Current approaches to the treatment of metastatic brain tumours

Key Points

  • An increased understanding of the molecular biology of metastatic processes, including cell migration, blood–brain barrier penetration, angiogenesis and tumour proliferation, is providing new opportunities for the development of targeted therapies

  • Advances in MRI, incorporating spectroscopy and perfusion techniques, and tracers unique to metastases, provide additional information on responses to treatment and enable the earlier detection of new tumours

  • Improvements in intraoperative tumour identification using MRI and fluorescent agents maximize the likelihood of complete tumour resection and minimize injury to normal tissue

  • Reduction of radiation-induced cerebral injury and cognitive decline through repeated use of stereotactic radiosurgery or hippocampal-avoidance whole-brain radiotherapy provide useful options for individuals with advanced cerebral metastatic disease

  • Targeted therapy is beneficial in molecularly-selected tumours, including erlotinib in EGFR-mutant lung tumours, crizotinib in lung carcinomas with EML4ALK translocations, trastuzumab in HER2+ breast cancer and dabrafenib in BRAF-mutant melanoma


Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The key molecular alterations in the primary cancers that most commonly metastasize to the brain.

Change history

  • 06 March 2014

    In the version of this article initially published online, details of Jack Arbiser’s primary affiliation were omitted from the correspondence section, and should have included 'Atlanta Veterans Administration Medical Center'. The error has been corrected for the print, HTML and PDF versions of the article.


  1. 1

    US Census Bureau. [online], (2010).

  2. 2

    Fox, B. D., Cheung, V. J., Patel, A. J., Suki, D. & Rao, G. Epidemiology of metastatic brain tumors. Neurosurg. Clin. N. Am. 22, 1–6 (2011).

  3. 3

    Smedby, K. E., Brandt, L., Backlund, M. L. & Blomqvist, P. Brain metastases admissions in Sweden between 1987 and 2006. Br. J. Cancer 101, 1919–1924 (2009).

  4. 4

    Nieder, C., Spanne, O., Mehta, M. P., Grosu, A. L. & Geinitz, H. Presentation, patterns of care, and survival in patients with brain metastases: what has changed in the last 20 years? Cancer 117, 2505–2512 (2011).

  5. 5

    Schouten, L. J., Rutten, J., Huveneers, H. A. & Twijnstra, A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94, 2698–2705 (2002).

  6. 6

    Barnholtz-Sloan, J. S. et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J. Clin. Oncol. 22, 2865–2872 (2004).

  7. 7

    Tabouret, E. et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res. 32, 4655–4662 (2012).

  8. 8

    Posner, J. B. & Chernik, N. L. Intracranial metastases from systemic cancer. Adv. Neurol. 19, 579–592 (1978).

  9. 9

    Percy, A. K. Neoplasms of the central nervous system: epidemiologic considerations. Neurology 20, 398–399 (1970).

  10. 10

    Pickren, J. W., Lopez, G., Tsukada, Y. & Lane, W. W. Brain metastases: an autopsy study. Cancer Treat. Symp. 2, 295–313 (1983).

  11. 11

    Tsukada, Y., Fouad, A., Pickren, J. W. & Lane, W. W. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 52, 2349–2354 (1983).

  12. 12

    National Cancer institute. [online], (2013).

  13. 13

    CDC. Decline in Breast Cancer Incidence—United States, 1999–2003. MMWR Morb. Mortal. Wkly Rep. 56, 549–553 (2007).

  14. 14

    CDC Press release. Rates of new lung cancer cases drop in U. S. men and women [online], (2014).

  15. 15

    Stemmler, H. J. et al. 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 18, 23–38 (2007).

  16. 16

    Pestalozzi, B. C., Brignoli, S. Trastuzumab in CSF. J. Clin. Oncol. 18, 2349–2351 (2000).

  17. 17

    Wen, P. Y. & Loeffler, J. S. Management of brain metastases. Oncol. (Williston Park) 13, 941–954, 957–961; discussion 961–962, 9 (1999).

  18. 18

    American Cancer Society. Cancer Facts & Figures 2013 [online], (2013).

  19. 19

    Eichler, A. F. et al. The biology of brain metastases—translation to new therapies. Nat. Rev. Clin. Oncol. 8, 344–356 (2011).

  20. 20

    Fidler, I. J., Balasubramanian, K., Lin, Q., Kim, S. W. & Kim, S. J. The brain microenvironment and cancer metastasis. Mol. Cells 30, 93–98 (2010).

  21. 21

    Park, E. S. et al. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis. Proc. Natl Acad. Sci. USA 108, 17456–17461 (2011).

  22. 22

    Kim, S. J. et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13, 286–298 (2011).

  23. 23

    Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

  24. 24

    Dvorak, H. F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol. 20, 4368–4380 (2002).

  25. 25

    Rampling, R. Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 29, 427–431 (1994).

  26. 26

    Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

  27. 27

    Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

  28. 28

    Batchelor, T. T. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28, 2817–2823 (2010).

  29. 29

    Kodack, D. P. et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc. Natl Acad. Sci. USA 109, E3119–E3127 (2012).

  30. 30

    Pivot, X., Bedairia, N., Thiery-Vuillemin, A., Espie, M. & Marty, M. Combining molecular targeted therapies: clinical experience. Anticancer Drugs 22, 701–710 (2011).

  31. 31

    Zhang, L. et al. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci. Transl. Med. 5, 180ra48 (2013).

  32. 32

    Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

  33. 33

    Sijens, P. E. et al. 1H MR spectroscopy in patients with metastatic brain tumors: a multicenter study. Magn. Reson. Med. 33 818–826 (2005).

  34. 34

    Kelly, P. J. et al. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin. Proc. 62, 450–459 (1987).

  35. 35

    Law, M. et al. High-grade gliomas and solitary metastases: differentiation by using perfusion and proton spectroscopic MR imaging. Radiology 222, 715–721 (2002).

  36. 36

    Cha, S. Neuroimaging in neuro-oncology. Neurotherapeutics 6, 465–477 (2009).

  37. 37

    Connell, J. J. et al. Selective permeablization of the blood–brain barrier at sites of metastasis. J. Natl Cancer Inst. 105, 1634–1643 (2013).

  38. 38

    Serres, S. et al. Molecular MRI enables early and sensitive detection of brain metastases. Proc. Natl Acad. Sci. USA 109, 6674–6679 (2012).

  39. 39

    Kalkanis, S. 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. 96, 33–43 (2010).

  40. 40

    Patchell, R. A. et al. A randomized trial of surgery in the treatment of single metastases to the brain. N. Engl. J. Med. 322, 494–500 (1990).

  41. 41

    Vecht, C. J. et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann. Neurol. 33, 583–590 (1993).

  42. 42

    Katz, H. R. The relative effectiveness of radiation therapy, corticosteroids and surgery in the management of melanoma metastatic to the central nervous system. Int. J. Radiat. Oncol. Biol. Phys. 7, 897–906 (1981).

  43. 43

    Bindal, R. K., Sawaya, R., Leavens, M. E. & Lee, J. J. Surgical treatment of multiple brain metastases. J. Neurosurg. 79, 210–216 (1993).

  44. 44

    Bindal, R. K., Sawaya, R., Leavens, M. E., Hess, K. R. & Taylor, S. H. Reoperation for recurrent metastatic brain tumors. J. Neurosurg. 83, 600–604 (1995).

  45. 45

    Al-Zabin, M., Ullrich, W. O., Brawanski, A. & Proescholdt, M. A. Recurrent brain metastases from lung cancer: the impact of reoperation. Acta Neurochir. (Wien) 152, 1887–1892 (2010).

  46. 46

    Hatiboglu, M. A., Wildrick, D. M. & Sawaya, R. The role of surgical resection in patients with brain metastases. Ecancermedicalscience 7, 308 (2013).

  47. 47

    Iwadate, Y., Namba, H. & Yamaura, A. Significance of surgical resection for the treatment of multiple brain metastases. Anticancer Res. 20, 573–577 (2000).

  48. 48

    Andrews, D. W. et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363, 1665–1672 (2004).

  49. 49

    Kondziolka, D., Patel, A., Lunsford, L. D., Kassam, A. & Flickinger, J. C. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 45, 427–434 (1999).

  50. 50

    US National Library of Medicine. [online], (2013).

  51. 51

    McGirt, M. J. et al. Association of surgically acquired motor and language deficits on overall survival after resection of glioblastoma multiforme. Neurosurgery 65, 463–469 (2009).

  52. 52

    Gulati, S. et al. The risk of getting worse: surgically acquired deficits, perioperative complications, and functional outcomes after primary resection of glioblastoma. World Neurosurg. 76, 572–579 (2011).

  53. 53

    Youmans, J. R. & Winn, R. H. (eds) Youmans Neurological Surgery. (Saunders/Elsevier, 2011).

  54. 54

    Garber, S. T. & Jensen, R. L. Image guidance for brain metastases resection. Surg. Neurol. Int. 3, S111–S117 (2012).

  55. 55

    Sills, A. K. Current treatment approaches to surgery for brain metastases. Neurosurgery 57, S24–S32 (2005).

  56. 56

    Levitt, M. R., Levitt, R. & Silbergeld, D. L. Controversies in the management of brain metastases. Surg. Neurol. Int. 4, S231–S235 (2013).

  57. 57

    Narang, J. et al. Differentiating treatment-induced necrosis from recurrent/progressive brain tumor using nonmodel-based semiquantitative indices derived from dynamic contrast-enhanced T1-weighted MR perfusion. Neuro. Oncol. 13, 1037–1046 (2011).

  58. 58

    Eyüpoglu, I. Y., Buchfelder, M. & Savaskan, N. E. Surgical resection of malignant gliomas—role in optimizing patient outcome. Nat. Rev. Neurol. 9, 141–151 (2013).

  59. 59

    Kellogg, R. G. & Munoz, L. F. Selective excision of cerebral metastases from the precentral gyrus. Surg. Neurol. Int. 4, 66 (2013).

  60. 60

    Weil, R. J. & Lonser, R. R. Selective excision of metastatic brain tumors originating in the motor cortex with preservation of function. J. Clin. Oncol. 23, 1209–1217 (2005).

  61. 61

    Walter, J., Kuhn, S. A., Waschke, A., Kalff, R. & Ewald, C. Operative treatment of subcortical metastatic tumours in the central region. J. Neurooncol. 103, 567–573 (2011).

  62. 62

    Orringer, D. A., Golby, A. & Jolesz, F. Neuronavigation in the surgical management of brain tumors: current and future trends. Expert Rev. Med. Devices 9, 491–500 (2012).

  63. 63

    Schackert, G., Steinmetz, A., Meier, U. & Sobottka, S. B. Surgical management of single and multiple brain metastases: results of a retrospective study. Onkologie 24, 246–255 (2001).

  64. 64

    Nimsky, C., Ganslandt, O., Tomandl, B., Buchfelder, M. & Fahlbusch, R. Low-field magnetic resonance imaging for intraoperative use in neurosurgery: a 5-year experience. Eur. Radiol. 12, 2690–2703 (2002).

  65. 65

    Kubben, P. L. et al. Intraoperative MRI-guided resection of glioblastoma multiforme: a systematic review. Lancet Oncol. 12, 1062–1070 (2011).

  66. 66

    Martirosyan, N. L. et al. Use of in vivo near-infrared laser confocal endomicroscopy with indocyanine green to detect the boundary of infiltrative tumor. J. Neurosurg. 115, 1131–1138 (2011).

  67. 67

    Sanai, N. et al. Intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans. Neurosurgery 68, 282–290 (2011).

  68. 68

    Kircher, M. F. et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat. Med. 18, 829–834 (2012).

  69. 69

    Kalkanis, S. N. et al. Raman spectroscopy to distinguish grey matter, necrosis, and glioblastoma multiforme in frozen tissue sections. J. Neurooncol.

  70. 70

    US National Library of Medicine. [online], (2011).

  71. 71

    US National Library of Medicine. [online], (2012).

  72. 72

    US National Library of Medicine. [online], (2013).

  73. 73

    US National Library of Medicine. [online], (2012).

  74. 74

    US National Library of Medicine. [online], (2011).

  75. 75

    US National Library of Medicine. [online], (2013).

  76. 76

    US National Library of Medicine. [online], (2013).

  77. 77

    US National Library of Medicine. [online], (2013).

  78. 78

    US National Library of Medicine. [online], (2014).

  79. 79

    US National Library of Medicine. [online], (2013).

  80. 80

    Sahgal, A., Soliman, H. & Larson, D. A. Whole-brain radiation therapy of brain metastasis. Prog. Neurol. Surg. 25, 82–95 (2012).

  81. 81

    Gaspar, L. 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. 37, 745–751 (1997).

  82. 82

    Kohler, B. A. 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. 103, 714–736 (2011).

  83. 83

    Li, J. et al. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int. J. Radiat. Oncol. Biol. Phys. 71, 64–70 (2008).

  84. 84

    DeAngelis, L. M., Delattre, J. Y. & Posner, J. B. Radiation-induced dementia in patients cured of brain metastases. Neurology 39, 789–796 (1989).

  85. 85

    Welzel, G. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 73, 919–926 (2009).

  86. 86

    Borgelt, B. et al. The palliation of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int. J. Radiat. Oncol. Biol. Phys. 6, 1–9 (1980).

  87. 87

    Murray, K. J. et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int. J. Radiat. Oncol. Biol. Phys. 39, 571–574 (1997).

  88. 88

    Noordijk, E. M. et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int. J. Radiat. Oncol. Biol. Phys. 29, 711–717 (1994).

  89. 89

    Addeo, R. et al. Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Cancer 113, 2524–2531 (2008).

  90. 90

    Chua, D. et al. Whole-brain radiation therapy plus concomitant temozolomide for the treatment of brain metastases from non-small-cell lung cancer: a randomized, open-label phase II study. Clin. Lung Cancer 11, 176–181 (2010).

  91. 91

    Kouvaris, J. R. et al. Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors. Onkologie 30, 361–366 (2007).

  92. 92

    Verger, E. et al. Temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 61, 185–191 (2005).

  93. 93

    Welsh, J. W. et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J. Clin. Oncol. 31, 895–902 (2013).

  94. 94

    Sperduto, P. W. et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int. J. Radiat. Oncol. Biol. Phys. 85, 1312–1318 (2013).

  95. 95

    Aoyama, H. et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295, 2483–2491 (2006).

  96. 96

    Sneed, P. K. et al. Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int. J. Radiat. Oncol. Biol. Phys. 43, 549–558 (1999).

  97. 97

    Sneed, P. K. 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. 53, 519–526 (2002).

  98. 98

    Chang, E. L. et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 10, 1037–1044 (2009).

  99. 99

    Tsao, M., Xu, W. & Sahgal, A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer 118, 2486–2493 (2012).

  100. 100

    Aoyama, H. et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int. J. Radiat. Oncol. Biol. Phys. 68, 1388–1395 (2007).

  101. 101

    Kocher, M. 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. 29, 134–141 (2011).

  102. 102

    Soffietti, R. et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J. Clin. Oncol. 31, 65–72 (2013).

  103. 103

    Sahgal, A. et al. Individual patient data meta-analysis of randomized controlled trials comparing stereotactic radiosurgery alone to SRS plus whole brain radiation therapy in patients with brain metastasis. Int. J. Radiat. Oncol. Biol. Phys. 87, 1187 (2013).

  104. 104

    Barani, I. J., Larson, D. A. & Berger, M. S. Future directions in treatment of brain metastases. Surg. Neurol. Int. 4 (Suppl. 4), S220–S230 (2013).

  105. 105

    Slotman, B. et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N. Engl. J. Med. 357, 664–672 (2007).

  106. 106

    Gore, E. M. et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of Radiation Therapy Oncology Group Study RTOG 0214. J. Clin. Oncol. 29, 272–278 (2011).

  107. 107

    Sun, A. et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J. Clin. Oncol. 29, 279–286 (2011).

  108. 108

    Brown, P. 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. 15, 1429–1437 (2013).

  109. 109

    Gondi, V. et al. Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 78, 1244–1252 (2010).

  110. 110

    Gutierrez, A. N. et al. Whole-brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int. J. Radiat. Oncol. Biol. Phys. 69, 589–597 (2007).

  111. 111

    Gondi, V. et al. Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy (WBRT) for patients with brain metastases: primary endpoint results of RTOG 0933. Int. J. Radiat. Oncol. Biol. Phys. 87, 1186 (2013).

  112. 112

    Hall, W. A., Djalilian, H. R., Nussbaum, E. S. & Cho, K. H. Long-term survival with metastatic cancer to the brain. Med. Oncol. 17, 279–286 (2000).

  113. 113

    Maclean, J. et al. Multi-disciplinary management for patients with oligometastases to the brain: results of a 5 year cohort study. Radiat. Oncol. 8, 156 (2013).

  114. 114

    Gril, B. et al. Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis. Clin. Cancer Res. 17, 142–153 (2011).

  115. 115

    Palmieri, D. et al. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol. Cancer Res. 7, 1438–1445 (2009).

  116. 116

    Shaw, A. T. et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC [abstract]. J. Clin. Oncol. 31 (Suppl.), abstract 8010 (2013).

  117. 117

    Fukuoka, M. et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J. Clin. Oncol. 29, 2866–2874 (2011).

  118. 118

    Sosman, J. A. et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012).

  119. 119

    Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

  120. 120

    Kallioniemi, O. P. et al. Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int. J. Cancer 49, 650–655 (1991).

  121. 121

    Nie, F. et al. Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis. Cancer 118, 5198–5209 (2012).

  122. 122

    Gril, B. et al. Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies. Eur. J. Cancer 46, 1204–1210 (2010).

  123. 123

    Rahmathulla, G., Toms, S. A. & Weil, R. J. The molecular biology of brain metastasis. J. Oncol. 2012, 723541 (2012).

  124. 124

    Sun, M. et al. HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin. Cancer Res. 15, 4829–4837 (2009).

  125. 125

    Benedettini, E. et al. Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am. J. Pathol. 177, 415–423 (2010).

  126. 126

    Breindel, J. L. et al. EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res. 73, 5053–5065 (2013).

  127. 127

    Li, B. et al. Elevated PLGF contributes to small-cell lung cancer brain metastasis. Oncogene 32, 2952–2962 (2013).

  128. 128

    Nguyen, D. X. et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138, 51–62 (2009).

  129. 129

    Grinberg-Rashi, H. et al. The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin. Cancer Res. 15, 1755–1761 (2009).

  130. 130

    Wu, P. F. et al. Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas. J. Neurooncol. 115, 61–70 (2013).

  131. 131

    Chen, G., Wang, Z., Liu, X. Y. & Liu, F. Y. High-level CXCR4 expression correlates with brain-specific metastasis of non-small cell lung cancer. World J. Surg. 35, 56–61 (2011).

  132. 132

    Yoshimasu, T. et al. Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci. 95, 142–148 (2004).

  133. 133

    Shintani, Y. et al. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 64, 4190–4196 (2004).

  134. 134

    Minotti, V. et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 20, 93–98 (1998).

  135. 135

    Kelly, K. & Bunn, P. A. Jr. Is it time to reevaluate our approach to the treatment of brain metastases in patients with non-small cell lung cancer? Lung Cancer 20, 85–91 (1998).

  136. 136

    Pietanza, M. C. et al. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin. Cancer Res. 18, 1138–1145 (2012).

  137. 137

    Cortes, J. et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 64, 28–35 (2003).

  138. 138

    Bernardo, G. et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest. 20, 293–302 (2002).

  139. 139

    Robinet, G. et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95–1. Ann. Oncol. 12, 59–67 (2001).

  140. 140

    Heimberger, A. B. et al. Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (Iressa). Clin. Cancer Res. 8, 3496–3502 (2002).

  141. 141

    Lai, C. S., Boshoff, C., Falzon, M. & Lee, S. M. Complete response to erlotinib treatment in brain metastases from recurrent NSCLC. Thorax 61, 91 (2006).

  142. 142

    Yap, T. A. et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J. Clin. Oncol. 28, 3965–3972 (2010).

  143. 143

    Kuiper, J. L. & Smit, E. F. High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases—one with a remarkable thoracic response as well. Lung Cancer 80, 102–105 (2013).

  144. 144

    Grommes, C. et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13, 1364–1369 (2011).

  145. 145

    Katayama, T. et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J. Thorac. Oncol. 4, 1415–1419 (2009).

  146. 146

    Heon, S. et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin. Cancer Res. 18, 4406–4414 (2012).

  147. 147

    Doebele, R. C. et al. Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118, 4502–4511 (2012).

  148. 148

    Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

  149. 149

    Camidge, D. R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012).

  150. 150

    Camidge, D. R. et al. Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies [abstract 3401]. Presented at the European Cancer Congress, 2013 (2013).

  151. 151

    Solomon, B., Wilner, K. D. & Shaw, A. T. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin. Pharmacol. Ther. 95, 15–23 (2013).

  152. 152

    Costa, D. B. et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J. Clin. Oncol. 20, e443–e445 (2011).

  153. 153

    Tang, S. C. et al. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int. J. Cancer 134, 1484–1494 (2014).

  154. 154

    Kinoshita, Y., Koga, Y., Sakamoto, A. & Hidaka, K. Long-lasting response to crizotinib in brain metastases due to EML4-ALK-rearranged non-small-cell lung cancer. BMJ Case Rep.

  155. 155

    Kim, Y. H. et al. High-dose crizotinib for brain metastases refractory to standard-dose crizotinib. J. Thor. Oncol. 8, e85–e86 (2013).

  156. 156

    Gandhi, L., Drappatz, J., Ramaiya, N. H. & Otterson, G. A. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer. J. Thorac. Oncol. 8, e3–e5 (2013).

  157. 157

    Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

  158. 158

    Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

  159. 159

    Guiu, S. et al. Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann. Oncol. 23, 2997–3006 (2012).

  160. 160

    Heitz, F. et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur. J. Cancer 45, 2792–2798 (2009).

  161. 161

    Dawood, S. et al. Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer. Cancer 118, 4652–4659 (2012).

  162. 162

    Fokstuen, T. et al. Radiation therapy in the management of brain metastases from breast cancer. Breast Cancer Res. Treat. 62, 211–216 (2000).

  163. 163

    Anders, C. K. et al. The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer 117, 1602–1611 (2011).

  164. 164

    Niwinska, A., Murawska, M. & Pogoda, K. Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT). Ann. Oncol. 21, 942–948 (2010).

  165. 165

    Melisko, M. E., Moore, D. H., Sneed, P. K., De Franco, J. & Rugo, H. S. Brain metastases in breast cancer: clinical and pathologic characteristics associated with improvements in survival. J. Neurooncol. 88, 359–365 (2008).

  166. 166

    Amir, E. et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J. Clin. Oncol. 30, 587–592 (2012).

  167. 167

    Niikura, N. et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J. Clin. Oncol. 30, 593–599 (2012).

  168. 168

    Sezgin, C., Gokmen, E., Esassolak, M., Ozdemir, N. & Goker, E. Risk factors for central nervous system metastasis in patients with metastatic breast cancer. Med. Oncol. 24, 155–161 (2007).

  169. 169

    Ryberg, M. et al. Predictors of central nervous system metastasis in patients with metastatic breast cancer. A competing risk analysis of 579 patients treated with epirubicin-based chemotherapy. Breast Cancer Res. Treat. 91, 217–225 (2005).

  170. 170

    Musolino, A. et al. Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study. Cancer 117, 1837–1846 (2011).

  171. 171

    Pestalozzi, B. C. et al. Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann. Oncol. 17, 935–944 (2006).

  172. 172

    Ray, P. S. et al. FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res. 70, 3870–3876 (2010).

  173. 173

    Lorger, M., Krueger, J. S., O'Neal, M., Staflin, K. & Felding-Habermann, B. Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain. Proc. Natl Acad. Sci. USA 106, 10666–10671 (2009).

  174. 174

    Nam, D. H. I. Activation of notch signaling in a xenograft model of brain metastasis. Clin. Cancer Res. 14, 4059–4066 (2008).

  175. 175

    Zhang, S. et al. SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases. Cancer Res. 73, 5764–5774 (2013).

  176. 176

    Saldana, S. M. et al. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis. PLoS ONE 8, e73406 (2013).

  177. 177

    Palmieri, D. et al. Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin. Cancer Res. 15, 6148–6157 (2009).

  178. 178

    Lee, Y. T. Breast carcinoma: pattern of metastasis at autopsy. J. Surg. Oncol. 23, 175–180 (1983).

  179. 179

    Trudeau, M. E. et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada—Clinical Trials Group (NCIC-CTG). Ann. Oncol. 17, 952–956 (2006).

  180. 180

    Siena, S. et al. Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Ann. Oncol. 21, 655–661 (2010).

  181. 181

    Iwamoto, F. M. et al. A phase II trial of vinorelbine and intensive temozolomide for patients with recurrent or progressive brain metastases. J. Neurooncol. 87, 85–90 (2008).

  182. 182

    Christodoulou, C. et al. Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) phase II study. J. Neurooncol. 71, 61–65 (2005).

  183. 183

    Ekenel, M., Hormigo, A. M., Peak, S., Deangelis, L. M. & Abrey, L. E. Capecitabine therapy of central nervous system metastases from breast cancer. J. Neurooncol. 85, 223–227 (2007).

  184. 184

    Wang, M. L., Yung, W. K., Royce, M.E., Schomer, D. F. & Theriault, R. L. Capecitabine for 5-fluorouracil-resistant brain metastases from breast cancer. Am. J. Clin. Oncol. 24, 421–424 (2001).

  185. 185

    Rivera, E. et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer 107, 1348–1354 (2006).

  186. 186

    Lin, N. U. et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 26, 1993–1999 (2008).

  187. 187

    Lin, N. U. et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin. Cancer Res. 15, 1452–1459 (2009).

  188. 188

    Metro, G. et al. Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann. Oncol. 22, 625–630 (2011).

  189. 189

    Sutherland, S. et al. Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases—the UK experience. Br. J. Cancer 102, 995–1002 (2010).

  190. 190

    Lin, N. U. et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J. Neurooncol. 105, 613–620 (2011).

  191. 191

    Batchelor, T. et al. 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. 14, 64–71 (2013).

  192. 192

    Bourdeanu, L., Reilly, A. A. & Luu, T. CNS metastases in breast cancer: a comparison report [abstract P6-11-12]. Presented at the San Antonio Breast Cancer Symposium 2013.

  193. 193

    Fitzgerald, D. P. et al. TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol. Cancer Ther. 11, 1959–1967 (2012).

  194. 194

    US National Library of Medicine. [online], (2013).

  195. 195

    US National Library of Medicine. [online], (2014).

  196. 196

    US National Library of Medicine. [online], (2013).

  197. 197

    Ro, J. et al. Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea. BMC Cancer 12, 322 (2012).

  198. 198

    Yap, Y. S. et al. Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival. Br. J. Cancer 107, 1075–1082 (2012).

  199. 199

    US National Library of Medicine. [online], (2014).

  200. 200

    US National Library of Medicine. [online], (2013).

  201. 201

    Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

  202. 202

    Curran, M. P. Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Paediatr. Drugs 14, 51–60 (2012).

  203. 203

    Bendell, J. C. et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2012).

  204. 204

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

  205. 205

    O'Shaughnessy, J. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364, 205–214 (2011).

  206. 206

    Mehta, M. P. et al. Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases [abstract 2013]. Int. J. Radiat. Oncol. Biol. Phys. 84 (Suppl.), S269–S270 (2012).

  207. 207

    Byrne, T. N., Cascino, T. L. & Posner, J. B. Brain metastasis from melanoma. J. Neurooncol. 1, 313–317 (1983).

  208. 208

    Davies, M. A. et al. Integrated molecular and clinical analysis of Akt activation in metastatic melanoma. Clin. Cancer Res. 15, 7538–7546 (2009).

  209. 209

    Govindarajan, B. et al. Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J. Clin. Invest. 117, 719–729 (2007).

  210. 210

    Bonner, M. Y. & Arbiser, J. L. Targeting NADPH oxidases for the treatment of cancer and inflammation. Cell. Mol. Life Sci. 69, 2435–2442 (2012).

  211. 211

    Boivin, B., Zhang, S., Arbiser, J. L., Zhang, Z. Y. & Tonks, N. K. A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells. Proc. Natl Acad. Sci. USA 105, 9959–9964 (2008).

  212. 212

    Munson, J. M. et al. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci. Transl. Med. 4, 127–136 (2012).

  213. 213

    Hamilton, R. et al. Pathologic and gene expression features of metastatic melanomas to the brain. Cancer 119, 2737–2746 (2013).

  214. 214

    Arpaia, E. et al. The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and ERK. Oncogene 31, 884–896 (2012).

  215. 215

    Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

  216. 216

    Arnold, S. M. et al. Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis. Clin. Cancer Res. 5, 4028–4033 (1999).

  217. 217

    Kusters, B. et al. Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma. Cancer Res. 63, 5408–5413 (2003).

  218. 218

    Kusters, B. et al. Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res. 62, 341–345 (2002).

  219. 219

    Yano, S. et al. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res. 60, 4959–4967 (2000).

  220. 220

    Xie, T. X. et al. Activation of STAT3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).

  221. 221

    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. 47, 291–298 (2000).

  222. 222

    Margolin, K. et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13, 459–465 (2012).

  223. 223

    Kingsley, D. P. An interesting case of possible abscopal effect in malignant melanoma. Br. J. Radiol. 48, 863–866 (1975).

  224. 224

    Stamell, E. F. et al. The abscopal effect associated with a systemic anti-melanoma immune response. Int. J. Radiat. Oncol. Biol. Phys. 85, 293–295 (2013).

  225. 225

    Falchook, G. S. et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379, 1893–1901 (2012).

  226. 226

    Long, G. V. 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. 13, 1087–1095 (2012).

  227. 227

    Jang, S. & Atkins, M. B. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol. 14, e60–e69 (2013).

  228. 228

    Okwan-Duodu, D., Pollack, B. P., Lawson, D. & Khan, M. K. Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma. Am. J. Clin. Oncol.

  229. 229

    Martinez, N., Boire, A. & Deangelis, L. M. Molecular interactions in the development of brain metastases. Int. J. Mol. Sci. 14, 17157–17167 (2013).

  230. 230

    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  231. 231

    Ceresoli, G. L. et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann. Oncol. 15, 1042–1047 (2004).

  232. 232

    Wu, C. et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer 57, 359–364 (2007).

  233. 233

    Kim, J. E. 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 65, 351–354 (2009).

  234. 234

    Hotta, K. et al. Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. Lung Cancer 46, 255–261 (2004).

  235. 235

    Porta, R. et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur. Respir. J. 37, 624–631 (2011).

  236. 236

    Atkins, M. B. et al. Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. Cancer 113, 2139–2145 (2008).

  237. 237

    Konstantinou, M. P. et al. Ipilimumab in melanoma patients with brain metastasis: a retrospective multicentre evaluation of thirty-eight patients. Acta Derm. Venereol. 94, 45–49 (2014).

Download references

Author information

T.K.O., J.A., A.Z., A.R. and M.K.M. researched the data for this article. T.K.O., J.A., A.Z., H.-K.G.S., A.M.R., S.N.K. and J.J.O. made substantial contributions to all other stages of the preparation of the manuscript for submission. In addition, T.R. and K.M.E. contributed substantially to discussion of content and the writing of the article. T.G.W., B.S., N.L.T. and M.K.M. also made considerable contributions to the writing of the article.

Correspondence to Jeffrey J. Olson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Owonikoko, T., Arbiser, J., Zelnak, A. et al. Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol 11, 203–222 (2014) doi:10.1038/nrclinonc.2014.25

Download citation

Further reading