Recent advances in managing brain metastasis

Rupesh Kotecha, Vinai Gondi, Manmeet S Ahluwalia, Priscilla K Brastianos, Minesh P Mehta, Rupesh Kotecha, Vinai Gondi, Manmeet S Ahluwalia, Priscilla K Brastianos, Minesh P Mehta

Abstract

Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some point during the course of their disease. The management of brain metastasis is rapidly evolving and the roles of local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, and resection along with systemic therapies are in flux. An emphasis on the neurocognitive side effects associated with treatment has gained prominence. Novel molecular studies have demonstrated important evolutionary patterns underpinning the development of brain metastasis and leptomeningeal disease, which may be key to unlocking new therapeutic strategies. This article provides a framework for incorporating the results of recent randomized radiotherapy clinical trials into practice, expounds upon the emphasis on cognition being an important driver in therapeutic selection, describes the importance of CNS-penetrating systemic therapies, and provides an overview of the novel molecular insights that will likely set the stage for future developments in this field.

Keywords: brain metastasis; genomic; neurocognition; stereotactic radiosurgery; targeted therapy; whole brain radiation therapy.

Conflict of interest statement

No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

References

    1. Horton J, Baxter DH, Olson KB: The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol Radium Ther Nucl Med. 1971;111(2):334–6. 10.2214/ajr.111.2.334
    1. Mulvenna P, Nankivell M, Barton R, et al. : Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004–14. 10.1016/S0140-6736(16)30825-X
    2. F1000 Recommendation

    1. Patchell RA, Tibbs PA, Regine WF, et al. : Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA. 1998;280(17):1485–9. 10.1001/jama.280.17.1485
    1. Mahajan A, Ahmed S, McAleer MF, et al. : Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: A single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1040–8. 10.1016/S1470-2045(17)30414-X
    2. F1000 Recommendation

    1. Soliman H, Ruschin M, Angelov L, et al. : Consensus Contouring Guidelines for Postoperative Completely Resected Cavity Stereotactic Radiosurgery for Brain Metastases. Int J Radiat Oncol Biol Phys. 2018;100(2):436–42. 10.1016/j.ijrobp.2017.09.047
    2. F1000 Recommendation

    1. Atalar B, Modlin LA, Choi CY, et al. : Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2013;87(4):713–8. 10.1016/j.ijrobp.2013.07.034
    2. F1000 Recommendation

    1. Kocher M, Soffietti R, Abacioglu U, 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. 10.1200/JCO.2010.30.1655
    2. F1000 Recommendation

    1. Brown PD, Ballman KV, Cerhan JH, 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. 10.1016/S1470-2045(17)30441-2
    2. F1000 Recommendation

    1. Aoyama H, Shirato H, Tago M, et al. : Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–91. 10.1001/jama.295.21.2483
    2. F1000 Recommendation

    1. Chang EL, Wefel JS, Hess KR, 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. 10.1016/S1470-2045(09)70263-3
    2. F1000 Recommendation

    1. Brown PD, Jaeckle K, Ballman KV, 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. 10.1001/jama.2016.9839
    2. F1000 Recommendation

    1. McTyre E, Ayala-Peacock D, Contessa J, et al. : Multi-institutional competing risks analysis of distant brain failure and salvage patterns after upfront radiosurgery without whole brain radiotherapy for brain metastasis. Ann Oncol. 2018;29(2):497–503. 10.1093/annonc/mdx740
    1. Lester-Coll NH, Dosoretz AP, Hayman JA, et al. : Health State Utilities for Patients with Brain Metastases. Cureus. 2016;8(7):e667. 10.7759/cureus.667
    2. F1000 Recommendation

    1. Gondi V, Pugh SL, Tome WA, 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. 10.1200/JCO.2014.57.2909
    1. Sul J, Kluetz PG, Papadopoulos EJ, et al. : Clinical outcome assessments in neuro-oncology: A regulatory perspective: Table 1. Neuro Oncol Pract. 2016;3(1):4–9. 10.1093/nop/npv062
    2. F1000 Recommendation

    1. DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39(6):789–96. 10.1212/WNL.39.6.789
    1. Chen HS, Pellegrini JW, Aggarwal SK, et al. : Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci. 1992;12(11):4427–36. 10.1523/JNEUROSCI.12-11-04427.1992
    1. Chen HS, Lipton SA: Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: Uncompetitive antagonism. J Physiol (Lond). 1997;499(Pt 1):27–46. 10.1113/jphysiol.1997.sp021909
    1. Orgogozo JM, Rigaud AS, Stöffler A, et al. : Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002;33(7):1834–9. 10.1161/01.STR.0000020094.08790.49
    1. Wilcock G, Möbius HJ, Stöffler A: A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6):297–305.
    1. Brown PD, Pugh S, Laack NN, et al. : Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429–37. 10.1093/neuonc/not114
    1. Eriksson PS, Perfilieva E, Björk-Eriksson T, et al. : Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313–7. 10.1038/3305
    1. Monje ML, Mizumatsu S, Fike JR, Palmer TD, et al. : Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–62. 10.1038/nm749
    1. Eichler AF, Chung E, Kodack DP, et al. : The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol. 2011;8(6):344–56. 10.1038/nrclinonc.2011.58
    1. Fortin D: The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets. 2012;12(3):247–59. 10.2174/156800912799277511
    1. Welsh JW, Komaki R, Amini A, 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. 2013;31(7):895–902. 10.1200/JCO.2011.40.1174
    2. F1000 Recommendation

    1. Ceresoli GL, Cappuzzo F, Gregorc V, et al. : Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042–7. 10.1093/annonc/mdh276
    1. Mok TS, Wu YL, Ahn MJ, et al. : Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629–40. 10.1056/NEJMoa1612674
    2. F1000 Recommendation

    1. Ahn M, Tsai CM, Yang JC, et al. : AZD9291 activity in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) and brain metastases: data from phase II studies. Eur J Cancer. 2015;51(Supplement 3):S625–6. 10.1016/S0959-8049(16)31724-5
    1. Wu YL, Ahn MJ, Garassino MC, et al. : CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). J Clin Oncol. 2018;36(26):2702–9. 10.1200/JCO.2018.77.9363
    2. F1000 Recommendation

    1. Ahn MJ, Kim DW, Cho BC, et al. : Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases.| 2017 ASCO Annual Meeting Abstracts. J Clin Oncol. 2017;35(suppl 5):2006 10.1200/JCO.2017.35.15_suppl.2006
    1. Cho BC, Ahn MJ, Lee JS, et al. : Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy. J Clin Oncol. 2017;35(suppl 5):2069 10.1200/JCO.2017.35.15_suppl.2069
    1. Wang H, Zhang L, Zheng X, et al. : The ability of avitinib to penetrate the blood brain barrier and its control of intra-/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. J Clin Oncol. 2017;35(suppl 5). 10.1200/JCO.2017.35.15_suppl.e20613
    1. Economopoulou P, Mountzios G: Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy. Transl Lung Cancer Res. 2016;5(6):588–98. 10.21037/tlcr.2016.12.06
    2. F1000 Recommendation

    1. Gadgeel SM, Shaw AT, Govindan R, et al. : Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(34):4079–85. 10.1200/JCO.2016.68.4639
    2. F1000 Recommendation

    1. Crinò L, Ahn MJ, De Marinis F, et al. : Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol. 2016;34(24):2866–73. 10.1200/JCO.2015.65.5936
    2. F1000 Recommendation

    1. Gettinger S, Kim D, Tiseo M: Brigatinib activity in patients with ALK+ NSCLC and intracranial CNS metastases in two clinical trials. International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer Vienna, Austria;2016.
    1. Camidge DR, Kim HR, Ahn MJ, et al. : Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2018. 10.1056/NEJMoa1810171
    2. F1000 Recommendation

    1. Venur VA, Ahluwalia MS: Targeted Therapy in Brain Metastases: Ready for Primetime? Am Soc Clin Oncol Educ Book. 2016;35:e123–30. 10.1200/EDBK_100006
    1. Venur VA, Leone JP: Targeted Therapies for Brain Metastases from Breast Cancer. Int J Mol Sci. 2016;17(9): pii: E1543. 10.3390/ijms17091543
    2. F1000 Recommendation

    1. Lin NU, Diéras V, Paul D, et al. : Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15(4):1452–9. 10.1158/1078-0432.CCR-08-1080
    2. F1000 Recommendation

    1. Lin NU, Carey LA, Liu MC, 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. 2008;26(12):1993–9. 10.1200/JCO.2007.12.3588
    1. Bachelot T, Romieu G, Campone M, 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. 2013;14(1):64–71. 10.1016/S1470-2045(12)70432-1
    2. F1000 Recommendation

    1. Freedman RA, Gelman RS, Wefel JS, et al. : Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol. 2016;34(9):945–52. 10.1200/JCO.2015.63.0343
    2. F1000 Recommendation

    1. Freedman R, Gelman R, Melisko M, et al. : TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(15_suppl):1005 10.1200/JCO.2017.35.15_suppl.1005
    1. Borges VF, Ferrario C, Aucoin N, et al. : Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases. J Clin Oncol.ASCO Meeting Abstracts,2016;34(15_suppl):513 10.1200/JCO.2016.34.15_suppl.513
    1. Lin NU, Freedman RA, Miller K, et al. : Determination of the maximum tolerated dose (MTD) of the CNS penetrant tyrosine kinase inhibitor (TKI) tesevatinib administered in combination with trastuzumab in HER2+ patients with metastatic breast cancer (BC). J Clin Oncol.ASCO Meeting Abstracts2016;34(15_suppl):514 10.1200/JCO.2016.34.15_suppl.514
    1. McArthur GA, Maio M, Arance A, 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. 10.1093/annonc/mdw641
    2. F1000 Recommendation

    1. Long GV, Trefzer U, Davies MA, 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. 10.1016/S1470-2045(12)70431-X
    2. F1000 Recommendation

    1. Davies MA, Saiag P, Robert C, 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. 10.1016/S1470-2045(17)30429-1
    2. F1000 Recommendation

    1. Berghoff AS, Venur VA, Preusser M, et al. : Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment. Am Soc Clin Oncol Educ Book. 2016;35:e116–22. 10.1200/EDBK_100005
    1. Margolin K, Ernstoff MS, Hamid O, et al. : Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65. 10.1016/S1470-2045(12)70090-6
    2. F1000 Recommendation

    1. Goldberg SB, Gettinger SN, Mahajan A, 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. 10.1016/S1470-2045(16)30053-5
    2. F1000 Recommendation

    1. Tawbi H, Forsyth P, Algazi A, et al. : Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204. J Clin Oncol. 2017;35(15_suppl):9507 10.1200/JCO.2017.35.15_suppl.9507
    1. Long G, Atkinson V, Menzies A, et al. : A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). J Clin Oncol. 2017;35(15_suppl):9508 10.1200/JCO.2017.35.15_suppl.9508
    1. Tawbi HA, Forsyth PA, Algazi A, et al. : Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med. 2018;379(8):722–30. 10.1056/NEJMoa1805453
    2. F1000 Recommendation

    1. Kotecha R, Miller JA, Venur VA, 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. 10.3171/2017.1.JNS162797
    1. Lim SH, Lee JY, Lee MY, et al. : A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol. 2015;26(4):762–8. 10.1093/annonc/mdu584
    2. F1000 Recommendation

    1. Xie L, Nagpal S, Wakelee HA, et al. : Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study. Oncologist. 2018; pii: theoncologist.2018-0264. 10.1634/theoncologist.2018-0264
    2. F1000 Recommendation

    1. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. : Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol. 2017;35(10):1070–7. 10.1200/JCO.2016.69.7144
    1. Ding L, Ellis MJ, Li S, et al. : Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 2010;464(7291):999–1005. 10.1038/nature08989
    2. F1000 Recommendation

    1. Brastianos PK, Carter SL, Santagata S, et al. : Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015;5(11):1164–77. 10.1158/-15-0369
    2. F1000 Recommendation

    1. Chen G, Chakravarti N, Aardalen K, 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(21):5537–46. 10.1158/1078-0432.CCR-13-3003
    1. Paik PK, Shen R, Won H, et al. : Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases. Cancer Discov. 2015;5(6):610–21. 10.1158/-14-1129
    2. F1000 Recommendation

    1. Hohensee I, Lamszus K, Riethdorf S, et al. : Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. Am J Pathol. 2013;183(1):83–95. 10.1016/j.ajpath.2013.03.023
    1. Preusser M, Berghoff AS, Berger W, et al. : High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer. Lung Cancer. 2014;83(1):83–9. 10.1016/j.lungcan.2013.10.004

Source: PubMed

Подписаться