Targeted Oncology

, Volume 14, Issue 4, pp 423–431 | Cite as

Epidermal Growth Factor Receptor (EGFR)–Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinoma

  • Changhui Li
  • Bo Zhang
  • Jindong Guo
  • Fang Hu
  • Wei Nie
  • Xiaoxuan Zheng
  • Lixin Wang
  • Yuqing Lou
  • Yinchen Shen
  • Baohui HanEmail author
  • Xueyan ZhangEmail author
Original Research Article



Whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy can delay the occurrence of brain metastasis (BM) is unclear.


This retrospective study aimed to evaluate whether EGFR–TKIs combined with chemotherapy can delay BM and decrease the incidence of BM as initial progression.

Patients and Methods

The data of 100 patients with EGFR-mutant advanced lung adenocarcinoma were retrospectively reviewed. The patients had no BM at initial diagnosis, and BM occurred during the treatment. Patients received EGFR–TKI only or EGFR–TKI combined with chemotherapy. Intracranial progression-free survival (iPFS), systemic progression-free survival (PFS), and overall survival (OS) were evaluated.


The overall median OS was 39 months (95% confidence interval (CI), 35.6–42.4 months). The median OS of EGFR–TKI combined with chemotherapy and EGFR–TKI only are 41 months (95% CI 35.5–46.5 months) and 39 months (95% CI 36.8–41.2 months), respectively. Patients in the combination treatment group had longer PFS (16 vs. 10 months; P = 0.030) and iPFS (21 vs. 14 months; P = 0.026). Further, as initial progression, fewer patients developed BM in the combined treatment group compared with the EGFR–TKI-only group (30.6% vs. 52.9%, P = 0.002) with a hazard ratio of 0.64 (95% CI 0.43–0.96). After controlling for significant covariables in a multivariable model, the different treatment strategies were independently associated with improved iPFS.


In this retrospective analysis, EGFR–TKIs combined with chemotherapy could improve PFS. Further, the combined treatment could delay BM occurrence and decrease the incidence of BM as initial progression.



The authors greatly appreciate all patients who contributed to this study.

Compliance with Ethical Standards


This study was funded by the Science and Technology Commission of Shanghai Municipality, China (No.18441904700), and the nurture projects for basic research of Shanghai Chest Hospital (No. 2018YNJCM05).

Conflict of interest

Changhui Li, Bo Zhang, Jindong Guo, Fang Hu, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Yuqing Lou, Yinchen Shen, Baohui Han, and Xueyan Zhang declare that they have no conflicts of interest that might be relevant to the content of this article.


  1. 1.
    Merchut MP. Brain metastases from undiagnosed systemic neoplasms. Arch Intern Med. 1989;149(5):1076–80. Scholar
  2. 2.
    Li L, Luo S, Lin H, et al. Correlation between EGFR mutation status and the incidence of brain metastases in patients with non-small cell lung cancer. J Thorac Dis. 2017;9(8):2510–20. Scholar
  3. 3.
    Hsu F, De Caluwe A, Anderson D, Nichol A, Toriumi T, Ho C. EGFR mutation status on brain metastases from non-small cell lung cancer. Lung Cancer. 2016;96:101–7. Scholar
  4. 4.
    Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9:195–9. Scholar
  5. 5.
    Yoshida T, Yoh K, Niho S, et al. RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation. Lung Cancer. 2015;90:477–83. Scholar
  6. 6.
    Gallego Perez-Larraya J, Hildebrand J. Brain metastases. Handb Clin Neurol. 2014;121:1143–57. Scholar
  7. 7.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2014;350:2129–39. Scholar
  8. 8.
    Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57. Scholar
  9. 9.
    Gao G, Ren S, Li A, et al. Epidermal growth factor receptor–tyrosine kinase inhibitor therapy is effective as first–line treatment of advanced non-small–cell lung cancer with mutated EGFR: a meta–analysis from six phase III randomized controlled trials. Int J Cancer. 2012;131:822–9. Scholar
  10. 10.
    Rosell R, Carcereny E, Gervais R, et al. 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. Scholar
  11. 11.
    Han Baohui, Jin Bo, Chu Tianqing, et al. Combination of chemotherapy and gefitinib as first–line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: a randomized controlled trial. Int J Cancer. 2017;141:1249–56. Scholar
  12. 12.
    Cheng Ying, Murakami Haruyasu, Yang Pan-Chyr, et al. Randomized phase II trial of gefitinib with and without pemetrexed as first–Line therapy in patients with advanced nonsquamous non-small–cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016;34:3258–66. Scholar
  13. 13.
    Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small–cell lung cancer (FASTACT–2): a randomised, doubleblind trial. Lancet Oncol. 2013;14:777–86. Scholar
  14. 14.
    Sugawara S, Oizumi S, Minato K, et al. Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol. 2015;26:888–94. Scholar
  15. 15.
    Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol. 2018;36(15_suppl):9005. Scholar
  16. 16.
    Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9:195–9. Scholar
  17. 17.
    Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis–specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30:419–25. Scholar
  18. 18.
    Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008;72:1311–8. Scholar
  19. 19.
    Peters S, Bexelius C, Munk V, et al. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small–cell lung cancer. Cancer Treat Rev. 2016;45:139–62. Scholar
  20. 20.
    Roughley A, Damonte E, Taylor-Stokes G, et al. Impact of brain metastases on quality of life and estimated life expectancy in patients with advanced non-small cell lung cancer. Value Health. 2014;17:A650. Scholar
  21. 21.
    Fernandes AW, Wu B, Turner RM. Brain metastases in non-small cell lung cancer patients on epidermal growth factor receptor tyrosine kinase inhibitors: symptom and economic burden. J Med Econ. 2017;20:1136–47. Scholar
  22. 22.
    Zhang J, Shi X, Cai D, et al. MINI01.11: radiotherapy plus EGFR TKIs for brain metastasis in EGFR–mutant non-small cell lung cancer: a retrospective analysis of a single institution: topic: medical oncology. J Thorac Oncol. 2016;11:S263. Scholar
  23. 23.
    Jiang Tao, Min Weijie, Li Yanan, et al. Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis. Cancer Med. 2016;5:1055–65. Scholar
  24. 24.
    Chen Yongshun, Yang Jing, Li Xue, et al. 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. Scholar
  25. 25.
    Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25. Scholar
  26. 26.
    Aguiar PN Jr, Haaland B, Park W, et al. Cost-effectiveness of osimertinib in the first–line treatment of patients with EGFR–mutated advanced non-small cell lung cancer. JAMA Oncol. 2018;4:1080–4. Scholar
  27. 27.
    BinWu XiaohuaGu, Qiang Z. Cost-effectiveness of osimertinib for EGFR mutation–positive non-small cell lung cancer after progression following First-Line EGFR TKI therapy. J Thorac Oncol. 2018;13:184–93. Scholar
  28. 28.
    Yang Z, Tam KY. Combination strategies using EGFR–TKI in NSCLC therapy: learning from the gap between pre–clinical results and clinical outcomes. Int J Biol Sci. 2018;14:204–16. Scholar
  29. 29.
    Yang CH, Huang CJ, Yang CS, et al. Gefitinib reverses chemotherapy resistance in gefitinibinsensitive multidrug resistant cancer cells expressing ATP–binding cassette family protein. Cancer Res. 2005;65:6943–9. Scholar
  30. 30.
    Okabe T, Okamoto I, Tsukioka S, et al. Synergistic antitumor effect of S–1 and the epidermal growth factor receptor inhibitor gefitinib in nonsmall cell lung cancer cell lines: role of gefitinibinduced down–regulation of thymidylate synthase. Mol Cancer Ther. 2008;7:599–606. Scholar
  31. 31.
    Hsiao SH, Lu YJ, Li YQ, et al. Osimertinib (AZD9291) attenuates the function of multidrug resistance–linked ATP–binding cassette transporter ABCB1 in vitro. Mol Pharm. 2016;13:2117–25. Scholar
  32. 32.
    Dai CL, Tiwari AK, Wu CP, et al. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP–binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008;68:7905–14. Scholar
  33. 33.
    Cortes-Dericks L, Carboni GL, Schmid RA, et al. Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed. Int J Oncol. 2010;37:437–44. Scholar
  34. 34.
    Mani SA, Guo W, Liao MJ, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15. Scholar
  35. 35.
    La Monica S, Madeddu D, Tiseo M, et al. Combination of gefitinib and pemetrexed prevents the acquisition of TKI resistance in NSCLC cell lines carrying EGFR-activating mutation. J Thorac Oncol. 2016;11(7):1051–63. Scholar
  36. 36.
    Liao S, Penney BC, Wroblewski K, et al. Prognostic value of metabolic tumor burden on 18F–FDG PET in nonsurgical patients with non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2012;39:27–38. Scholar
  37. 37.
    Bazan JG, Duan F, Snyder BS, et al. Metabolic tumor volume predicts overall survival and local control in patients with stage III non-small cell lung cancer treated in ACRIN 6668/RTOG 0235. Eur J Nucl Med Mol Imaging. 2017;44:17–24. Scholar

Copyright information

© The Author(s) 2019
corrected publication 2019

Authors and Affiliations

  1. 1.Department of Pulmonary Medicine, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of Radiation Oncology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Integrated TCM and Western Medicine DepartmentShanghai Pulmonary Hospital Affiliated to Tongji UniversityShanghaiChina

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