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Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non-small cell lung cancer in the era of targeted therapy

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Abstract

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations commonly present brain metastases (BM) at the time of NSCLC diagnosis or during the clinical course. Conventionally, the prognosis of BM has been extremely poor, but the advent of EGFR-tyrosine kinase inhibitors (TKIs) has drastically improved the prognosis in these patients. Despite the presence of the blood–brain barrier, EGFR-TKIs have dramatic therapeutic effects on both BM and extracranial disease. In addition, recent systemic chemotherapies reportedly play a role in controlling BM. These treatment modalities can potentially replace whole brain radiotherapy (WBRT) to prevent or delay neurocognitive decline. Therefore, how to utilize these treatments is one issue. The other issue is what kind of treatment is best for recurrence after TKI therapy. Recent reports have shown a positive effect of a combination therapy of EGFR-TKI and radiotherapy on BM. Although neurocognitive decline is underscored when WBRT is considered, a survival benefit from WBRT has been proven especially in the potential long survivors with good prognostic index, especially disease-specific graded prognostic index (DS-GPA). In this review, treatment strategy including chemotherapeutic agents and radiotherapy is discussed in terms of risk–benefit balance in conjunction with DS-GPA.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  PubMed  Google Scholar 

  2. Arrieta O, Saavedra-Perez D, Kuri R, Aviles-Salas A, Martinez L, Mendoza-Posada D, Castillo P, Astorga A, Guzman E, De la Garza J. Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis. BMC Cancer. 2009;9:119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hanna NH, Dahlberg SE, Kolesar JM, Aggarwal C, Hirsch FR, Ramalingam SS, Schiller JH. Three-arm, randomized, phase 2 study of carboplatin and paclitaxel in combination with cetuximab, cixutumumab, or both for advanced non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG) study (E4508). Cancer. 2015;121:2253–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.

    Article  CAS  PubMed  Google Scholar 

  5. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L, Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C., Associazione Italiana Oncologia T. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46.

    Article  CAS  PubMed  Google Scholar 

  6. Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, Lee JS. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012;77:556–60.

    Article  CAS  PubMed  Google Scholar 

  7. Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y, Yang JJ. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24:993–9.

    Article  PubMed  Google Scholar 

  8. Iuchi T, Shingyoji M, Sakaida T, Hatano K, Nagano O, Itakura M, Kageyama H, Yokoi S, Hasegawa Y, Kawasaki K, Iizasa T. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;82:282–7.

    Article  CAS  PubMed  Google Scholar 

  9. 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;5:588–98.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, Chang JY, Wefel JS, McGovern SL, Garland LL, Chen SS, Holt J, Liao Z, Brown P, Sulman E, Heymach JV, Kim ES, Stea B. 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;31:895–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, Uhlmann EJ, Wong ET, Dahlberg SE, Huberman MS, Costa DB. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88:108–11.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Serlin Y, Shelef I, Knyazer B, Friedman A. Anatomy and physiology of the blood-brain barrier. Semin Cell Dev Biol. 2015;38:2–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014;15:13768–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.

    Article  CAS  PubMed  Google Scholar 

  15. Pitz MW, Desai A, Grossman SA, Blakeley JO. Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neurooncol. 2011;104:629–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16:5664–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev. 2014;40:716–22.

    Article  CAS  PubMed  Google Scholar 

  18. Li MX, He H, Ruan ZH, Zhu YX, Li RQ, He X, Lan BH, Zhang ZM, Liu GD, Xiao HL, Wu Y, Zhu B, Wang G, Yang ZZ. Central nervous system progression in advanced non-small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study. BMC Cancer. 2017;17:245.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sekine A, Satoh H, Iwasawa T, Tamura K, Hayashihara K, Saito T, Kato T, Arai M, Okudela K, Ohashi K, Ogura T. Prognostic factors for brain metastases from non-small cell lung cancer with EGFR mutation: influence of stable extracranial disease and erlotinib therapy. Med Oncol. 2014;31:228.

    Article  PubMed  CAS  Google Scholar 

  20. Bai H, Han B. The effectiveness of erlotinib against brain metastases in non-small cell lung cancer patients. Am J Clin Oncol. 2013;36:110–5.

    Article  CAS  PubMed  Google Scholar 

  21. Deng Y, Feng W, Wu J, Chen Z, Tang Y, Zhang H, Liang J, Xian H, Zhang S. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol. 2014;2:116–20.

    CAS  PubMed  Google Scholar 

  22. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237–46.

    Article  CAS  PubMed  Google Scholar 

  23. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149–58.

    Article  CAS  PubMed  Google Scholar 

  24. Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, Sakamori Y, Nagai H, Kim YH, Katsura T, Mishima M. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;70:399–405.

    Article  CAS  PubMed  Google Scholar 

  25. Kawamura T, Hata A, Takeshita J, Fujita S, Hayashi M, Tomii K, Katakami N. High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs. Cancer Chemother Pharmacol. 2015;75:1261–6.

    Article  CAS  PubMed  Google Scholar 

  26. Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, Clarke JL, Lassman AB. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13:1364–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kolbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577–89.

    Article  CAS  PubMed  Google Scholar 

  28. Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, Serke M, Stohlmacher-Williams J, Marten A, Maria Huber R, Dickgreber NJ, Afatinib Compassionate Use C. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10:156–63.

    Article  CAS  PubMed  Google Scholar 

  29. Hata A, Katakami N. Afatinib for erlotinib refractory brain metastases in a patient with EGFR-mutant non-small-cell lung cancer: can high-affinity TKI substitute for high-dose TKI? J Thorac Oncol. 2015;10:e65–6.

    Article  PubMed  Google Scholar 

  30. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8.

    Article  CAS  PubMed  Google Scholar 

  31. Goto K, Nishio M, Yamamoto N, Chikamori K, Hida T, Maemondo M, Katakami N, Kozuki T, Yoshioka H, Seto T, Fukuyama T, Tamura T. A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Lung Cancer. 2013;82:109–14.

    Article  PubMed  Google Scholar 

  32. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, Ando M, Yamazaki K, Saijo Y, Gemma A, Miyazawa H, Tanaka T, Ikebuchi K, Nukiwa T, Morita S, Hagiwara K, North East Japan Gefitinib Study G. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394–400.

    Article  CAS  PubMed  Google Scholar 

  33. Yang Z, Hackshaw A, Feng Q, Fu X, Zhang Y, Mao C, Tang J. Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: a meta-analysis. Int J Cancer. 2017;140:2805–19.

    Article  CAS  PubMed  Google Scholar 

  34. Stopfer P, Marzin K, Narjes H, Gansser D, Shahidi M, Uttereuther-Fischer M, Ebner T. Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother Pharmacol. 2012;69:1051–61.

    Article  CAS  PubMed  Google Scholar 

  35. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–34.

    Article  CAS  PubMed  Google Scholar 

  36. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88:74–9.

    Article  PubMed  Google Scholar 

  37. Lampson BL, Nishino M, Dahlberg SE, Paul D, Santos AA, Janne PA, Oxnard GR. Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: implications for targeted therapy development. Cancer. 2016. doi:10.1002/cncr.30270.

    PubMed  Google Scholar 

  38. Yamanaka Y, Sekine A, Kato T, Yamakawa H, Ikeda S, Baba T, Iwasawa T, Okudela K, Ogura T. Afatinib therapy for brain metastasis aggravated by a reduction in the dose of erlotinib due to the development of hepatotoxicity: a case report. Intern Med. 2017. Accepted.

  39. Wu C, Li YL, Wang ZM, Li Z, Zhang TX, Wei Z. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer. 2007;57:359–64.

    Article  PubMed  Google Scholar 

  40. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92.

    Article  CAS  PubMed  Google Scholar 

  41. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, Blackhall F, Haggstrom D, Yoh K, Novello S, Gold K, Hirashima T, Lin CC, Mann H, Cantarini M, Ghiorghiu S, Janne PA. Osimertinib in pretreated T790 M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 2017;35:1288–96.

    Article  PubMed  Google Scholar 

  43. Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, Pickup K, Jordan A, Hickey M, Grist M, Box M, Johnstrom P, Varnas K, Malmquist J, Thress KS, Janne PA, Cross D. 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;22:5130–40.

    Article  CAS  PubMed  Google Scholar 

  44. Jiang T, Zhou C. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. Transl Lung Cancer Res. 2014;3:370–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ahn MJ, Tsai CM, Yang JC, Shepherd FA, Satouchi M, Kim DW, Bazhenova LA, Hirashima T, Rukazenkov Y, Cantarini M, Mann H, Ramalingam SS, Mitsudomi T, Janne PA, Goss GD. 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:S625–6.

    Article  Google Scholar 

  46. Kim DW, Yang JC, Chen K, Cheng Z, Yin L, Martin PD, Yang Z, Jiang H, Ahn MJ. AZD 3759, an EGFR inhibitor with blood brain barrier (BBB) penetration for the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM): preclinical evidence and clinical cases. J Clin Oncol. 2015;33:abstr 8016.

    Google Scholar 

  47. Ahn MJ, Kim DW, Kim TM, Lin CC, Ratnayake J, Carlie DJ, Yin X, Yang Z, Jiang H, Yang JC. Phase 1 study of AZD 3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastases (BM) and leptomeningeal metastases (LM). J Clin Oncol. 2016;34:abstr 9003.

    Google Scholar 

  48. Jacobs SS, Fox E, Dennie C, Morgan LB, McCully CL, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Cancer Res. 2005;11:1669–74.

    Article  CAS  PubMed  Google Scholar 

  49. Inno A, Di Noia V, D’Argento E, Modena A, Gori S. State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer. Transl Lung Cancer Res. 2016;5:599–609.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Edelman MJ, Belani CP, Socinski MA, Ansari RH, Obasaju CK, Chen R, Monberg MJ, Treat J, Alpha Oncology Research N. Outcomes associated with brain metastases in a three-arm phase III trial of gemcitabine-containing regimens versus paclitaxel plus carboplatin for advanced non-small cell lung cancer. J Thorac Oncol. 2010;5:110–6.

    Article  PubMed  Google Scholar 

  51. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–51.

    Article  CAS  PubMed  Google Scholar 

  52. Syrigos KN, Vansteenkiste J, Parikh P, von Pawel J, Manegold C, Martins RG, Simms L, Sugarman KP, Visseren-Grul C, Scagliotti GV. Prognostic and predictive factors in a randomized phase III trial comparing cisplatin-pemetrexed versus cisplatin-gemcitabine in advanced non-small-cell lung cancer. Ann Oncol. 2010;21:556–61.

    Article  CAS  PubMed  Google Scholar 

  53. Kumthekar P, Grimm SA, Avram MJ, Kaklamani V, Helenowski I, Rademaker A, Cianfrocca M, Gradishar W, Patel J, Mulcahy M, McCarthy K, Raizer JJ. Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases. J Neurooncol. 2013;112:247–55.

    Article  CAS  PubMed  Google Scholar 

  54. Barlesi F, Gervais R, Lena H, Hureaux J, Berard H, Paillotin D, Bota S, Monnet I, Chajara A, Robinet G. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol. 2011;22:2466–70.

    Article  CAS  PubMed  Google Scholar 

  55. Bailon O, Chouahnia K, Augier A, Bouillet T, Billot S, Coman I, Ursu R, Belin C, Zelek L, Des Guetz G, Levy C, Carpentier AF, Morere JF. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol. 2012;14:491–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bearz A, Garassino I, Tiseo M, Caffo O, Soto-Parra H, Boccalon M, Talamini R, Santoro A, Bartolotti M, Murgia V, Berretta M, Tirelli U. Activity of Pemetrexed on brain metastases from non-small cell lung cancer. Lung Cancer. 2010;68:264–8.

    Article  PubMed  Google Scholar 

  57. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19:843–50.

    Article  CAS  PubMed  Google Scholar 

  58. Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, Akerley W. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27:5255–61.

    Article  CAS  PubMed  Google Scholar 

  59. Besse B, Le Moulec S, Mazieres J, Senellart H, Barlesi F, Chouaid C, Dansin E, Berard H, Falchero L, Gervais R, Robinet G, Ruppert AM, Schott R, Lena H, Clement-Duchene C, Quantin X, Souquet PJ, Tredaniel J, Moro-Sibilot D, Perol M, Madroszyk AC, Soria JC. Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized phase II study. Clin Cancer Res. 2015;21:1896–903.

    Article  CAS  PubMed  Google Scholar 

  60. De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, Omuro AM, Holodny AI, Lassman AB. Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol. 2010;100:443–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Sandler A, Hirsh V, Reck M, von Pawel J, Akerley W, Johnson DH. An evidence-based review of the incidence of CNS bleeding with anti-VEGF therapy in non-small cell lung cancer patients with brain metastases. Lung Cancer. 2012;78:1–7.

    Article  PubMed  Google Scholar 

  62. Zustovich F, Ferro A, Lombardi G, Farina P, Zagonel V. Bevacizumab-based therapy for patients with brain metastases from non-small-cell lung cancer: preliminary results. Chemotherapy. 2014;60:294–9.

    Article  CAS  PubMed  Google Scholar 

  63. 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 Oncol. 2013;15:1257–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ilhan-Mutlu A, Osswald M, Liao Y, Gommel M, Reck M, Miles D, Mariani P, Gianni L, Lutiger B, Nendel V, Srock S, Perez-Moreno P, Thorsen F, von Baumgarten L, Preusser M, Wick W, Winkler F. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Mol Cancer Ther. 2016;15:702–10.

    Article  CAS  PubMed  Google Scholar 

  65. Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med. 2010;16:116–22.

    Article  CAS  PubMed  Google Scholar 

  66. Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh CH, O’Connor P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377:1846–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15:1236–44.

    Article  CAS  PubMed  Google Scholar 

  68. Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massuti B, Palmero R, Aix SP, Carcereny E, Fruh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gomez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA, group Bc. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017;5:435–44.

    Article  CAS  PubMed  Google Scholar 

  69. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Perol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–73.

    Article  CAS  PubMed  Google Scholar 

  70. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  PubMed  Google Scholar 

  71. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L. Investigators K-Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  PubMed  Google Scholar 

  73. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR. Investigators K-Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.

    Article  CAS  PubMed  Google Scholar 

  74. Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257–65.

    Article  CAS  PubMed  Google Scholar 

  75. Lee CK, Man J, Lord S, Links M, Gebski V, Mok T, Yang JC. Checkpoint Inhibitors in Metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis. J Thorac Oncol. 2017;12:403–7.

    Article  PubMed  Google Scholar 

  76. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, Van Buuren MM, ‘t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome I, Consortium IBC, Consortium IM-S, PedBrain I, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nieder C, Grosu AL, Gaspar LE. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat Oncol. 2014;9:155.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, Xu W, Sahgal A. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;(4):CD003869. doi:10.1002/14651858.CD003869.pub3.

  79. Zeng YD, Liao H, Qin T, Zhang L, Wei WD, Liang JZ, Xu F, Dinglin XX, Ma SX, Chen LK. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget. 2015;6:8366–76.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008;14:162–8.

    Article  CAS  PubMed  Google Scholar 

  81. Johung KL, Yao X, Li F, Yu JB, Gettinger SN, Goldberg S, Decker RH, Hess JA, Chiang VL, Contessa JN. A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer. Clin Cancer Res. 2013;19:5523–32.

    Article  CAS  PubMed  Google Scholar 

  82. Tallet AV, Azria D, Barlesi F, Spano JP, Carpentier AF, Goncalves A, Metellus P. Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol. 2012;7:77.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Rosenman J, Choi NC. Improved quality of life of patients with small-cell carcinoma of the lung by elective irradiation of the brain. Int J Radiat Oncol Biol Phys. 1982;8:1041–3.

    Article  CAS  PubMed  Google Scholar 

  84. Li N, Zeng ZF, Wang SY, Ou W, Ye X, Li J, He XH, Zhang BB, Yang H, Sun HB, Fang Q, Wang BX. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann Oncol. 2015;26:504–9.

    Article  CAS  PubMed  Google Scholar 

  85. Pechoux CL, Sun A, Slotman BJ, De Ruysscher D, Belderbos J, Gore EM. Prophylactic cranial irradiation for patients with lung cancer. Lancet Oncol. 2016;17:e277–93.

    Article  PubMed  Google Scholar 

  86. Arriagada R, Le Chevalier T, Borie F, Riviere A, Chomy P, Monnet I, Tardivon A, Viader F, Tarayre M, Benhamou S. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst. 1995;87:183–90.

    Article  CAS  PubMed  Google Scholar 

  87. Gregor A, Cull A, Stephens RJ, Kirkpatrick JA, Yarnold JR, Girling DJ, Macbeth FR, Stout R, Machin D. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997;33:1752–8.

    Article  CAS  PubMed  Google Scholar 

  88. Le Pechoux C, Laplanche A, Faivre-Finn C, Ciuleanu T, Wanders R, Lerouge D, Keus R, Hatton M, Videtic GM, Senan S, Wolfson A, Jones R, Arriagada R, Quoix E, Dunant A, Prophylactic Cranial Irradiation Collaborative G. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol. 2011;22:1154–63.

    Article  PubMed  Google Scholar 

  89. Attia A, Page BR, Lesser GJ, Chan M. Treatment of radiation-induced cognitive decline. Curr Treat Options Oncol. 2014;15:539–50.

    Article  PubMed  Google Scholar 

  90. Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E, Group EGW. Small-cell lung cancer (SCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl l6):vi99–105.

    PubMed  Google Scholar 

  91. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8:955–62.

    Article  CAS  PubMed  Google Scholar 

  92. Pospisil P, Kazda T, Hynkova L, Bulik M, Dobiaskova M, Burkon P, Laack NN, Slampa P, Jancalek R. Post-WBRT cognitive impairment and hippocampal neuronal depletion measured by in vivo metabolic MR spectroscopy: results of prospective investigational study. Radiother Oncol. 2017;122:373–9.

    Article  PubMed  Google Scholar 

  93. Ghia A, Tome WA, Thomas S, Cannon G, Khuntia D, Kuo JS, Mehta MP. Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation. Int J Radiat Oncol Biol Phys. 2007;68:971–7.

    Article  PubMed  Google Scholar 

  94. Kundapur V, Ellchuk T, Ahmed S, Gondi V. Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial irradiation: a safety profile study for hippocampal sparing during prophylactic or therapeutic cranial irradiation. Int J Radiat Oncol Biol Phys. 2015;91:781–6.

    Article  PubMed  Google Scholar 

  95. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic L, Mehta MP. 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;32:3810–6.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Danysz W, Parsons CG, Karcz-Kubicha M, Schwaier A, Popik P, Wedzony K, Lazarewicz J, Quack G. GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality. Amino Acids. 1998;14:235–9.

    Article  CAS  PubMed  Google Scholar 

  97. Rapp SR, Case LD, Peiffer A, Naughton MM, Chan MD, Stieber VW, Moore DF Jr, Falchuk SC, Piephoff JV, Edenfield WJ, Giguere JK, Loghin ME, Shaw EG. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J Clin Oncol. 2015;33:1653–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, Yamanaka K, Sato Y, Jokura H, Yomo S, Nagano O, Kenai H, Moriki A, Suzuki S, Kida Y, Iwai Y, Hayashi M, Onishi H, Gondo M, Sato M, Akimitsu T, Kubo K, Kikuchi Y, Shibasaki T, Goto T, Takanashi M, Mori Y, Takakura K, Saeki N, Kunieda E, Aoyama H, Momoshima S, Tsuchiya K. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15:387–95.

    Article  PubMed  Google Scholar 

  99. Network NCC. Central nervous system cancers (Version 1. 2015). https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.

  100. Wang TJ, Saad S, Qureshi YH, Jani A, Nanda T, Yaeh AM, Rozenblat T, Sisti MB, Bruce JN, McKhann GM, Lesser J, Halmos B, Stoopler MB, Lassman AB, Cheng SK, Isaacson SR. Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation? Neuro Oncol. 2015;17:1022–8.

    Article  CAS  PubMed  Google Scholar 

  101. Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP. 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;29:134–41.

    Article  PubMed  Google Scholar 

  102. Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A. 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. 2013;31:65–72.

    Article  PubMed  Google Scholar 

  103. Brown P, Asher A, Ballman K, Farace E, Cerhan J, Anderson S. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol. 2015; abstr LBA4.

  104. Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys. 2000;47:1001–6.

    Article  CAS  PubMed  Google Scholar 

  105. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77:655–61.

    Article  PubMed  Google Scholar 

  106. Sperduto PW, Yang TJ, Beal K, Pan H, Brown PD, Bangdiwala A, Shanley R, Yeh N, Gaspar LE, Braunstein S, Sneed P, Boyle J, Kirkpatrick JP, Mak KS, Shih HA, Engelman A, Roberge D, Arvold ND, Alexander B, Awad MM, Contessa J, Chiang V, Hardie J, Ma D, Lou E, Sperduto W, Mehta MP. Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA). JAMA Oncol. 2016.

  107. Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. 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;388:2004–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Li YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, Yan HH, Wu YL. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol. 2016;11:1962–9.

    Article  PubMed  Google Scholar 

  109. Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:322–9.

    Article  CAS  PubMed  Google Scholar 

  110. Lee DW, Lee KH, Kim JW, Keam B. Molecular targeted therapies for the treatment of leptomeningeal carcinomatosis: current evidence and future directions. Int J Mol Sci. 2016;17:E1074. doi:10.3390/ijms17071074.

    Article  PubMed  Google Scholar 

  111. Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, Kris MG, Chan TA, DeAngelis LM, Omuro AM. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012;7:382–5.

    Article  PubMed  Google Scholar 

  112. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, Johnson BE. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16:5873–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, Abrey LE. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005;103:2344–8.

    Article  CAS  PubMed  Google Scholar 

  114. Sperduto PW, Shanley R, Luo X, Andrews D, Werner-Wasik M, Valicenti R, Bahary JP, Souhami L, Won M, Mehta M. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J Radiat Oncol Biol Phys. 2014;90:526–31.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Aoyama H, Tago M, Shirato H, Japanese Radiation Oncology Study GroupI. stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA Oncol. 2015;1:457–64.

    Article  PubMed  Google Scholar 

  116. 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;114:167–72.

    Article  CAS  PubMed  Google Scholar 

  117. Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, Boreta LC, Balasubramanian SK, Ahluwalia MS, Rana NG, Attia A, Gettinger SN, Contessa JN, Yu JB, Chiang VL. Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol 2017:JCO2016697144.

  118. Jiang T, Su C, Li X, Zhao C, Zhou F, Ren S, Zhou C, Zhang J. 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;11:1718–28.

    Article  PubMed  Google Scholar 

  119. Chen Y, Yang J, Li X, Hao D, Wu X, Yang Y, He C, Wang W, Wang J. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016;107:1800–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, Souhami L, Buyyounouski MK, Khuntia D, Demas W, Shah SA, Nedzi LA, Perry G, Suh JH, Mehta MP. 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. 2013;85:1312–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan

    Akimasa Sekine

  2. Department of Internal Medicine, Mito Medical Center, University of Tsukuba, Tsukuba, Japan

    Hiroaki Satoh

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  1. Akimasa Sekine
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Dr. Sekine has received a lecture fees from Boehringer Ingelheim and Chugai Pharmaceuticals. Dr. Satoh has no conflict of interest to declare.

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Sekine, A., Satoh, H. Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non-small cell lung cancer in the era of targeted therapy. Med Oncol 34, 121 (2017). https://doi.org/10.1007/s12032-017-0978-2

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