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Systemic Therapy for Brain Metastases: Melanoma

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Central Nervous System Metastases

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Abstract

Brain metastases are a significant cause of morbidity and mortality in patients with advanced melanoma and constitute a therapeutic challenge. Systemic treatment targeting both mutant BRAF and immune checkpoints has revolutionized the management of metastatic melanoma and prolonged patient survival. However, the impact of these drugs on central nervous system metastases was less well understood as historically many clinical trials for melanoma excluded patients with brain metastases. As the field has progressed, multiple clinical trials focusing specifically on systemic therapy approaches for melanoma brain metastases have been completed or are underway. Although combined BRAF and MEK inhibition has now shown intracranial response rates of over 50%, responses appear to be less durable in the brain than in extracranial metastatic sites. Anti-PD-1 monotherapy and combined ipilimumab and nivolumab have intracranial response rates of over 20% and 50%, respectively, with concordant responses among brain and extracranial sites with clear durability. In this chapter, we discuss the results of clinical trials studying the use and combination of targeted agents and immunotherapy for melanoma brain metastases, local approaches such as stereotactic radiosurgery, and current challenges in the management of melanoma brain metastases.

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References

  1. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48–54.

    Article  PubMed  Google Scholar 

  2. Zhang D, Wang Z, Shang D, Yu J, Yuan S. Incidence and prognosis of brain metastases in cutaneous melanoma patients: a population-based study. Melanoma Res. 2018;29:77.

    Article  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;117:1687–96.

    Article  PubMed  Google Scholar 

  4. Budman DR, Camacho E, Wittes RE. The current causes of death in patients with malignant melanoma. Eur J Cancer. 1978;14:327–30.

    Article  CAS  PubMed  Google Scholar 

  5. Gardner LJ, Ward M, Andtbacka RHI, Boucher KM, Bowen GM, Bowles TL, et al. Risk factors for development of melanoma brain metastasis and disease progression: a single-center retrospective analysis. Melanoma Res. 2017;27:477–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tio M, Wang X, Carlino MS, Shivalingam B, Fogarty GB, Guminski AD, et al. Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy. Pigment Cell Melanoma Res. 2018;31:509–15.

    Article  PubMed  Google Scholar 

  7. 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;22:1293–300.

    Article  CAS  PubMed  Google Scholar 

  8. Kaba SE, Kyritsis AP, Hess K, Yung WK, Mercier R, Dakhil S, et al. TPDC-FuHu chemotherapy for the treatment of recurrent metastatic brain tumors. J Clin Oncol. 1997;15:1063–70.

    Article  CAS  PubMed  Google Scholar 

  9. Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85:1599–605.

    Article  CAS  PubMed  Google Scholar 

  10. Richard MA, Grob JJ, Zarrour H, Basseres N, Bizzari JP, Gerard B, et al. Combined treatment with dacarbazine, cisplatin, fotemustine and tamoxifen in metastatic malignant melanoma. Melanoma Res. 1998;8:170–4.

    Article  CAS  PubMed  Google Scholar 

  11. 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;18:158–66.

    Article  CAS  PubMed  Google Scholar 

  12. Agarwala SS, Kirkwood JM, Gore M, Dreno B, Thatcher N, Czarnetski B, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol. 2004;22:2101–7.

    Article  CAS  PubMed  Google Scholar 

  13. Jacquillat C, Khayat D, Banzet P, Weil M, Fumoleau P, Avril MF, 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;66:1873–8.

    Article  CAS  PubMed  Google Scholar 

  14. Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, et al. Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma. Cancer Radiother. 2003;7:1–8.

    Article  CAS  PubMed  Google Scholar 

  15. Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Capper D, Berghoff AS, Magerle M, Ilhan A, Wohrer A, Hackl M, et al. Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol. 2012;123:223–33.

    Article  CAS  PubMed  Google Scholar 

  17. Chen G, Chakravarti N, Aardalen K, Lazar AJ, Tetzlaff MT, Wubbenhorst B, et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res. 2014;20:5537–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30:2522–9.

    Article  PubMed  Google Scholar 

  19. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res. 2009;15:7538–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Niessner H, Forschner A, Klumpp B, Honegger JB, Witte M, Bornemann A, et al. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med. 2013;2:76–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xie TX, Huang FJ, Aldape KD, Kang SH, Liu M, Gershenwald JE, et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 2006;66:3188–96.

    Article  CAS  PubMed  Google Scholar 

  22. Huang FJ, Steeg PS, Price JE, Chiu WT, Chou PC, Xie K, et al. Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. Cancer Res. 2008;68:9634–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur. J. Cancer. 2014;50:611–21.

    Article  CAS  PubMed  Google Scholar 

  24. 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;13:1087–95.

    Article  CAS  PubMed  Google Scholar 

  25. Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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;18:863–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2014;372:30–9.

    Article  PubMed  CAS  Google Scholar 

  28. Glitza Oliva IC, Schvartsman G, Tawbi H. Advances in the systemic treatment of melanoma brain metastases. Ann Oncol. 2018;29:1509–20.

    Article  CAS  PubMed  Google Scholar 

  29. Seifert H, Hirata E, Gore M, Khabra K, Messiou C, Larkin J, et al. Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases. Pigment Cell Melanoma Res. 2016;29:92–100.

    Article  CAS  PubMed  Google Scholar 

  30. Weber JS, Amin A, Minor D, Siegel J, Berman D, O’Day SJ. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res. 2011;21:530–4.

    Article  CAS  PubMed  Google Scholar 

  31. 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;13:459–65.

    Article  CAS  PubMed  Google Scholar 

  32. 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;17:976–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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. 2018;37(1):52–60. https://doi.org/10.1200/JCO.18.00204.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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;19:672–81.

    Article  CAS  PubMed  Google Scholar 

  35. 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;379:722–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018;1:CD003869.

    PubMed  Google Scholar 

  37. Fan XW, Wang JQ, Wu JL, Wang HB, Wu KL. Simultaneously avoiding the hippocampus and hypothalamic-pituitary axis during whole brain radiotherapy: a planning study. Med Dosim. 2018;44(2):130–5.

    Article  PubMed  Google Scholar 

  38. Flanigan JC, Jilaveanu LB, Faries M, Sznol M, Ariyan S, Yu JB, et al. Melanoma brain metastases: is it time to reassess the bias? Curr Probl Cancer. 2011;35:200–10.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Redmond AJ, Diluna ML, Hebert R, Moliterno JA, Desai R, Knisely JP, et al. Gamma knife surgery for the treatment of melanoma metastases: the effect of intratumoral hemorrhage on survival. J Neurosurg. 2008;109(Suppl):99–105.

    Article  PubMed  Google Scholar 

  40. DiLuna ML, King JT Jr, Knisely JP, Chiang VL. Prognostic factors for survival after stereotactic radiosurgery vary with the number of cerebral metastases. Cancer. 2007;109:135–45.

    Article  PubMed  Google Scholar 

  41. Raldow AC, Chiang VL, Knisely JP, Yu JB. Survival and intracranial control of patients with 5 or more brain metastases treated with gamma knife stereotactic radiosurgery. Am J Clin Oncol. 2013;36:486–90.

    Article  PubMed  Google Scholar 

  42. Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013;2:899–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Anderson ES, Postow MA, Wolchok JD, Young RJ, Ballangrud A, Chan TA, et al. Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J Immunother Cancer. 2017;5:76.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Liniker E, Menzies AM, Kong BY, Cooper A, Ramanujam S, Lo S, et al. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology. 2016;5:e1214788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Williams NL, Wuthrick EJ, Kim H, Palmer JD, Garg S, Eldredge-Hindy H, et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol Biol Phys. 2017;99:22–30.

    Article  CAS  PubMed  Google Scholar 

  46. Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer. 2016;122:3051–8.

    Article  CAS  PubMed  Google Scholar 

  47. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys. 2016;95:632–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16:e270–8.

    Article  PubMed  Google Scholar 

  50. Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16:e534–e42.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Qian JM, Mahajan A, Yu JB, Tsiouris AJ, Goldberg SB, Kluger HM, et al. Comparing available criteria for measuring brain metastasis response to immunotherapy. J Neuro-Oncol. 2017;132:479–85.

    Article  CAS  Google Scholar 

  52. Colaco RJ, Martin P, Kluger HM, Yu JB, Chiang VL. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg. 2016;125:17–23.

    Article  CAS  PubMed  Google Scholar 

  53. Rahmathulla G, Recinos PF, Valerio JE, Chao S, Barnett GH. Laser interstitial thermal therapy for focal cerebral radiation necrosis: a case report and literature review. Stereotact Funct Neurosurg. 2012;90:192–200.

    Article  PubMed  Google Scholar 

  54. Alomari A, Rauch PJ, Orsaria M, Minja FJ, Chiang VL, Vortmeyer AO. Radiologic and histologic consequences of radiosurgery for brain tumors. J Neuro-Oncol. 2014;117:33–42.

    Article  CAS  Google Scholar 

  55. Nath SK, Sheridan AD, Rauch PJ, Yu JB, Minja FJ, Vortmeyer AO, et al. Significance of histology in determining management of lesions regrowing after radiosurgery. J Neuro-Oncol. 2014;117:303–10.

    Article  Google Scholar 

  56. Lu AY, Turban JL, Damisah EC, Li J, Alomari AK, Eid T, et al. Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following gamma knife radiosurgery. J Neurosurg. 2017;127:388–96.

    Article  CAS  PubMed  Google Scholar 

  57. Tye K, Engelhard HH, Slavin KV, Nicholas MK, Chmura SJ, Kwok Y, et al. An analysis of radiation necrosis of the central nervous system treated with bevacizumab. J Neuro-Oncol. 2014;117:321–7.

    Article  CAS  Google Scholar 

  58. Remon J, Le Pechoux C, Caramella C, Dhermain F, Louvel G, Soria JC, et al. Brain radionecrosis treated with bevacizumab in a patient with resected squamous cell carcinoma of the lung. J Thorac Oncol. 2017;12:e1–3.

    Article  PubMed  Google Scholar 

  59. Delishaj D, Ursino S, Pasqualetti F, Pesaresi I, Desideri I, Cosottini M, et al. The effectiveness of bevacizumab in radionecrosis after radiosurgery of a single brain metastasis. Rare Tumors. 2015;7:6018.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Boothe D, Young R, Yamada Y, Prager A, Chan T, Beal K. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro-Oncology. 2013;15:1257–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cohen JV, Tawbi H, Margolin KA, Amravadi R, Bosenberg M, Brastianos PK, et al. Melanoma central nervous system metastases: current approaches, challenges, and opportunities. Pigment Cell Melanoma Res. 2016;29:627–42.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Geukes Foppen MH, Brandsma D, Blank CU, van Thienen JV, Haanen JB, Boogerd W. Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol. 2016;27:1138–42.

    Article  CAS  PubMed  Google Scholar 

  63. Glitza IC, Rohlfs M, Guha-Thakurta N, Bassett RL Jr, Bernatchez C, Diab A, et al. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2. ESMO Open. 2018;3:e000283.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Medicine (Medical Oncology), Yale University, New Haven, CT, USA

    Sarah Weiss & Harriet Kluger

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  1. Sarah Weiss
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  2. Harriet Kluger
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Correspondence to Harriet Kluger .

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Editors and Affiliations

  1. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, Director - Brain Metastases Program, New York, NY, USA

    Rohan Ramakrishna

  2. Department of Neurology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Rajiv S. Magge

  3. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Ali A. Baaj

  4. Department of Radiation Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Jonathan P.S. Knisely

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Weiss, S., Kluger, H. (2020). Systemic Therapy for Brain Metastases: Melanoma. In: Ramakrishna, R., Magge, R., Baaj, A., Knisely, J. (eds) Central Nervous System Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-42958-4_16

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