Intracranial control and survival outcome of tyrosine kinase inhibitor (TKI) alone versus TKI plus radiotherapy for brain metastasis of epidermal growth factor receptor-mutant non-small cell lung cancer

  • SooYoon Sung
  • Sea-Won Lee
  • Yoo-Kang Kwak
  • Jin Hyung Kang
  • Sook Hee Hong
  • Yeon-Sil Kim
Clinical Study

Abstract

Introduction

The efficacy of tyrosine kinase inhibitors (TKIs) with and without radiotherapy (RT) has not been determined in patients with brain metastases from epidermal growth factor receptor-mutant TKI naïve non-small cell lung cancer (NSCLC).

Methods

Between 2008 and 2016, 586 patients were diagnosed with NSCLC and treated with TKIs at a hospital in Seoul, South Korea; 81 of these patients met the eligibility criteria for our study. Outcomes analyzed included intracranial progression (ICP), neurological death, and overall survival (OS).

Results

The 2-year cumulative incidence of ICP was 36.5% in the TKI plus RT group and 62.2% in the TKI alone group (P = 0.006). The chronological pattern analysis indicated that 64.3% of ICP developed within 12 months of the start of TKI treatment in the TKI alone group. The multivariate analysis revealed that treatment group (P = 0.003) and duration of TKI treatment ≤ 12 months (P < 0.001) were significantly associated with ICP. However, no significant differences were observed in the 2-year OS rate (P = 0.267) or the 2-year cumulative incidence of neurological death (P = 0.740).

Conclusions

Cumulative incidence of ICP was significantly lower with TKI plus RT than with TKI alone; however, there was no significant difference in OS or neurological death. Deferring brain RT may not compromise neurologic and survival outcome in selected patients, but close magnetic resonance imaging follow-up is recommended for patients who defer brain RT.

Keywords

Non-small-cell lung carcinoma EGFR Brain metastasis EGFR tyrosine kinase inhibitor Radiotherapy 

Notes

Acknowledgements

Advice on the statistical analyses described in this article was provided by staff at the Catholic Medical Center Clinical Research Coordinating Center, Seoul, South Korea. This study was supported by Korean Cancer Foundation (K20170519).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11060_2018_2861_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 KB)

References

  1. 1.
    Jung KW, Won YJ, Oh CM et al (2017) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat 49:292–305CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics. CA Cancer J Clin 65:5–29CrossRefPubMedGoogle Scholar
  3. 3.
    Bhatt VR, Kedia S, Kessinger A et al (2013) Brain metastasis in patients with non-small-cell lung cancer and epidermal growth factor receptor mutations. J Clin Oncol 31:3162–3164CrossRefPubMedGoogle Scholar
  4. 4.
    Barnholtz-Sloan JS, Sloan AE, Davis FG et al (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865–2872CrossRefPubMedGoogle Scholar
  5. 5.
    Shin DY, Na II, Kim CH et al (2014) EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 9:195–199CrossRefPubMedGoogle Scholar
  6. 6.
    Kocher M, Maarouf M, Bendel M et al (2004) Linac radiosurgery versus whole brain radiotherapy for brain metastases. A survival comparison based on the RTOG recursive partitioning analysis. Strahlenther Onkol 180:263–267CrossRefPubMedGoogle Scholar
  7. 7.
    Andrews DW, Scott CB, Sperduto PW et al (2004) 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 363:1665–1672CrossRefPubMedGoogle Scholar
  8. 8.
    Won YK, Lee JY, Kang YN et al (2015) Stereotactic radiosurgery for brain metastasis in non-small cell lung cancer. Radiat Oncol J 33:207–216CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Park SJ, Kim HT, Lee DH et al (2012) 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 77:556–560CrossRefPubMedGoogle Scholar
  10. 10.
    Wu YL, Zhou C, Cheng Y et al (2013) 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 24:993–999CrossRefPubMedGoogle Scholar
  11. 11.
    Iuchi T, Shingyoji M, Sakaida T et al (2013) Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 82:282–287CrossRefPubMedGoogle Scholar
  12. 12.
    Welsh JW, Komaki R, Amini A et al (2013) 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 31:895–902CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lind JS, Lagerwaard FJ, Smit EF et al (2009) Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 74:1391–1396CrossRefPubMedGoogle Scholar
  14. 14.
    Kim TJ, Park CK, Yeo CD et al (2014) Simultaneous diagnostic platform of genotyping EGFR, KRAS, and ALK in 510 Korean patients with non-small-cell lung cancer highlights significantly higher ALK rearrangement rate in advanced stage. J Surg Oncol 110:245–251CrossRefPubMedGoogle Scholar
  15. 15.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
  16. 16.
    Patchell RA, Tibbs PA, Regine WF et al (1998) Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280:1485–1489CrossRefPubMedGoogle Scholar
  17. 17.
    Scheike TH, Zhang MJ. (2011) Analyzing Competing risk data using the R timereg package. J Stat Softw 38:i02CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chan BA, Hughes BG (2015) Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 4:36–54PubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen YM (2013) Update of epidermal growth factor receptor-tyrosine kinase inhibitors in non-small-cell lung cancer. J Chin Med Assoc 76:249–257CrossRefPubMedGoogle Scholar
  20. 20.
    Rosell R, Carcereny E, Gervais R et al (2012) 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 13:239–246CrossRefPubMedGoogle Scholar
  21. 21.
    Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957CrossRefPubMedGoogle Scholar
  22. 22.
    Zhou C, Wu YL, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742CrossRefPubMedGoogle Scholar
  23. 23.
    Rangachari D, Yamaguchi N, VanderLaan PA et al (2015) Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 88:108–111CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ceresoli GL, Cappuzzo F, Gregorc V et al (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 15:1042–1047CrossRefPubMedGoogle Scholar
  25. 25.
    Kim JE, Lee DH, Choi Y et al (2009) 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 65:351–354CrossRefPubMedGoogle Scholar
  26. 26.
    Ma S, Xu Y, Deng Q et al (2009) Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer 65:198–203CrossRefPubMedGoogle Scholar
  27. 27.
    Gerber NK, Yamada Y, Rimner A et al (2014) Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 89:322–329CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chen Y, Yang J, Li X et al (2016) 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 107:1800–1805CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  2. 2.Division of Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea

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