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Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD)

Journal of Neuro-Oncology volume 142, pages 499–509 (2019)Cite this article

Abstract

Purpose

Although the survival of most melanoma patients diagnosed with leptomeningeal disease (LMD) is short, some patients can have better outcomes and prolonged survival. A large retrospective cohort of patients was analyzed to identify features associated with survival with LMD from melanoma.

Methods

Clinical characteristics, treatments and survival were collected for melanoma patients diagnosed with LMD from 1999 to 2015. The Kaplan–Meier method was used to estimate overall survival (OS) and Cox proportional hazards regression was used to test statistical significance of associations with survival. Multivariate analysis was performed using Cox proportional regression modeling.

Results

178 melanoma patients with LMD were identified. Median age at LMD diagnosis was 51 years. Most (n = 153) patients received at least one treatment for LMD, including radiation (n = 98), chemotherapy (n = 89), targeted therapy (n = 60), immunotherapy (n = 12), or intrathecal (IT) therapy (n = 64). Median OS from LMD diagnosis was 3.5 months. One-, two-, and five-year OS rates were 22%, 14%, and 9%, respectively. Factors significantly associated with OS on multivariate analysis included Eastern Cooperative Oncology Group [ECOG] performance status > 0 (HR 2.1, P < 0.0001); neurological symptoms (HR 1.6, P < 0.0001); absent systemic disease (HR 0.4, P < 0.0001); and LMD treatment (HR 0.4, P = 0.0024), targeted therapy (HR 0.6, P = 0.0060), or IT therapy (HR 0.5, P = 0.0019).

Conclusion

Despite their overall poor prognosis a subset of melanoma patients with LMD achieve longer survival. The factors associated with outcomes may be used to guide patient management and to inform the design of future clinical trials for this population.

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References

  1. Cohen JV, Tawbi H, Margolin KA, Amravadi R, Bosenberg M, Brastianos PK, Chiang VL, de Groot J, Glitza IC, Herlyn M et al (2016) Melanoma central nervous system metastases: current approaches, challenges, and opportunities. Pigment Cell Melanoma Res 29(6):627–642

    Article  Google Scholar 

  2. Glitza Oliva I, Tawbi H, Davies MA (2017) Melanoma brain metastases: current areas of investigation and future directions. Cancer J 23(1):68–74

    Article  Google Scholar 

  3. Le Rhun E, Taillibert S, Chamberlain MC (2013) Carcinomatous meningitis: leptomeningeal metastases in solid tumors. Surg Neurol Int 4(Suppl 4):S265–S288

    PubMed  PubMed Central  Google Scholar 

  4. Leal T, Chang JE, Mehta M, Robins HI (2011) Leptomeningeal metastasis: challenges in diagnosis and treatment. Curr Cancer Ther Rev 7(4):319–327

    Article  Google Scholar 

  5. Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, Hwu P, Bedikian A (2011) Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117(8):1687–1696

    Article  Google Scholar 

  6. Groves MD (2011) Leptomeningeal disease. Neurosurg Clin N Am 22(1):67–78, vii

    Article  Google Scholar 

  7. Raizer JJ, Hwu WJ, Panageas KS, Wilton A, Baldwin DE, Bailey E, von Althann C, Lamb LA, Alvarado G, Bilsky MH et al (2008) Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro Oncol 10(2):199–207

    Article  Google Scholar 

  8. Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH et al (2014) Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol 32(33):3697–3704

    CAS  Article  Google Scholar 

  9. Luke JJ, Flaherty KT, Ribas A, Long GV (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14(8):463–482

    CAS  Article  Google Scholar 

  10. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern cooperative oncology group. Am J Clin Oncol 5(6):649–655

    CAS  Article  Google Scholar 

  11. Gao D, Ma X (2017) Serum lactate dehydrogenase is a predictor of poor survival in malignant melanoma. Panminerva Med 59(4):332–337

    PubMed  Google Scholar 

  12. Egberts F, Kotthoff EM, Gerdes S, Egberts JH, Weichenthal M, Hauschild A (2012) Comparative study of YKL-40, S-100B and LDH as monitoring tools for stage IV melanoma. Eur J Cancer 48(5):695–702

    CAS  Article  Google Scholar 

  13. Davies MA, Gershenwald JE (2011) Targeted therapy for melanoma: a primer. Surg Oncol Clin N Am 20(1):165–180

    Article  Google Scholar 

  14. Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D (2017) Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol 43(3):604–611

    CAS  Article  Google Scholar 

  15. Verma S, Petrella T, Hamm C, Bak K, Charette M (2008) Melanoma disease site group of cancer care Ontario’s program in evidence-based C: biochemotherapy for the treatment of metastatic malignant melanoma: a clinical practice guideline. Curr Oncol 15(2):85–89

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Firth D (1993) Bias reduction of maximum-likelihood-estimates. Biometrika 80(1):27–38

    Article  Google Scholar 

  17. Team RC (2017) R: a language and environment for statistical computing. R foundation for statistical computing, Vienna

    Google Scholar 

  18. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133

    CAS  Article  Google Scholar 

  19. Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L et al (2017) Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18(7):863–873

    CAS  Article  Google Scholar 

  20. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L et al (2016) 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 17(7):976–983

    CAS  Article  Google Scholar 

  21. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF et al (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465

    CAS  Article  Google Scholar 

  22. Fathallah-Shaykh HM, Zimmerman C, Morgan H, Rushing E, Schold SC Jr, Unwin DH (1996) Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2: a case report. Cancer 77(8):1544–1550

    CAS  Article  Google Scholar 

  23. Glitza IC, Rohlfs M, Guha-Thakurta N, Bassett RL Jr, Bernatchez C, Diab A, Woodman SE, Yee C, Amaria RN, Patel SP et al (2018) Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. ESMO Open 3(1):e000283

    Article  Google Scholar 

  24. Samlowski WE, Park KJ, Galinsky RE, Ward JH, Schumann GB (1993) Intrathecal administration of interleukin-2 for meningeal carcinomatosis due to malignant melanoma: sequential evaluation of intracranial pressure, cerebrospinal fluid cytology, and cytokine induction. J Immunother Emphas Tumor Immunol 13(1):49–54

    CAS  Article  Google Scholar 

  25. Shonka NA, Kessinger AM, Aizenberg MR (2014) Intrathecal interleukin-2 for melanomatous meningitis. J Clin Oncol 32(33):e111–e113

    Article  Google Scholar 

  26. Geukes Foppen MH, Brandsma D, Blank CU, van Thienen JV, Haanen JB, Boogerd W (2016) Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol 27(6):1138–1142

    CAS  Article  Google Scholar 

  27. Glitza IC, Ferguson SD, Guha-Thakurta N (2017) Rapid resolution of leptomeningeal disease with targeted therapy in a metastatic melanoma patient. J Neurooncol 133(3):663–665

    Article  Google Scholar 

  28. Kim DW, Barcena E, Mehta UN, Rohlfs ML, Kumar AJ, Penas-Prado M, Kim KB (2015) Prolonged survival of a patient with metastatic leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report. BMC Cancer 15:400

    Article  Google Scholar 

  29. Floudas CS, Chandra AB, Xu Y (2016) Vemurafenib in leptomeningeal carcinomatosis from melanoma: a case report of near-complete response and prolonged survival. Melanoma Res 26(3):312–315

    CAS  Article  Google Scholar 

  30. Lee SJ, Lee JI, Nam DH, Ahn YC, Han JH, Sun JM, Ahn JS, Park K, Ahn MJ (2013) Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol 8(2):185–191

    Article  Google Scholar 

  31. Schafer N, Scheffler B, Stuplich M, Schaub C, Kebir S, Rehkamper C, Mack F, Niehusmann P, Simon M, Greschus S et al (2013) Vemurafenib for leptomeningeal melanomatosis. J Clin Oncol 31(11):e173–e174

    Article  Google Scholar 

  32. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, Martinez-Bernal G, Ferrara R, Lai WV, Hendriks LEL et al (2018) Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 36(28):2872–2878

    CAS  Article  Google Scholar 

  33. Libert C, Dejager L (2014) How steroids steer T cells. Cell Rep 7(4):938–939

    CAS  Article  Google Scholar 

  34. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10(11):1037–1044

    Article  Google Scholar 

  35. Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H (2016) Management of leptomeningeal metastases: prognostic factors and associated outcomes. J Clin Neurosci 27:130–137

    Article  Google Scholar 

  36. 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  Google Scholar 

  37. Palma JA, Fernandez-Torron R, Esteve-Belloch P, Fontes-Villalba A, Hernandez A, Fernandez-Hidalgo O, Gallego Perez-Larraya J, Martinez-Vila E (2013) Leptomeningeal carcinomatosis: prognostic value of clinical, cerebrospinal fluid, and neuroimaging features. Clin Neurol Neurosurg 115(1):19–25

    Article  Google Scholar 

  38. Bruna J, Gonzalez L, Miro J, Velasco R, Gil M, Tortosa A (2009) Neuro-oncology unit of the Institute of Biomedical Investigation of B: leptomeningeal carcinomatosis: prognostic implications of clinical and cerebrospinal fluid features. Cancer 115(2):381–389

    Article  Google Scholar 

  39. Clamon G, Doebbeling B (1987) Meningeal carcinomatosis from breast cancer: spinal cord versus brain involvement. Breast Cancer Res Treat 9(3):213–217

    CAS  Article  Google Scholar 

  40. Harstad L, Hess KR, Groves MD (2008) Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol 10(6):1010–1018

    Article  Google Scholar 

  41. Sherman AM, Jaeckle K, Meyers CA (2002) Pretreatment cognitive performance predicts survival in patients with leptomeningeal disease. Cancer 95(6):1311–1316

    Article  Google Scholar 

  42. Sampson JH, Carter JH Jr, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88(1):11–20

    CAS  Article  Google Scholar 

  43. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, Yamanaka K, Sato Y, Jokura H, Yomo S et al (2014) Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 15(4):387–395

    Article  Google Scholar 

  44. Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD (1998) Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 82(4):733–739

    CAS  Article  Google Scholar 

  45. Ballester LY, Glitza Oliva IC, Douse DY, Chen MM, Lan C, Haydu LE, Huse JT, Roy-Chowdhuri S, Luthra R, Wistuba II et al (2018) Evaluating circulating tumor DNA From the cerebrospinal fluid of patients with melanoma and leptomeningeal disease. J Neuropathol Exp Neurol 77(7):628–635

    Article  Google Scholar 

  46. Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, Omuro A, Lin X, Fleisher M, Grommes C et al (2016) Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol 34(20):2404–2415

    CAS  Article  Google Scholar 

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Acknowledgements

We thank David M. Wildrick, Ph.D., for editorial assistance.

Funding

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the AIM at Melanoma Foundation; and philanthropic support from the MD Anderson Melanoma Moon Shot Program.

Author information

Affiliations

  1. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sherise D. Ferguson, Shivani Bindal, Ian E. McCutcheon & Amy B. Heimberger

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Roland L. Bassett Jr.

  3. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lauren E. Haydu

  4. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jing Li

  5. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Barbara J. O’Brien

  6. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nandita Guha-Thakurta

  7. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael T. Tetzlaff

  8. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hussein Tawbi, Michael A. Davies & Isabella C. Glitza

  9. The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, 77030, Houston, TX, USA

    Sherise D. Ferguson

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  1. Sherise D. Ferguson
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  2. Shivani Bindal
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Corresponding author

Correspondence to Sherise D. Ferguson.

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Conflict of interest

Dr. Davies has served on the advisory boards for BMS, Norvartis, Roche/Genetech, GSK, Sanofi-Aventis, Vaccinex and Syndax and has been the PI of institution grants from BMS, Astrzeneca, GSK, Roche/Genetech, Myriad and Oncothyreon. Dr. Tetzlaff has advisory board relationships with Novartis, Myriad and Seattle Genetics.

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Ferguson, S.D., Bindal, S., Bassett, R.L. et al. Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD). J Neurooncol 142, 499–509 (2019). https://doi.org/10.1007/s11060-019-03121-2

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  • DOI: https://doi.org/10.1007/s11060-019-03121-2

Keywords

  • Melanoma
  • Leptomeningeal disease
  • Intrathecal therapy
  • Targeted therapy
  • Immunotherapy