Skip to main content

Advertisement

Log in

Current Treatment of Melanoma Brain Metastasis

  • Skin Cancer (T Ito, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

With greater understanding of underlying biology and development of effective BRAF-targeted therapy and immunotherapy, along with remarkable advances in local treatment such as stereotactic radiosurgery, melanoma brain metastasis (MBM) is witnessing continually improving outcome, with 1-year overall survival rate approaching 85%. Given disease complexity and myriad treatment options, all patients with MBM should ideally be evaluated in a multidisciplinary setting to allow an individualized treatment approach based on prognostic groups, molecular classification, number and size of brain metastasis, and performance status. With improving outcome, pendulum has now swayed to focus more on effective treatment modalities with minimal neurological toxicity while maintaining quality of life. Surgery is usually considered in symptomatic and large MBMs, while stereotactic radiosurgery considered in 1–4 lesions, and now also being explored for up to 15 brain metastases for improved local control. The role of whole brain radiotherapy is diminishing given its neurocognitive toxicities and is reserved for patients with diffuse brain involvement. Cytotoxic chemotherapy has largely been ineffective without evidence for survival benefit. Immune checkpoint inhibitors have become the cornerstone of management for melanoma brain metastasis with durable intracranial tumor control and excellent toxicity profile. For patients with asymptomatic MBMs, ipilimumab and nivolumab have shown intracranial response near 60% and provides comparable clinical benefit in MBMs as for extracranial metastases. For patients with driver BRAF mutation, BRAFi-/MEKi-targeted agents are proven to be effective in MBM with high rate intracranial responses (44–59%). However, the durability of intracranial responses induced by BRAFi/MEKi seems to be shorter than that of extracranial disease. Emerging data support novel combination of systemic therapy and stereotactic radiosurgery, which appears to be safe and effective; however, potential benefits and risks should be evaluated prospectively. Promising ongoing trials will further expand therapeutic evidence in MBM, and patients should be encouraged to participate in clinical trials.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References and Recommended Reading

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

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. https://doi.org/10.1002/ijc.29210.

    Article  PubMed  CAS  Google Scholar 

  2. Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, et al. Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103(9):714–36. https://doi.org/10.1093/jnci/djr077.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117(8):1687–96. https://doi.org/10.1002/cncr.25634.

    Article  PubMed  Google Scholar 

  4. Sampson JH, Carter JH Jr, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg. 1998;88(1):11–20. https://doi.org/10.3171/jns.1998.88.1.0011.

    Article  CAS  PubMed  Google Scholar 

  5. Sloot S, Chen YA, Zhao X, Weber JL, Benedict JJ, Mule JJ, et al. Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies. Cancer. 2018;124(2):297–305. https://doi.org/10.1002/cncr.30946.

    Article  CAS  PubMed  Google Scholar 

  6. Frinton E, Tong D, Tan J, Read G, Kumar V, Kennedy S, et al. Metastatic melanoma: prognostic factors and survival in patients with brain metastases. J Neuro-Oncol. 2017;135(3):507–12. https://doi.org/10.1007/s11060-017-2591-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9(4):274–84. https://doi.org/10.1038/nrc2622.

    Article  CAS  PubMed  Google Scholar 

  8. Izraely S, Klein A, Sagi-Assif O, Meshel T, Tsarfaty G, Hoon DS, et al. Chemokine-chemokine receptor axes in melanoma brain metastasis. Immunol Lett. 2010;130(1–2):107–14. https://doi.org/10.1016/j.imlet.2009.12.003.

    Article  CAS  PubMed  Google Scholar 

  9. Voura EB, Ramjeesingh RA, Montgomery AM, Siu CH. Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol Biol Cell. 2001;12(9):2699–710. https://doi.org/10.1091/mbc.12.9.2699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kircher DA, Silvis MR, Cho JH, Holmen SL. Melanoma brain metastasis: mechanisms, models, and medicine. Int J Mol Sci. 2016;17(9). https://doi.org/10.3390/ijms17091468.

    Article  PubMed Central  CAS  Google Scholar 

  11. Johnson DB, Menzies AM, Zimmer L, Eroglu Z, Ye F, Zhao S, et al. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer. 2015;51(18):2792–9. https://doi.org/10.1016/j.ejca.2015.08.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bedikian AY, Wei C, Detry M, Kim KB, Papadopoulos NE, Hwu WJ, et al. Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma. Am J Clin Oncol. 2011;34(6):603–10. https://doi.org/10.1097/COC.0b013e3181f9456a.

    Article  PubMed  Google Scholar 

  13. Ballo MT, Ross MI, Cormier JN, Myers JN, Lee JE, Gershenwald JE, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys. 2006;64(1):106–13. https://doi.org/10.1016/j.ijrobp.2005.06.030.

    Article  PubMed  Google Scholar 

  14. Huismans AM, Haydu LE, Shannon KF, Quinn MJ, Saw RP, Spillane AJ, et al. Primary melanoma location on the scalp is an important risk factor for brain metastasis: a study of 1,687 patients with cutaneous head and neck melanomas. Ann Surg Oncol. 2014;21(12):3985–91. https://doi.org/10.1245/s10434-014-3829-9.

    Article  PubMed  Google Scholar 

  15. Carlino MS, Haydu LE, Kakavand H, Menzies AM, Hamilton AL, Yu B, et al. Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma. Br J Cancer. 2014;111(2):292–9. https://doi.org/10.1038/bjc.2014.287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–51. https://doi.org/10.1016/s0360-3016(96)00619-0.

    Article  CAS  PubMed  Google Scholar 

  17. Morris SL, Low SH, A’Hern RP, Eisen TG, Gore ME, Nutting CM, 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 

  18. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008;70(2):510–4. https://doi.org/10.1016/j.ijrobp.2007.06.074.

    Article  PubMed  Google Scholar 

  19. Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419–25. https://doi.org/10.1200/JCO.2011.38.0527.

    Article  PubMed  Google Scholar 

  20. •• Sperduto PW, Jiang W, Brown PD, Braunstein S, Sneed P, Wattson DA, et al. Estimating survival in melanoma patients with brain metastases: an update of the graded prognostic assessment for melanoma using molecular markers (Melanoma-molGPA). Int J Radiat Oncol Biol Phys. 2017;99(4):812–6. https://doi.org/10.1016/j.ijrobp.2017.06.2454 The study updated the DS-GPA specific for MBMs by including molecular markers in a large (n=823) and more contemporary (2006–2015) patient cohort. Melanoma-molGPA scores of 4.0 and 0.0 were associated with the best and worst prognoses. There were 5 significant prognostic factors for survival (age, KPS, extracranial metastases, number of brain metastases, and BRAF status), whereas only KPS and number of brain metastases were included in the original Melanoma-GPA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carapella CM, Gorgoglione N, Oppido PA. The role of surgical resection in patients with brain metastases. Curr Opin Oncol. 2018;30(6):390–5. https://doi.org/10.1097/CCO.0000000000000484.

    Article  PubMed  Google Scholar 

  22. • Fischer GM, Jalali A, Kircher DA, Lee WC, McQuade JL, Haydu LE, et al. Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer Discov. 2019;9(5):628–45. https://doi.org/10.1158/2159-8290.CD-18-1489 Comprehensive molecular profiling on MBMs and patient-matched extracranial metastases showed unique MBM biology as compared with patient-matched extracranial metastases.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol. 2004;22(7):1293–300. https://doi.org/10.1200/JCO.2004.08.140.

    Article  CAS  PubMed  Google Scholar 

  24. Wasif N, Bagaria SP, Ray P, Morton DL. Does metastasectomy improve survival in patients with stage IV melanoma? A cancer registry analysis of outcomes. J Surg Oncol. 2011;104(2):111–5. https://doi.org/10.1002/jso.21903.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gazzeri R, Nalavenkata S, Teo C. Minimally invasive key-hole approach for the surgical treatment of single and multiple brain metastases. Clin Neurol Neurosurg. 2014;123:117–26. https://doi.org/10.1016/j.clineuro.2014.05.010.

    Article  PubMed  Google Scholar 

  26. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. 1993;79(2):210–6. https://doi.org/10.3171/jns.1993.79.2.0210.

    Article  CAS  PubMed  Google Scholar 

  27. Hagen NA, Cirrincione C, Thaler HT, DeAngelis LM. The role of radiation therapy following resection of single brain metastasis from melanoma. Neurology. 1990;40(1):158–60. https://doi.org/10.1212/wnl.40.1.158.

    Article  CAS  PubMed  Google Scholar 

  28. Skibber JM, Soong SJ, Austin L, Balch CM, Sawaya RE. Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol. 1996;3(2):118–23. https://doi.org/10.1007/bf02305789.

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Susko MS, Garcia MA, Ma L, Nakamura JL, Raleigh DR, Fogh S, et al. Stereotactic radiosurgery to greater than 10 brain metastases: evidence to support the role of radiosurgery for ideal hippocampal sparing in the treatment of multiple brain metastases. World Neurosurg. 2019. https://doi.org/10.1016/j.wneu.2019.11.089.

    Article  PubMed  Google Scholar 

  31. Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429–37. https://doi.org/10.1093/neuonc/not114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–62. https://doi.org/10.1038/nm749.

    Article  CAS  PubMed  Google Scholar 

  33. Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348–54. https://doi.org/10.1016/j.ijrobp.2012.11.031.

    Article  PubMed  Google Scholar 

  34. Gondi V, Tome WA, Marsh J, Struck A, Ghia A, Turian JV, et al. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol. 2010;95(3):327–31. https://doi.org/10.1016/j.radonc.2010.02.030.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, 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 

  36. Memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with brain metastases. https://clinicaltrialsgov/ct2/show/NCT02360215.

  37. • Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS 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;JCO1902767. https://doi.org/10.1200/JCO.19.02767 Phase III trial of WBRT (30 Gy in 10 fractions) plus memantine with or without hippocampal avoidance, showed better preservation of neurocognitive function and patient-reported symptoms, with hippocampal avoidance, while achieving similar intracranial control and survival.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Doss LL, Memula N. The radioresponsiveness of melanoma. Int J Radiat Oncol Biol Phys. 1982;8(7):1131–4. https://doi.org/10.1016/0360-3016(82)90060-8.

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Watanabe S, et al. Stereotactic radiosurgery for patients with multiple brain metastases: a case-matched study comparing treatment results for patients with 2-9 versus 10 or more tumors. J Neurosurg. 2014;121(Suppl):16–25. https://doi.org/10.3171/2014.8.GKS141421.

    Article  PubMed  Google Scholar 

  40. Rava P, Leonard K, Sioshansi S, Curran B, Wazer DE, Cosgrove GR, et al. Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery. J Neurosurg. 2013;119(2):457–62. https://doi.org/10.3171/2013.4.JNS121751.

    Article  PubMed  Google Scholar 

  41. 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 Cancer Netw. 2008;6(5):505–13; quiz 14. https://doi.org/10.6004/jnccn.2008.0038.

    Article  Google Scholar 

  42. Liew DN, Kano H, Kondziolka D, Mathieu D, Niranjan A, Flickinger JC, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article J Neurosurg. 2011;114(3):769–79. https://doi.org/10.3171/2010.5.JNS1014.

    Article  PubMed  Google Scholar 

  43. Muacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neuro-Oncol. 2008;87(3):299–307. https://doi.org/10.1007/s11060-007-9510-4.

    Article  Google Scholar 

  44. Rades D, Bohlen G, Pluemer A, Veninga T, Hanssens P, Dunst J, et al. Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer. 2007;109(12):2515–21. https://doi.org/10.1002/cncr.22729.

    Article  PubMed  Google Scholar 

  45. Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–41. https://doi.org/10.1200/JCO.2010.30.1655.

    Article  PubMed  Google Scholar 

  46. Sneed PK, Suh JH, Goetsch SJ, Sanghavi SN, Chappell R, Buatti JM, et al. A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys. 2002;53(3):519–26. https://doi.org/10.1016/s0360-3016(02)02770-0.

    Article  PubMed  Google Scholar 

  47. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, 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 

  48. •• Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316(4):401–9. https://doi.org/10.1001/jama.2016.9839 The landmark Alliance trial showed lesser cognitive deterioration with SRS alone as compared with WBRT, with similar overall survival. This study abloshed the practice of combined SRS + WBRT, and WBRT is now mostly reserved for diffuse MBMs.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, 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 

  50. Jeong WJ, Park JH, Lee EJ, Kim JH, Kim CJ, Cho YH. Efficacy and safety of fractionated stereotactic radiosurgery for large brain metastases. J Korean Neurosurg Soc. 2015;58(3):217–24. https://doi.org/10.3340/jkns.2015.58.3.217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Burton S, Amankulor N, Engh J, Flickinger J. Fractionated stereotactic radiosurgery for large brain metastases. https://clinicaltrialsgov/ct2/show/NCT02054689. 2019.

  52. Soltys SG, Adler JR, Lipani JD, Jackson PS, Choi CY, Puataweepong P, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2008;70(1):187–93. https://doi.org/10.1016/j.ijrobp.2007.06.068.

    Article  PubMed  Google Scholar 

  53. Minniti G, Esposito V, Clarke E, Scaringi C, Lanzetta G, Salvati M, et al. Multidose stereotactic radiosurgery (9 Gy x 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 

  54. Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, 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 

  55. ClinicalTrials.gov. Single fraction stereotactic radiosurgery compared with fractionated stereotactic radiosurgery in treating patients with resected metastatic brain disease. https://clinicaltrialsgov/ct2/show/NCT04114981.(12 Jan 2020, date last accessed).

  56. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–66. https://doi.org/10.1200/JCO.2000.18.1.158.

    Article  CAS  PubMed  Google Scholar 

  57. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19(1):21–34.

    CAS  PubMed  Google Scholar 

  58. Wiernik PH, Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst Monogr. 1993;15:185–7.

    Google Scholar 

  59. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19. https://doi.org/10.1056/NEJMoa1002011.

    Article  CAS  PubMed  Google Scholar 

  60. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–46. https://doi.org/10.1200/JCO.2010.32.4327.

    Article  PubMed  Google Scholar 

  61. Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344(3):655–64. https://doi.org/10.1124/jpet.112.201475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306–12. https://doi.org/10.1200/JCO.2006.10.0677.

    Article  PubMed  Google Scholar 

  63. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, 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 

  64. McArthur GA, Maio M, Arance A, Nathan P, Blank C, Avril MF, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol. 2017;28(3):634–41. https://doi.org/10.1093/annonc/mdw641.

    Article  CAS  PubMed  Google Scholar 

  65. Harding JJ, Catalanotti F, Munhoz RR, Cheng DT, Yaqubie A, Kelly N, 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 

  66. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901. https://doi.org/10.1016/S0140-6736(12)60398-5.

    Article  CAS  Google Scholar 

  67. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, 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 

  68. Azer MW, Menzies AM, Haydu LE, Kefford RF, Long GV. Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib. Cancer. 2014;120(4):530–6. https://doi.org/10.1002/cncr.28445.

    Article  CAS  PubMed  Google Scholar 

  69. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387–90. https://doi.org/10.1038/nature10662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29(22):3085–96. https://doi.org/10.1200/JCO.2010.33.2312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, 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  Google Scholar 

  72. •• Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAF(V600)-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 COMBI-MB is a phase II clinical trial, which showed intracranial response rates between 44% and 59% with dabrafenib and trametinib. The study established this combination for MBMs, and along with COMBI-AD study (NCT01682083) led to FDA approval of this combination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012;11(4):909–20. https://doi.org/10.1158/1535-7163.MCT-11-0989.

    Article  CAS  PubMed  Google Scholar 

  74. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19(5):275–82. https://doi.org/10.1097/CMR.0b013e32832eabd5.

    Article  PubMed  Google Scholar 

  75. Kaufman HL, Wong MK, Daniels GA, McDermott DF, Aung S, Lowder JN, et al. The use of registries to improve cancer treatment: a national database for patients treated with interleukin-2 (IL-2). J Pers Med. 2014;4(1):52–64. https://doi.org/10.3390/jpm4010052.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Guirguis LM, Yang JC, White DE, Steinberg SM, Liewehr DJ, Rosenberg SA, et al. Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases. J Immunother. 2002;25(1):82–7. https://doi.org/10.1097/00002371-200201000-00009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hong JJ, Rosenberg SA, Dudley ME, Yang JC, White DE, Butman JA, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res. 2010;16(19):4892–8. https://doi.org/10.1158/1078-0432.CCR-10-1507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–24. https://doi.org/10.1093/intimm/dxm057.

    Article  CAS  PubMed  Google Scholar 

  79. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75. https://doi.org/10.1200/JCO.2009.26.7609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, 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 

  81. Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015;33(10):1191–6. https://doi.org/10.1200/JCO.2014.56.6018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, 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 

  83. Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central nervous system. J Clin Invest. 2010;120(5):1368–79. https://doi.org/10.1172/JCI41911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Di Giacomo AM, Ascierto PA, Queirolo P, Pilla L, Ridolfi R, Santinami M, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol. 2015;26(4):798–803. https://doi.org/10.1093/annonc/mdu577.

    Article  PubMed  Google Scholar 

  85. Di Giacomo AM, Ascierto PA, Pilla L, Santinami M, Ferrucci PF, Giannarelli D, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 2012;13(9):879–86. https://doi.org/10.1016/S1470-2045(12)70324-8.

    Article  CAS  PubMed  Google Scholar 

  86. ClinicalTrials.gov. A study of fotemustine (FTM) vs FTM and ipilimumab (IPI) or IPI and nivolumab in melanoma brain metastasis (NIBITM2). https://clinicaltrialsgov/ct2/show/NCT02460068. (12 Dec 2019, date last accessed).

  87. Kluger HM, Chiang V, Mahajan A, Zito CR, Sznol M, Tran T, 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 

  88. • Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, 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 This phase II study was initial and seminal evidence to show durable response rate of 22–26% with pembrolizumab in untreated MBMs with an acceptable safety profile. Important to note in this study, brain metastasis and systemic responses were concordant.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. • Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722–30. https://doi.org/10.1056/NEJMoa1805453 Landmark phase II study CheckMate 204 investigated combination of nivolumab + ipilimumab in asymptomatic non-irradiated MBM, which showed intracranial response of 57%, including 26% complete response rates, which was concordant with extracranial activity. Although relatively small non-randomized study, reported data is pertinent to clinical practice with given the high intracranial and extracranial response rate, rapid time to response, and manageable side-effect profile.

    Article  CAS  PubMed  Google Scholar 

  90. Tawbi HA-H, Forsyth PAJ, Hodi FS. Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). J Clin Oncol. 2019;37:9501. https://doi.org/10.1200/JCO.2019.37.15_suppl.9501.

    Article  Google Scholar 

  91. Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, 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 

  92. Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117(2):227–33. https://doi.org/10.3171/2012.5.JNS111929.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol. 2016;27(12):2288–94. https://doi.org/10.1093/annonc/mdw417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Du Four S, Hong A, Chan M, Charakidis M, Duerinck J, Wilgenhof S, et al. Symptomatic histologically proven necrosis of brain following stereotactic radiation and Ipilimumab in six lesions in four melanoma patients. Case Rep Oncol Med. 2014;2014:417913. https://doi.org/10.1155/2014/417913.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Acharya S, Mahmood M, Mullen D, Yang D, Tsien CI, Huang J, et al. Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents. Adv Radiat Oncol. 2017;2(4):572–80. https://doi.org/10.1016/j.adro.2017.07.003.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Mastorakos P, Xu Z, Yu J, Hess J, Qian J, Chatrath A, et al. BRAF V600 mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases: a multicenter retrospective study. Neurosurgery. 2019;84(4):868–80. https://doi.org/10.1093/neuros/nyy203.

    Article  PubMed  Google Scholar 

  97. Hecht M, Meier F, Zimmer L, Polat B, Loquai C, Weishaupt C, et al. Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients. Br J Cancer. 2018;118(6):785–92. https://doi.org/10.1038/bjc.2017.489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hecht M, Zimmer L, Loquai C, Weishaupt C, Gutzmer R, Schuster B, et al. Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients. Ann Oncol. 2015;26(6):1238–44. https://doi.org/10.1093/annonc/mdv139.

    Article  CAS  PubMed  Google Scholar 

  99. Kroeze SG, Fritz C, Hoyer M, Lo SS, Ricardi U, Sahgal A, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev. 2017;53:25–37. https://doi.org/10.1016/j.ctrv.2016.11.013.

    Article  PubMed  Google Scholar 

  100. Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):104. https://doi.org/10.1186/s13045-018-0647-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hsiang-Hsuan Michael Yu MD, ScM.

Ethics declarations

Conflict of interest

Anupam Rishi declares that he has no conflict of interest. Hsiang-Hsuan Michael Yu declares that he has no conflict of interest.

Additional information

Publisher’s note

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

This article is part of the Topical collection on Skin Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rishi, A., Yu, HH.M. Current Treatment of Melanoma Brain Metastasis. Curr. Treat. Options in Oncol. 21, 45 (2020). https://doi.org/10.1007/s11864-020-00733-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-020-00733-z

Keywords

Navigation