The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI)

  • Shoji YomoEmail author
  • Toru Serizawa
  • Masaaki Yamamoto
  • Yoshinori Higuchi
  • Yasunori Sato
  • Takashi Shuto
  • Atsuya Akabane
  • Hidefumi Jokura
  • Jun Kawagishi
  • Hidefumi Aoyama
Clinical Study



Recent advances in targeted therapy have prolonged overall survival (OS) for patients with lung cancer. The impact of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) on brain metastases (BM) treated with stereotactic radiosurgery (SRS) has not, however, been fully elucidated. We investigated the influence of post-SRS EGFR-TKI use on the efficacy and toxicity of SRS for BM from lung adenocarcinoma.


We used the updated dataset of the Japanese Leksell Gamma Knife (JLGK) 0901 study, which proved the efficacy of Gamma Knife SRS in patients with BM. Propensity score matching (PSM) analysis was employed to determine the impact of concurrent or post-SRS EGFR-TKI use on OS, neurological death, intracranial disease recurrence and SRS-related adverse events.


Among 1194 patients registered in the JLGK0901 study, 608 eligible lung adenocarcinoma patients were identified and 238 (39%) had received EGFR-TKI concurrently or during the post-SRS clinical course. After PSM, there were 200 patient pairs with/without post-SRS EGFR-TKI use. EGFR-TKI use was associated with longer OS (median 25.5 vs. 11.0 months, HR 0.60, 95% CI 0.48–0.75, p < 0.001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45, 95% CI 1.12–1.89, p = 0.005). Neurological death, local recurrence and SRS-related adverse event rates did not differ significantly between the two groups.


Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use.


Non-small cell lung cancer Epidermal growth factor receptor Tyrosine kinase inhibitors Brain metastases Gamma knife radiosurgery Propensity score matching analysis 



Brain metastases


Epidermal growth factor receptor


Japanese Leksell Gamma Knife


National Cancer Institute Common Terminology Criteria for Adverse Events


Non-small cell lung cancer


Overall survival


Propensity score matching


Stereotactic radiosurgery


Tyrosine kinase inhibitors



We are grateful to Bierta Barfod, M.D., M.P.H. for her help with the language editing of this manuscript.


11,000,000 Japanese Yen were provided to the JLGK0901 study by the Japan Brain Foundation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The institutional review board of each facility participating in the JLGK0901 study approved all aspects of this study, and patients provided written informed consent before enrolment.


  1. 1.
    Yawn BP, Wollan PC, Schroeder C, Gazzuola L, Mehta M (2003) Temporal and gender-related trends in brain metastases from lung and breast cancer. Minn Med 86:32–37Google Scholar
  2. 2.
    Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865–2872. CrossRefGoogle Scholar
  3. 3.
    Moro-Sibilot D, Smit E, de Castro Carpeno J, Lesniewski-Kmak K, Aerts JG, Villatoro R, Kraaij K, Nacerddine K, Dyachkova Y, Smith KT, Girvan A, Visseren-Grul C, Schnabel PA (2015) Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: analysis from the European FRAME study. Lung Cancer 90:427–432. CrossRefGoogle Scholar
  4. 4.
    Iuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, Yoshida Y, Ashinuma H, Kawasaki K, Hasegawa Y, Sakaida T, Iizasa T (2015) Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol 20:674–679. CrossRefGoogle Scholar
  5. 5.
    Shin DY, Lee DH, Kim CH, Koh JS, Lee JC, Baek HJ, Kim SW, Choi CM, Na II (2016) Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung. J Cancer Res Ther 12:318–322. CrossRefGoogle Scholar
  6. 6.
    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, de 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 (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(3):239–246CrossRefGoogle Scholar
  7. 7.
    Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 15:1042–1047. CrossRefGoogle Scholar
  8. 8.
    Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, Lee JS (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 77:556–560. CrossRefGoogle Scholar
  9. 9.
    Iuchi T, Shingyoji M, Sakaida T, Hatano K, Nagano O, Itakura M, Kageyama H, Yokoi S, Hasegawa Y, Kawasaki K, Iizasa T (2013) Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 82:282–287. CrossRefGoogle Scholar
  10. 10.
    Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crino L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Janne PA, Yang JC (2017) CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. Google Scholar
  11. 11.
    Zeng YD, Zhang L, Liao H, Liang Y, Xu F, Liu JL, Dinglin XX, Chen LK (2012) Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study. Asian Pac J Cancer Prev 13:909–914CrossRefGoogle Scholar
  12. 12.
    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 (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 31:895–902. CrossRefGoogle Scholar
  13. 13.
    Soon YY, Leong CN, Koh WY, Tham IW (2015) 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 114:167–172. CrossRefGoogle Scholar
  14. 14.
    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 (2017) 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 35:1070–1077. CrossRefGoogle Scholar
  15. 15.
    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 (2014) Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 15:387–395. CrossRefGoogle Scholar
  16. 16.
    Yamamoto M, Serizawa T, Higuchi Y, Sato Y, Kawagishi J, Yamanaka K, Shuto T, Akabane A, Jokura H, Yomo S, Nagano O, Aoyama H (2017) A multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901 Study Update): irradiation-related complications and long-term maintenance of mini-mental state examination scores. Int J Radiat Oncol Biol Phys 99:31–40. CrossRefGoogle Scholar
  17. 17.
    Austin PC (2014) A comparison of 12 algorithms for matching on the propensity score. Stat Med 33:1057–1069. CrossRefGoogle Scholar
  18. 18.
    Parsons LS Reducing bias in a propensity score matched pair sample using greedy matching techniques. Accessed June 1 2019.Google Scholar
  19. 19.
    Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC (2008) Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res 14:162–168. CrossRefGoogle Scholar
  20. 20.
    Lee HL, Chung TS, Ting LL, Tsai JT, Chen SW, Chiou JF, Leung HW, Liu HE (2012) EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases. Radiat Oncol 7:181. CrossRefGoogle Scholar
  21. 21.
    Lee CC, Hsu SPC, Lin CJ, Wu HM, Chen YW, Luo YH, Chiang CL, Hu YS, Chung WY, Shiau CY, Guo WY, Hung-Chi Pan D, Yang HC (2019) Epidermal growth factor receptor mutations: association with favorable local tumor control following gamma knife radiosurgery in patients with non-small cell lung cancer and brain metastases. J Neurosurg. Google Scholar
  22. 22.
    Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS, Investigators F (2018) Osimertinib in Untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113–125. CrossRefGoogle Scholar
  23. 23.
    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 (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135. CrossRefGoogle Scholar
  24. 24.
    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM (2016) 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 17:976–983. CrossRefGoogle Scholar
  25. 25.
    Solomon B, Hagekyriakou J, Trivett MK, Stacker SA, McArthur GA, Cullinane C (2003) EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Epidermal growth factor receptor. Int J Radiat Oncol Biol Phys 55:713–723CrossRefGoogle Scholar
  26. 26.
    Das AK, Sato M, Story MD, Peyton M, Graves R, Redpath S, Girard L, Gazdar AF, Shay JW, Minna JD, Nirodi CS (2006) Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 66:9601–9608. CrossRefGoogle Scholar
  27. 27.
    Yomo S, Oda K (2018) Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients. Lung Cancer 119:120–126. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shoji Yomo
    • 1
    Email author
  • Toru Serizawa
    • 2
  • Masaaki Yamamoto
    • 3
  • Yoshinori Higuchi
    • 4
  • Yasunori Sato
    • 5
  • Takashi Shuto
    • 6
  • Atsuya Akabane
    • 7
  • Hidefumi Jokura
    • 8
  • Jun Kawagishi
    • 8
  • Hidefumi Aoyama
    • 9
  1. 1.Division of Radiation OncologyAizawa Comprehensive Cancer Center, Aizawa HospitalMatsumotoJapan
  2. 2.Tokyo Gamma Unit Center, Tsukiji Neurological ClinicTokyoJapan
  3. 3.Katsuta Hospital Mito Gamma HouseHitachinakaJapan
  4. 4.Department of Neurological SurgeryChiba University Graduate School of MedicineChibaJapan
  5. 5.Department of Preventive Medicine and Public HealthKeio University School of MedicineTokyoJapan
  6. 6.Department of NeurosurgeryYokohama Rosai HospitalYokohamaJapan
  7. 7.Gamma Knife CenterNTT Medical Center TokyoTokyoJapan
  8. 8.Jiro Suzuki Memorial Gamma House, Furukawa Seiryo HospitalOsakiJapan
  9. 9.Department of RadiologyNiigata University Graduate School of Medicine and Dental SciencesNiigataJapan

Personalised recommendations