eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 14
Basic research

Efficacy of brain radiotherapy plus EGFR-TKI for EGFR-mutated NSCLC patients who develop brain metastasis

Wenxian Wang, Zhengbo Song, Yiping Zhang

Arch Med Sci 2018; 14, 6: 1298–1307
Online publish date: 2018/10/23
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
To analyze the appropriate treatment methods or timing to use epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and brain radiation treatment (RT) for symptomatic and asymptomatic brain metastases (BM) in patients with EGFR mutation non-small cell lung cancer (NSCLC).

Material and methods
We retrospectively studied patients diagnosed with EGFR gene mutated NSCLC who developed brain metastasis between June 2006 and December 2015 at Zhejiang Cancer Hospital. Treatment data were assessed in 181 patients with 49 symptomatic BM and 132 asymptomatic BM retrospectively.

In 49 symptomatic BM patients, the median OS of the stereotactic radiosurgery (SRS)-treated group was longer than in the whole brain radiotherapy (WBRT) group (37.7 vs. 21.1 months) (p = 0.194). In the group of 132 asymptomatic brain metastasis patients, the median overall survival (mOS) was longer in upfront brain radiotherapy compared with the upfront TKI group (24.9 vs. 17.4 months) (p = 0.035). In further analysis regarding the timing of using radiotherapy, out of all 74 patients, 33 underwent concurrent TKI and brain radiation, 13 received TKI after first-line RT treatment and 28 patients received radiotherapy after TKI failure. The intracranial progression free survival (iPFS) of the three groups was 11.1 months, 11.3 months and 8.1 months (p = 0.032), respectively. The mOS of the three groups was 21.9 months, 26.2 months and 17.1 months, respectively (p = 0.085).

Our research indicated that delayed brain RT may result in inferior iPFS in EGFR mutated NSCLC patients with asymptomatic brain metastases, but no OS benefit was obtained. In addition, our study revealed that patients treated with SRS had a significantly longer OS for symptomatic BM. Future prospective study of the optimal management strategy with WBRT or SRS and TKI for this patient cohort is urgently needed.


brain metastases, epidermal growth factor recptor tyrosine kinase inhibitors, non-small cell lung cancer, radiotherapy

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108.
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66: 115-32.
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004; 22: 2865-72.
Berger LA, Riesenberg H, Bokemeyer C, Atanackovic D. CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives. Lung Cancer 2013; 80: 242-48.
Lombardi G, Di Stefano AL, Farina P, Zagonel V, Tabouret E. Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: an overview of the literature. Cancer Treat Rev 2014; 40: 951-9.
Owonikoko TK, Arbiser J, Zelnak A, et al. Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol 2014; 11: 203-22.
Mehta MP, Rodrigus P, Terhaard CH, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole brain radiation therapy in brain metastases. J Clin Oncol 2003; 21: 2529-36.
Sekine A, Kato T, Hagiwara E, et al. Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features. Lung Cancer 2012; 77: 64-9.
Shin DY, Na II, Kim CH, Park SH, Baek HJ, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014; 9: 195-9.
Eichler AF, Chung E, Kodack DP, et al. The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011; 8: 344-56.
Porta R, Sánchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011; 37: 624-31.
Scoccianti S, Ricardi U. Treatment of brain metastases: review of phase III randomized controlled trials. Radiother Oncol 2012; 102: 168-79.
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 lung cancer. Ann Oncol 2015; 26: 762-8.
Bowden G, Kano H, Caparosa E, et al. Gamma knife radiosurgery for the management of cerebral metastases from non-small cell lung cancer. J Neurosurg 2015; 122: 766-72.
Ettinger DS, Wood DE, Akerley W, et al. NCCN Guidelines insights: non-small cell lung cancer, version 4.2016. J Natl Compr Canc Netw 2016; 14: 255-64.
Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2012; 18: 4406-14.
Cai L, Zhu JF, Zhang XW, et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neurooncol 2014; 120: 423-30.
Wang F, Ning F, Liu C, et al. 2015. Comparison of gefitinib versus VMP in the combination with radiotherapy for multiple brain metastases from non-small cell lung cancer. Cell Biochem Biophys 2015; 71: 1261-5.
Zhuang HZ, Yuan JW, Zhao L, Pang Q, Wang P. Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma. Drug Des Devel Ther 2013; 7: 1179-86.
Lee SM, Lewanski CR, N Counsell C, et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst 2014; 106: pii: dju151.
Sperduto PW, Wang HI, Robins MC, et al. 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.
Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in non small cell lung cancer. Neuro Oncol 2010; 12: 1193-9.
Gow CH, Chien CR, Chang YL, et al. 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.
Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 2006; 24: 1295-304.
Togashi Y, Masago K, Fukudo M, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol 2010; 5: 950-5.
Togashi Y, Masago K, Fukudo M, et al. Efficacy of increased dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 2011; 68: 1089-92.
Fan Y, Huang Z, Fang L, et al. A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer. Cancer Chemother Pharmacol 2015; 76: 517-23.
Iuchi T, Shingyoji M, Sakaida T, et al. 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.
Wu YL, Zhou C, Cheng Y, et al. 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.
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: 1042-7.
Porta R, Sanchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011; 37: 624-31.
Weber B, Winterdahl M, Memon A, et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol 2011; 6: 1287-9.
Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012; 18: CD003869.
Gaspar LE, Mehta MP, Patchell RA, et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010; 96: 17-32.
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: 1037-44.
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: 134-41.
Xue J, Kubicek GJ, Grimm J, et al. Biological implications of whole-brain radiotherapy versus stereotactic radiosurgery of multiple brain metastases. J Neurosurg 2014; 121 Suppl: 60-8.
Matsumoto S, Takahashi K, Iwakawa R, et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer 2006; 119: 1491-4.
Lee DW, Shin DY, Kim JW, et al. Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastasis: integrating with lung specific GPA score. Lung Cancer 2014; 86: 363-8.
Sperduto PM, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT & SRS with temozolomide or erlotinib for non-small cell lung cancer and 1-3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys 2013; 85: 1312-8.
Brown P, Asher A, Ballman K, et al. BMET-05. NCCTG N0574 (ALLIANCE): a phase III randomized trial of WBRT in addition to SRS in patients with 1 to 3 brain metastases. Neuro-Oncology 2015; 17: 45-54.
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387-95.
Cai L, Qiu X, Yang H, et al. Evaluation on efficacy and safety of the addition of X-knife therapy to gefitinib in NSCLC patients with symptomatic brain metastases. Oncotarget 2017; 8: 57470-6.
Liu S, Qiu B, Chen L, et al. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. Radiat Oncol 2015; 10: 118.
Jiang T, Su C, Li X, et al. 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.
Chen Y, Yang J, Li X, et al. First-line EGFR-TKI alone or with whole-brain radiotherapy for brain metastases in EGFR-mutated lung adenocarcinoma patients. Cancer Sci 2016; 107: 1800-5.
Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of deferring radiation therapy in patients with epidermal growth factor receptor-mutant non-small cell lung cancer who develop brain metastases. Int J Radiat Oncol Biol Phys 2016; 95: 673-9.
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe