Combining Radiosurgery and Systemic Therapies for Treatment of Brain Metastases

  • Veronica ChiangEmail author
  • Stephanie Cheok


For decades, the treatment of brain metastases was limited to surgery, radiation, and, occasionally, chemotherapy. Advances in the understanding of oncogenic molecular pathways, the blood–brain barrier, focused radiation, and immunology have built a new foundation on how we think about and treat brain metastases. This chapter will review systemic treatments, with emphases on targeted therapy and immunotherapy, and their use in combination with radiosurgery. The substantial, yet still growing, literature will be presented and reviewed, along with data and recommendations from our own institution.


Brain metastasis Leptomeningeal disease Stereotactic radiosurgery (SRS) Whole brain radiation therapy (WBRT) Targeted therapy Immunotherapy Tyrosine kinase inhibitors BRAF EGFR CTLA-4 PD-1 


  1. 1.
    Qin H, Pan F, Li J, Zhang X, Liang H, Ruan Z. Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis. PLoS One. 2014;9(10):e111475.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Herscher LL, Cook JA, Pacelli R, Pass HI, Russo A, Mitchell JB. Principles of chemoradiation: theoretical and practical considerations. Oncology (Williston Park). 1999;13(10 Suppl 5):11–22.Google Scholar
  3. 3.
    Wolf A, Kvint S, Chachoua A, Pavlick A, Wilson M, Donahue B, et al. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg. 2018;128(1):23–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol. 2013;24(6):1526–33.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs. 2007;18(1):23–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Bachelot T, Romieu G, Campone M, Diéras V, Cropet C, Dalenc F, Jimenez M, Le Rhun E, Pierga J-Y, Gonçalves A, Leheurteur M, Domont J, Gutierrez M, Curé H, Ferrero J-M, Labbe-Devilliers C. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Han CH, Brastianos PK. Genetic characterization of brain metastases in the era of targeted therapy. Front Oncol. 2017;7:230.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sperduto PW, Kased N, Roberge D, Chao ST, Shanley R, Luo X, et al. The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer. J Neurooncol. 2013;112(3):467–72.PubMedCrossRefGoogle Scholar
  10. 10.
    Yomo S, Hayashi M, Cho N. Impacts of HER2-overexpression and molecular targeting therapy on the efficacy of stereotactic radiosurgery for brain metastases from breast cancer. J Neurooncol. 2013;112(2):199–207.PubMedCrossRefGoogle Scholar
  11. 11.
    Ramakrishna N, Temin S, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(27):2804–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Fleeman N, Bagust A, Beale S, Boland A, Dickson R, Dwan K, et al. Dabrafenib for treating unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma: an evidence review group perspective. Pharmacoeconomics. 2015;33(9):893–904.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim G, McKee AE, Ning YM, Hazarika M, Theoret M, Johnson JR, et al. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res. 2014;20(19):4994–5000.PubMedCrossRefGoogle Scholar
  14. 14.
    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(3):611–21.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Gaudy-Marqueste C, Carron R, Delsanti C, Loundou A, Monestier S, Archier E, et al. On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases. Ann Oncol. 2014;25(10):2086–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Ly D, Bagshaw HP, Anker CJ, Tward JD, Grossmann KF, Jensen RL, et al. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J Neurosurg. 2015;123(2):395–401.PubMedCrossRefGoogle Scholar
  18. 18.
    Kotecha R, Miller JA, Venur VA, Mohammadi AM, Chao ST, Suh JH, et al. Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome. J Neurosurg. 2018;129(1):50–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Patel KR, Chowdhary M, Switchenko JM, Kudchadkar R, Lawson DH, Cassidy RJ, et al. BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis. Melanoma Res. 2016;26(4):387–94.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    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(2):632–46.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ceresoli GL. Role of EGFR inhibitors in the treatment of central nervous system metastases from non-small cell lung cancer. Curr Cancer Drug Targets. 2012;12(3):237–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009;65(3):351–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Yang JJ, Zhou C, Huang Y, Feng J, Lu S, Song Y, et al. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 2017;5(9):707–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhuang H, Yuan Z, Wang J, Zhao L, Pang Q, Wang P. Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma. Drug Des Devel Ther. 2013;7:1179–86.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Byeon S, Ham JS, Sun JM, Lee SH, Ahn JS, Park K, et al. Analysis of the benefit of sequential cranial radiotherapy in patients with EGFR mutant non-small cell lung cancer and brain metastasis. Med Oncol. 2016;33(8):97.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Jiang T, Su C, Li X, Zhao C, Zhou F, Ren S, et al. EGFR TKIs plus WBRT demonstrated no survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastases. J Thorac Oncol. 2016;11(10):1718–28.PubMedCrossRefGoogle Scholar
  29. 29.
    Sung S, Lee SW, Kwak YK, Kang JH, Hong SH, Kim YS. Intracranial control and survival outcome of tyrosine kinase inhibitor (TKI) alone versus TKI plus radiotherapy for brain metastasis of epidermal growth factor receptor-mutant non-small cell lung cancer. J Neurooncol. 2018;139(1):205–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys. 2016;95(2):673–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Soon YY, Leong CN, Koh WY, Tham IW. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015;114(2):167–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15(10):1119–28.PubMedCrossRefGoogle Scholar
  34. 34.
    Shaw AT, Mehra R, Tan DSW, Felip E, Chow LQ, Camige DR, et al. Evaluation of ceritinib-treated patients (PTS) with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ascend-1 study. Ann Oncol. 2014;25(suppl_4):iv455–iv6.CrossRefGoogle Scholar
  35. 35.
    Gainor JF, Sherman CA, Willoughby K, Logan J, Kennedy E, Brastianos PK, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol. 2015;10(2):232–6.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Jindal V, Gupta S. Expected paradigm shift in brain metastases therapy-immune checkpoint inhibitors. Mol Neurobiol. 2018;55(8):7072–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol. 2017;43(3):604–11.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Gibney GT, Atkins MB. Swinging for the fences: long-term survival with ipilimumab in metastatic melanoma. J Clin Oncol. 2015;33(17):1873–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Hodi FS, Oble DA, Drappatz J, Velazquez EF, Ramaiya N, Ramakrishna N, et al. CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS. Nat Clin Pract Oncol. 2008;5(9):557–61.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Skrepnik T, Sundararajan S, Cui H, Stea B. Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab. Oncoimmunology. 2017;6(3):e1283461.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013;2(6):899–906.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys. 2015;92(2):368–75.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Schoenfeld JD, Mahadevan A, Floyd SR, Dyer MA, Catalano PJ, Alexander BM, et al. Ipilimumab and cranial radiation in metastatic melanoma patients: a case series and review. J Immunother Cancer. 2015;3:50.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, et al. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol. 2017;125(1):80–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62.PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    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(1):76.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27(3):434–41.PubMedCrossRefGoogle Scholar
  55. 55.
    Diao K, Bian SX, Routman DM, Yu C, Ye JC, Wagle NA, et al. Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. J Neurooncol. 2018;139(2):421–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Rahman R, Cortes A, Niemierko A, Oh KS, Flaherty KT, Lawrence DP, et al. The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J Neurooncol. 2018;138(2):299–306.PubMedCrossRefGoogle Scholar
  57. 57.
    Gabani P, Fischer-Valuck BW, Johanns TM, Hernandez-Aya LF, Keller JW, Rich KM, et al. Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: patterns of care and treatment outcomes. Radiother Oncol. 2018;128(2):266–73.PubMedCrossRefGoogle Scholar
  58. 58.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    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(19):3051–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Yusuf MB, Amsbaugh MJ, Burton E, Chesney J, Woo S. Peri-SRS administration of immune checkpoint therapy for melanoma metastatic to the brain: investigating efficacy and the effects of relative treatment timing on lesion response. World Neurosurg. 2017;100:632–40 e4.PubMedCrossRefGoogle Scholar
  61. 61.
    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.PubMedCrossRefGoogle Scholar
  62. 62.
    Martin AM, Cagney DN, Catalano PJ, Alexander BM, Redig AJ, Schoenfeld JD, et al. Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol. 2018;4(8):1123–4.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Nardin C, Mateus C, Texier M, Lanoy E, Hibat-Allah S, Ammari S, et al. Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. Melanoma Res. 2018;28(2):111–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Du Four S, Janssen Y, Michotte A, Van Binst AM, Van den Begin R, Duerinck J, et al. Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab. Cancer Med. 2018;7:4870–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    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(1):17–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Sneed PK, Mendez J, Vemer-van den Hoek JG, Seymour ZA, Ma L, Molinaro AM, et al. Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg. 2015;123(2):373–86.PubMedCrossRefGoogle Scholar
  67. 67.
    Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16(1):269–78.PubMedCrossRefGoogle Scholar
  68. 68.
    Levy C, Allouache D, Lacroix J, Dugue AE, Supiot S, Campone M, et al. REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. Ann Oncol. 2014;25(12):2351–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. 2007;67(2):323–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79(5):1487–95.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of NeurosurgeryYale UniversityNew HavenUSA

Personalised recommendations