

  31. Perissinotti AJ, Reeves DJ (2010) Role of intrathecal rituximab and trastuzumab in the management of leptomeningeal carcinomatosis. Ann Pharmacother 44(10):1633–1640

    Article  CAS  PubMed  Google Scholar 

  32. Figura NB, Long W, Yu M et al (2018) Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience. Breast Cancer Res Treat 169(2):391–396

    Article  CAS  PubMed  Google Scholar 

  33. Bonneau C, Paintaud G, Tredan O et al (2018) Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis. Eur J Cancer 95:75–84

    Article  CAS  PubMed  Google Scholar 

  34. Park WY, Kim HJ, Kim K et al (2016) Intrathecal trastuzumab treatment in patients with breast cancer and leptomeningeal carcinomatosis. Cancer Res Treat 48(2):843–847

    Article  CAS  PubMed  Google Scholar 

  35. Mir O, Ropert S, Alexandre J, Lemare F, Goldwasser F (2008) High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer. Ann Oncol 19(11):1978–1980

    Article  CAS  PubMed  Google Scholar 

  36. Law V, Baldwin M, Ramamoorthi G, et al (2021) A murine Ommya xenograft model to study direct-targeted therapy of leptomeningeal disease. J Vis Exp. (167)

  37. Shapiro WR, Young DF, Posner JB (1975) Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293(4):161–166

    Article  CAS  PubMed  Google Scholar 

  38. de Oca M, Delgado M, Cacho Diaz B, Santos Zambrano J et al (2018) The comparative treatment of intraventricular chemotherapy vs lumbar puncture in patients with leptomeningeal carcinomatosis. Front Oncol 8:509

    Article  Google Scholar 

  39. El Shafie RA, Bohm K, Weber D et al (2018) Palliative radiotherapy for leptomeningeal carcinomatosis-analysis of outcome, prognostic factors, and symptom response. Front Oncol 8:641

    Article  PubMed  Google Scholar 

  40. Lai R, Abrey LE, Rosenblum MK, DeAngelis LM (2004) Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 62(3):451–456

    Article  PubMed  Google Scholar 

  41. Yang TJ, Wijetunga NA, Yamada J et al (2020) Clinical trial of proton craniospinal irradiation for leptomeningeal metastases. Neuro Oncol 23(1):134–143

    Article  PubMed Central  Google Scholar 

  42. Ron DA, Labandeira CM, Manrique MCA, et al. Dramatic response of leptomeningeal carcinomatosis to nivolumab in PD-L1 highly expressive non-small cell lung cancer: a case report. Front Oncol. 20

  43. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133(3421):571–573

    Article  Google Scholar 

  44. Remsik J, Chi Y, Tong X, et al (2020) Leptomeningeal metastatic cells adopt two phenotypic states. Cancer Rep. e1236

  45. Raizer J, Pentsova E, Omuro A, et al (2014) Phase 1 tria of intrathecal trastuzumab in HER2 positive leptomeningeal metastases. AT-47. Neuro Onco. 16(Supp 5):v19

  46. Reijneveld JC, Brandsma D, Boogerd W et al (2005) CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases. Neurology 65(7):1120–1122

    Article  CAS  PubMed  Google Scholar 

  47. Smalley I, Law V, Wyatt C et al (2020) Proteomic analysis of CSF from patients with leptomeningeal melanoma metastases identifies signatures associated with disease progression and therapeutic resistance. Clin Cancer Res 26(9):2163–2175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chi Y, Remsik J, Kiseliovas V et al (2020) Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 369(6501):276–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Boire A, Zou Y, Shieh J, Macalinao DG, Pentsova E, Massague J (2017) Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 168(6):1101-1113.e13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Malani R, Fleischer M, Kumthekar P et al (2020) Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. J Neurooncol 148(3):599–606

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jiang BY, Li YS, Guo WB et al (2017) Detection of driver and resistance mutations in leptomeningeal metastases of NSCLC by next –generation sequencing of cerebrospinal fluid circulating tumor cells. Clin Cancer Res 23(18):5480–5488

    Article  CAS  PubMed  Google Scholar 

  52. Lin X, Fleisher M, Rosenblum M et al (2017) Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro Oncol 19(9):1248–1254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wijetunga NA, Boire AA, Yamada Y et al (2021) Cerebrospinal fluid circulating tumor cells as a predictive biomarker for proton craniospinal irradiation for leptomeningeal metastases. J Clin Oncol 39(15_suppl):2011

    Article  Google Scholar 

  54. Bale TA, Yang SR, Solomon JP et al (2021) Clinical experience of cerebrospinal fluid –based liquid biopsy demonstrates superiority of cell-free DNA over cell-pellet genomic DNA for molecular profiling. J Mol Diagn S1525–1578(21):00065–00069

    Google Scholar 

  55. Zheng MM, Li YS, Tu HY et al (2021) Genotyping of cerebrospinal fluid associated with osimertinib response and resistance for leptomeningeal metastases in EGFR-mutated NSCLC. J Thorac Oncol 16(2):250–258

    Article  CAS  PubMed  Google Scholar 

  56. Kumthekar P, Tang SC, Brenner AJ et al (2020) ANG1005, a brain penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and brain metastases. Clin Cancer Res 26(12):2789–2799

    Article  CAS  PubMed  Google Scholar 

  57. Tawbi HA, Forsyth PA, Algazi A et al (2018) Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 379(8):722–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gadgeel SM, Lukas RV, Goldschmidt J et al (2019) Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. Lung Cancer 128:105–112

    Article  PubMed  Google Scholar 

  59. Goldeberg SB, Schalper KA, Gettinger SN et al (2020) Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysisfrom a non-randomised, open-label, phase 2 trial. Lancet Oncol 21(5):655–663

    Article  Google Scholar 

  60. Brastianos PK, Lee EQ, Cohen JV et al (2020) Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Nat Med 26(8):1280–1284

    Article  CAS  PubMed  Google Scholar 

  61. Dudnik E, Yust-Katz S, Nechushtan H et al (2016) Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer 98:114–117

    Article  PubMed  Google Scholar 

  62. Bonomi L, Bettini AC, Arnoldi E, et al (2020) Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report. Tumori. 106(6):NP76-NP78

  63. Lum LG, Thakur A, Al-Kadhimi Z et al (2015) Targted T-cell therapy in stage IV breast cancer: a phase I clinical trial. Clin Cancer Res 21(10):2305–2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murthy RK, Loi S, Okines A et al (2020) Tucatinib, trastuzumab, and capecitabine for HER1-positive metastatic breast cancer. N Engl J Med 382:597–609

    Article  CAS  PubMed  Google Scholar 

  65. Kanojia D, Panek WK, Cordero A et al (2020) BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine. Sci Transl Med. 12(558):eaax2879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Soria JC, Ohe Y, Vansteenkiste Y (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113–125

    Article  CAS  PubMed  Google Scholar 

  67. Teh HS, Fadilah SA, Leong CF (2007) Transverse myelopathy following intrathecal administration of chemotherapy. Singapore Med J 48(2):e46–e49

    CAS  PubMed  Google Scholar 

  68. Tariq H, Gilbert A, Sharkey FE (2018) Intrathecal Methotrexate-Induced Necrotizing Myelopathy: A Case Report and Review of Histologic Features. Clin Med Insights Pathol 11:1179555718809071

    Article  PubMed  PubMed Central  Google Scholar 

  69. Chamberlain MC (2012) Neurotoxicity of intra-CSF liposomal cytarabine (DepoCyt) administered for the treatment of leptomeningeal metastases: a retrospective case series. J Neurooncol 109(1):143–148

    Article  CAS  PubMed  Google Scholar 

  70. Byrnes DM, Vargas F, Dermarkarian C et al (2019) Complications of intrathecal chemotherapy in adults: single-institution experience in 109 consecutive patients. J Oncol 2019:4047617

    Article  PubMed  PubMed Central  Google Scholar 

  71. Olmos-Jimenez R, Diaz-Carrasco MS, Cabanas-Perianes V, Valderrey-Pulido M, Espuny-Miro A (2017) Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients. Farm Hosp 41(5):611–617

    PubMed  Google Scholar 

  72. Kim JY, Kim ST, Nam DH, Lee JI, Park K, Kong DS (2011) Leukoencephalopathy and disseminated necrotizing leukoencephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia. J Korean Neurosurg Soc 50(4):304–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Boogerd W, vd Sande JJ, Moffie D, (1988) Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate. J Neurol Neurosurg Psychiatry 51(10):1277–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Northwestern University, Chicago, United States

    Rimas V. Lukas, Priya Kumthekar & Roger Stupp

  2. Lou & Jean Malnati Brain Tumor Institute, Chicago, USA

    Rimas V. Lukas, Priya Kumthekar, Roger Stupp & Maciej S. Lesniak

  3. Department of Neurological Surgery, Chicago, USA

    Roger Stupp & Maciej S. Lesniak

  4. Section of Hematology & Oncology, Chicago, USA

    Massimo Cristofanilli, Sunandana Chandra, Jeffrey A. Sosman & Jyoti D. Patel

  5. Department of Neurology, Loyola University, Maywood, USA

    Jigisha P. Thakkar

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  1. Rimas V. Lukas
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Lukas, R.V., Thakkar, J.P., Cristofanilli, M. et al. Leptomeningeal metastases: the future is now. J Neurooncol 156, 443–452 (2022). https://doi.org/10.1007/s11060-021-03924-2

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