Skip to main content

Advertisement

SpringerLink
Log in

Systemic Therapy for Melanoma Brain and Leptomeningeal Metastases

  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Melanoma has a high propensity to metastasize to the brain which portends a poorer prognosis. With advanced radiation techniques and targeted therapies, outcomes however are improving. Melanoma brain metastases are best managed in a multi-disciplinary approach, including medical oncologists, neuro-oncologists, radiation oncologists, and neurosurgeons. The sequence of therapies is dependent on the number and size of brain metastases, status of systemic disease control, prior therapies, performance status, and neurological symptoms. The goal of treatment is to minimize neurologic morbidity and prolong both progression free and overall survival while maximizing quality of life. Surgery should be considered for solitary metastases, or large and/or symptomatic metastases with edema. Stereotactic radiosurgery offers a benefit over whole-brain radiation attributed to the relative radioresistance of melanoma and reduction in neurotoxicity. Thus far, data supports a more durable response with systemic therapy using combination immunotherapy of ipilimumab and nivolumab, though targeting the presence of BRAF mutations can also be utilized. BRAF inhibitor therapy is often used after immunotherapy failure, unless a more rapid initial response is needed and then can be done prior to initiating immunotherapy. Further trials are needed, particularly for leptomeningeal metastases which currently require the multi-disciplinary approach to determine best treatment plan.

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

Similar content being viewed by others

References and Recommended Reading

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

  1. Saginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. Epidemiology of melanoma. Med Sci. 2021;9(4):63. https://doi.org/10.3390/medsci9040063.

    Article  CAS  Google Scholar 

  2. Sloan E, Nock CJ, Einstein DB. Diagnosis and treatment of mela-noma brain metastasis: a literature review. Cancer Control. 2009;16(3):248–55. https://doi.org/10.1177/107327480901600307.

    Article  PubMed  Google Scholar 

  3. Cagney DN, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511–21. https://doi.org/10.1093/neuonc/nox077.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vosoughi E, Lee JM, Miller JR, et al. Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies. BMC Cancer. 2018;18(1):490. https://doi.org/10.1186/s12885-018-4374-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wolfram M, Samlowski E, Julian M, Wu K. Management of brain metastases in melanoma. UpToDate Website

  6. Steininger J, et al. Leptomeningeal metastases in melanoma patients: an update on and future perspectives for diagnosis and treatment. Int J Mol Sci. 2023;24(14):11443. https://doi.org/10.3390/ijms241411443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Le Rhun E, et al. EANO–ESMO clinical practice guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017;28:iv84–99. https://doi.org/10.1093/annonc/mdx221.

    Article  PubMed  Google Scholar 

  8. Khaled ML, Tarhini AA, Forsyth PA, Smalley I, Piña Y. Leptomeningeal disease (LMD) in patients with melanoma metastases. Cancers (Basel). 2023;15(6):1884. https://doi.org/10.3390/cancers15061884.

    Article  CAS  PubMed  Google Scholar 

  9. Akbani R, et al. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96. https://doi.org/10.1016/j.cell.2015.05.044.

    Article  CAS  Google Scholar 

  10. Jakob JA, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118(16):4014–23. https://doi.org/10.1002/cncr.26724.

    Article  CAS  PubMed  Google Scholar 

  11. Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54. https://doi.org/10.1038/nature00766.

    Article  CAS  PubMed  Google Scholar 

  12. Curtin JA, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47. https://doi.org/10.1056/NEJMoa050092.

    Article  CAS  PubMed  Google Scholar 

  13. Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016;8(1):48–56. https://doi.org/10.1177/1758834015616934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sosman JA, et al. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14. https://doi.org/10.1056/NEJMoa1112302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Subbiah V, Baik C, Kirkwood JM. Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer. 2020;6(9):797–810. https://doi.org/10.1016/j.trecan.2020.05.009.

    Article  CAS  PubMed  Google Scholar 

  16. Harding JJ, et al. A retrospective evaluation of vemurafenib as treatment for BRAF-mutant melanoma brain metastases. Oncologist. 2015;20(7):789–97. https://doi.org/10.1634/theoncologist.2014-0012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gorka E, Fabó D, Gézsi A, Czirbesz K, Fedorcsák I, Liszkay G. Dabrafenib therapy in 30 patients with melanoma metastatic to the brain: a single-centre controlled retrospective study in Hungary. Pathol Oncol Res. 2018;24(2):401–6. https://doi.org/10.1007/s12253-017-0256-9.

    Article  CAS  PubMed  Google Scholar 

  18. Dzienis MR, Atkinson VG. Response rate to vemurafenib in patients with B-RAF-positive melanoma brain metastases. Melanoma Res. 2014;24(4):349–53. https://doi.org/10.1097/CMR.0000000000000068.

    Article  CAS  PubMed  Google Scholar 

  19. Martin-Algarra S, et al. Effectiveness of dabrafenib in the treatment of patients with BRAF V600–mutated metastatic melanoma in a Named Patient Program. Melanoma Res. 2019;29(5):527–32. https://doi.org/10.1097/CMR.0000000000000608.

    Article  CAS  PubMed  Google Scholar 

  20. Long GV, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–95. https://doi.org/10.1016/S1470-2045(12)70431-X.

    Article  CAS  PubMed  Google Scholar 

  21. Hauschild, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65. https://doi.org/10.1016/S0140-6736(12)60868-X.

    Article  CAS  PubMed  Google Scholar 

  22. Flaherty KT, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703. https://doi.org/10.1056/NEJMoa1210093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. GeukesFoppen MH, Boogerd W, Blank CU, van Thienen JV, Haanen JB, Brandsma D. Clinical and radiological response of BRAF inhibition and MEK inhibition in patients with brain metastases from BRAF-mutated melanoma. Melanoma Res. 2018;28(2):126–33. https://doi.org/10.1097/CMR.0000000000000429.

    Article  CAS  Google Scholar 

  24. Drago JZ, et al. Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. Melanoma Res. 2019;29(1):65–9. https://doi.org/10.1097/CMR.0000000000000527.

    Article  CAS  PubMed  Google Scholar 

  25. Holbrook K, et al. Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: a case series. Cancer. 2020;126(3):523–30. https://doi.org/10.1002/cncr.32547.

    Article  CAS  PubMed  Google Scholar 

  26. Long GV, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51. https://doi.org/10.1016/S0140-6736(15)60898-4.

    Article  CAS  PubMed  Google Scholar 

  27. Robert C, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9. https://doi.org/10.1056/NEJMoa1412690.

    Article  CAS  PubMed  Google Scholar 

  28. Davies MA, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863–73. https://doi.org/10.1016/S1470-2045(17)30429-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dummer R, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF -mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15. https://doi.org/10.1016/S1470-2045(18)30142-6.

    Article  CAS  PubMed  Google Scholar 

  30. R. Team. Encorafenib (Braftovi) in combination with binimetinib (Mektovi). Can J Health Technol. 2021;1(7):1. https://doi.org/10.51731/cjht.2021.107.

    Article  Google Scholar 

  31. Ahmed KA, et al. LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases. J Neurooncol. 2015;122(1):121–6. https://doi.org/10.1007/s11060-014-1685-x.

    Article  CAS  PubMed  Google Scholar 

  32. Larkin J, et al. Combined vemurafenib and cobimetinib in BRAF -mutated melanoma. N Engl J Med. 2014;371(20):1867–76. https://doi.org/10.1056/NEJMoa1408868.

    Article  CAS  PubMed  Google Scholar 

  33. Ascierto PA, et al. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol. 2023;24(1):33–44. https://doi.org/10.1016/S1470-2045(22)00687-8.

    Article  CAS  PubMed  Google Scholar 

  34. Cai C, Yunusa I, Tarhini A. Estimated cost-effectiveness of atezolizumab plus cobimetinib and vemurafenib for treatment of BRAF V600 variation metastatic melanoma. JAMA Netw Open. 2021;4(11): e2132262. https://doi.org/10.1001/jamanetworkopen.2021.32262.

    Article  PubMed  PubMed Central  Google Scholar 

  35. • Dummer R, et al. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2023. https://doi.org/10.1016/S1470-2045(23)00334-0. This study demonstrated that triplet combination therapy with atezolizumab plus vemurafenib plus cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma and CNS metastases.

  36. Long GV, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672–81. https://doi.org/10.1016/S1470-2045(18)30139-6.

    Article  CAS  PubMed  Google Scholar 

  37. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Margolin K, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65. https://doi.org/10.1016/S1470-2045(12)70090-6.

    Article  CAS  PubMed  Google Scholar 

  39. Kluger HM, et al. Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial. J Clin Oncol. 2019;37(1):52–60. https://doi.org/10.1200/JCO.18.00204.

    Article  CAS  PubMed  Google Scholar 

  40. Goldberg SB, et al. 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(7):976–83. https://doi.org/10.1016/S1470-2045(16)30053-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kethireddy N, Thomas S, Bindal P, Shukla P, Hegde U. Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. J Oncol Pharm Pract. 2021;27(1):207–11. https://doi.org/10.1177/1078155220921543.

    Article  CAS  PubMed  Google Scholar 

  42. Long GV, et al. Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol. 2021;39(15_suppl):9508–9508. https://doi.org/10.1200/JCO.2021.39.15_suppl.9508.

    Article  Google Scholar 

  43. Ganta N, et al. Rare adverse events related to nivolumab, an immune checkpoint inhibitor: a case series. Cureus. 2022. https://doi.org/10.7759/cureus.22070.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Glitza Oliva C, et al. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Nat Med. 2023;29(4):898–905. https://doi.org/10.1038/s41591-022-02170-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. • Tawbi HA, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. 2021;22(12): 1692–1704. https://doi.org/10.1016/S1470-2045(21)00545-3. This study presents 3-year follow-up data from the CheckMate 204 trial, offering insights into the efficacy of combined nivolumab and ipilimumab treatment for active melanoma brain metastases.

  46. Lebbé, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019;37(11):867–75. https://doi.org/10.1200/JCO.18.01998.

    Article  PubMed  PubMed Central  Google Scholar 

  47. • Atkins MB, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF -mutant melanoma: the DREAMseq Trial—ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186–97. https://doi.org/10.1200/JCO.22.01763. This paper demonstrates the optimal therapy sequence for BRAF V600-mutant metastatic melanoma: Nivolumab-Ipilimumab combination followed by BRAF-MEK inhibitor therapy.

    Article  CAS  PubMed  Google Scholar 

  48. Larkin MG, et al. A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. Br J Cancer. 2007;96(1):44–8. https://doi.org/10.1038/sj.bjc.6603503.

    Article  CAS  PubMed  Google Scholar 

  49. Avril MF, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004;22(6):1118–25. https://doi.org/10.1200/JCO.2004.04.165.

    Article  CAS  PubMed  Google Scholar 

  50. Jacquillat C, et al. Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer. 1990;66(9):1873–8. https://doi.org/10.1002/1097-0142(19901101)66:9%3c1873::AID-CNCR2820660904%3e3.0.CO;2-5.

    Article  CAS  PubMed  Google Scholar 

  51. Margolin, et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol. 2002;128(4):214–8. https://doi.org/10.1007/s00432-002-0323-8.

    Article  CAS  PubMed  Google Scholar 

  52. Le Rhun E, et al. Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe. J Neurooncol. 2017;133(2):419–27. https://doi.org/10.1007/s11060-017-2452-6.

    Article  CAS  PubMed  Google Scholar 

  53. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol. 1993;11(3):561–9. https://doi.org/10.1200/JCO.1993.11.3.561.

    Article  CAS  PubMed  Google Scholar 

  54. Glantz J, 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(11):3394–402.

    CAS  PubMed  Google Scholar 

  55. Lishner. Complications associated with Ommaya reservoirs in patients with cancer. Arch Intern Med. 1990;150(1):173. https://doi.org/10.1001/archinte.1990.00390130145023.

    Article  CAS  PubMed  Google Scholar 

  56. Bosse, et al. A retrospective review of complication rates of Ommaya reservoir placement for intrathecal medication administration. J Clin Oncol. 2018;36(15_suppl):e18532–e18532. https://doi.org/10.1200/JCO.2018.36.15_suppl.e18532.

    Article  Google Scholar 

  57. Glitza C, et al. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. ESMO Open. 2018;3(1): e000283. https://doi.org/10.1136/esmoopen-2017-000283.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Arasaratnam, et al. Leptomeningeal melanoma-a case series in the era of modern systemic therapy. Pigment Cell Melanoma Res. 2018;31(1):120–4. https://doi.org/10.1111/pcmr.12652.

    Article  PubMed  Google Scholar 

  59. DeAngelis LM, Boutros D. Leptomeningeal metastasis. Cancer Invest. 2005;23(2):145–54. https://doi.org/10.1081/CNV-50458.

    Article  PubMed  Google Scholar 

  60. GeukesFoppen MH, Brandsma D, Blank CU, van Thienen JV, Haanen JB, Boogerd W. Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol. 2016;27(6):1138–42. https://doi.org/10.1093/annonc/mdw134.

    Article  CAS  Google Scholar 

  61. Frinton E, et al. Metastatic melanoma: prognostic factors and survival in patients with brain metastases. J Neurooncol. 2017;135(3):507–12. https://doi.org/10.1007/s11060-017-2591-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morris SL, et al. A prognostic index that predicts outcome following palliative whole brain radiotherapy for patients with metastatic malignant melanoma. Br J Cancer. 2004;91(5):829–33. https://doi.org/10.1038/sj.bjc.6602018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. de la Fuente M, Beal K, Carvajal R, Kaley TJ. Whole-brain radiotherapy in patients with brain metastases from melanoma. CNS Oncol. 2014;3(6):401–6. https://doi.org/10.2217/cns.14.40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Susko MS, et al. Stereotactic radiosurgery to more than 10 brain metastases: evidence to support the role of radiosurgery for ideal hippocampal sparing in the treatment of multiple brain metastases. World Neurosurg. 2020;135:e174–80. https://doi.org/10.1016/j.wneu.2019.11.089.

    Article  PubMed  Google Scholar 

  65. Chang EL, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–44. https://doi.org/10.1016/S1470-2045(09)70263-3.

    Article  PubMed  Google Scholar 

  66. Hong M, et al. Adjuvant whole-brain radiation therapy compared with observation after local treatment of melanoma brain metastases: a multicenter, randomized phase III trial. J Clin Oncol. 2019;37(33):3132–41. https://doi.org/10.1200/JCO.19.01414.

    Article  CAS  PubMed  Google Scholar 

  67. Cross E, Glantz MJ. Neurologic complications of radiation therapy. Neurol Clin. 2003;21(1):249–77. https://doi.org/10.1016/S0733-8619(02)00031-2.

    Article  PubMed  Google Scholar 

  68. Young DF, Posner JB, Chu F, Nisce L. Rapid-course radiation therapy of cerebral metastases: results and complications. Cancer. 1974;34(4):1069–76. https://doi.org/10.1002/1097-0142(197410)34:4<1069::AID-CNCR2820340416>3.0.CO;2-4.

  69. Marks LB, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010;76(3):S10–9. https://doi.org/10.1016/j.ijrobp.2009.07.1754.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Emami B, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–22. https://doi.org/10.1016/0360-3016(91)90171-Y.

    Article  CAS  PubMed  Google Scholar 

  71. Gondi V, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32(34):3810–6. https://doi.org/10.1200/JCO.2014.57.2909.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Brown D, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG Oncology CC001. J Clin Oncol. 2020;38(10):1019–29. https://doi.org/10.1200/JCO.19.02767.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Brown D, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429–37. https://doi.org/10.1093/neuonc/not114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lal LS, Franzini L, Panchal J, Chang E, Meyers CA, Swint JM. Economic impact of stereotactic radiosurgery for malignant intracranial brain tumors. Expert Rev Pharmacoecon Outcomes Res. 2011;11(2):195–204. https://doi.org/10.1586/erp.11.10.

    Article  PubMed  Google Scholar 

  75. Hara W, et al. Cyberknife for brain metastases of malignant melanoma and renal cell carcinoma. Neurosurgery. 2009;64(2):A26–32. https://doi.org/10.1227/01.NEU.0000339118.55334.EA.

    Article  PubMed  Google Scholar 

  76. Selek U, et al. Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys. 2004;59(4):1097–106. https://doi.org/10.1016/j.ijrobp.2003.12.037.

    Article  PubMed  Google Scholar 

  77. Ewend MG, Morris DE, Carey LA, Ladha AM, Brem S. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J Natl Compr Canc Netw. 2008;6(5):505–14. https://doi.org/10.6004/jnccn.2008.0038.

    Article  PubMed  Google Scholar 

  78. Liew DN, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. J Neurosurg. 2011;114(3):769–79. https://doi.org/10.3171/2010.5.JNS1014.

    Article  PubMed  Google Scholar 

  79. • Gondi V, et al. Radiation therapy for brain metastases: an ASTRO clinical practice guideline. Pract Radiat Oncol. 2022;12(4): 265–282. https://doi.org/10.1016/j.prro.2022.02.003. This guideline provides updated evidence-based recommendations addressing advanced radiation therapy techniques such as SRS and hippocampal avoidance WBRT and the emergence of systemic therapies with central nervous system activity.

  80. Minniti G, et al. Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys. 2013;86(4):623–9. https://doi.org/10.1016/j.ijrobp.2013.03.037.

    Article  PubMed  Google Scholar 

  81. Brown PD, et al. 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(8):1049–60. https://doi.org/10.1016/S1470-2045(17)30441-2.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Shaw E, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys. 2000;47(2):291–8. https://doi.org/10.1016/S0360-3016(99)00507-6.

    Article  CAS  PubMed  Google Scholar 

  83. Thomson HM, Fortin Ensign SP, Edmonds VS, Sharma A, Butterfield RJ 3rd, Schild SE, Ashman JB, Zimmerman RS, Patel NP, Bryce AH, Vora SA, Sio TT, Porter AB. Clinical outcomes of stereotactic radiosurgery-related radiation necrosis in patients with intracranial metastasis from melanoma. Clin Med Insights Oncol. 2023;21(17):11795549231161878. https://doi.org/10.1177/11795549231161878.

    Article  Google Scholar 

  84. Trino E, Mantovani C, Badellino S, Ricardi U, Filippi AR. Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases. Expert Rev Anticancer Ther. 2017;17(4):347–56. https://doi.org/10.1080/14737140.2017.1296764.

    Article  CAS  PubMed  Google Scholar 

  85. Arbour C, et al. 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. 2018;36(28):2872–8. https://doi.org/10.1200/JCO.2018.79.0006.

    Article  CAS  PubMed  Google Scholar 

  86. da Silva P, et al. Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies. Pigment Cell Melanoma Res. 2019;32(4):553–63. https://doi.org/10.1111/pcmr.12775.

    Article  CAS  PubMed Central  Google Scholar 

  87. Mack F, et al. Therapy of leptomeningeal metastasis in solid tumors. Cancer Treat Rev. 2016;43:83–91. https://doi.org/10.1016/j.ctrv.2015.12.004.

    Article  CAS  PubMed  Google Scholar 

  88. Chamberlain MC. Radioisotope CSF flow studies in leptomeningeal metastases. J Neurooncol. 1998;38(2/3):135–40. https://doi.org/10.1023/A:1005982826121.

    Article  CAS  PubMed  Google Scholar 

  89. Lee M, Mehta UN, Dsouza LH, Guadagnolo BA, Sanders DL, Kim KB. Long-term stabilization of leptomeningeal disease with whole-brain radiation therapy in a patient with metastatic melanoma treated with vemurafenib. Melanoma Res. 2013;23(2):175–8. https://doi.org/10.1097/CMR.0b013e32835e589c.

    Article  PubMed  Google Scholar 

  90. Bot I, Blank CU, Brandsma D. Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. J Neurol. 2012;259(9):1976–8. https://doi.org/10.1007/s00415-012-6488-4.

    Article  CAS  PubMed  Google Scholar 

  91. Yang TJ, et al. Clinical trial of proton craniospinal irradiation for leptomeningeal metastases. Neuro Oncol. 2021;23(1):134–43. https://doi.org/10.1093/neuonc/noaa152.

    Article  CAS  PubMed  Google Scholar 

  92. • Yang JT, et al. Randomized phase II trial of proton craniospinal irradiation versus photon involved-field radiotherapy for patients with solid tumor leptomeningeal metastasis. J Clin Oncol. 2022;40(33):3858–67. https://doi.org/10.1200/JCO.22.01148. This study demonstrated that proton craniospinal irradiation improves CNS progression free survival in patients with leptomeningeal metastasis from solid tumors compared with photon involved-field radiotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Paek H, Audu PB, Sperling MR, Cho J, Andrews DW. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery. 2005;56(5):1021–34 (discussion 1021-34).

    PubMed  Google Scholar 

  94. Kalkanis N, et al. The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010;96(1):33–43. https://doi.org/10.1007/s11060-009-0061-8.

    Article  PubMed  Google Scholar 

  95. Wroński M, Arbit E. Surgical treatment of brain metastases from melanoma: a retrospective study of 91 patients. J Neurosurg. 2000;93(1):9–18. https://doi.org/10.3171/jns.2000.93.1.0009.

    Article  PubMed  Google Scholar 

  96. Mahajan, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1040–8. https://doi.org/10.1016/S1470-2045(17)30414-X.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Cagney DN, et al. Association of neurosurgical resection with development of pachymeningeal seeding in patients with brain metastases. JAMA Oncol. 2019;5(5):703. https://doi.org/10.1001/jamaoncol.2018.7204.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Turner BE, et al. Nodular leptomeningeal disease—a distinct pattern of recurrence after postresection stereotactic radiosurgery for brain metastases: a multi-institutional study of interobserver reliability. Int J Radiat Oncol Biol Phys. 2020;106(3):579–86. https://doi.org/10.1016/j.ijrobp.2019.10.002.

    Article  PubMed  Google Scholar 

  99. Lonser RR, et al. Surgical management of melanoma brain metastases in patients treated with immunotherapy. J Neurosurg. 2011;115(1):30–6. https://doi.org/10.3171/2011.3.JNS091107.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Janavicius M, Lachej N, Anglickiene G, Vincerzevskiene I, Brasiuniene B. Outcomes of treatment for melanoma brain metastases. J Skin Cancer. 2020;2020:1–10. https://doi.org/10.1155/2020/7520924.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Division of Neuro-Oncology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA

    Wendy J. Sherman MD

  2. Vita e Salute San Raffaele University in Milan, Via Olgettina, 58, 20132, Milan, MI, Italy

    Edoardo Romiti

  3. Department of Neurosurgery, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA

    Loizos Michaelides MD, Diogo Moniz-Garcia MD, Kaisorn L. Chaichana MD & Alfredo Quiñones-Hinojosa MD

  4. Department of Neurology, Division of Neuro-Oncology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA

    Alyx B. Porter MD

Authors
  1. Wendy J. Sherman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edoardo Romiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Loizos Michaelides MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diogo Moniz-Garcia MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaisorn L. Chaichana MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Quiñones-Hinojosa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alyx B. Porter MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WS, ER, LM wrote the main manuscript text. LM and DM prepared the table. All authors reviewed the manuscript.

Corresponding author

Correspondence to Wendy J. Sherman MD.

Ethics declarations

Conflict of Interests

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sherman, W.J., Romiti, E., Michaelides, L. et al. Systemic Therapy for Melanoma Brain and Leptomeningeal Metastases. Curr. Treat. Options in Oncol. 24, 1962–1977 (2023). https://doi.org/10.1007/s11864-023-01155-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-023-01155-3

Keywords

Search

Navigation