Cited by 110Brain Metastases and TreatmentLung Cancer Treatments and MutationsGlioma Diagnosis and Treatment

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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

Soon, Yu Yang, Leong, Cheng Nang, Koh, Wee Yao, Tham, Ivan Weng Keong·2015·Radiotherapy and Oncology

DOI 10.1016/j.radonc.2014.12.011

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Abstract

Background and purpose EGFR TKIs alone have demonstrated activity against intracranial disease in EGFR mutant non-small cell lung cancer (NSCLC). This study aimed to determine if upfront cranial radiotherapy improves intracranial disease control and survival outcomes in EGFR mutant NSCLC with brain metastases relative to TKIs alone.Materials and methods We searched MEDLINE and various conference proceedings from 2008 to July 2014 for eligible studies where patients received upfront cranial radiotherapy or TKIs alone. Outcomes of interest were overall intracranial disease response rate (ORR), four-month intracranial disease progression-free survival (PFS), two-year overall survival (OS) and neurological adverse events (AE). We used random effects models to pool outcomes across studies and compared them using interaction tests.Results We found 12 non-comparative observational studies (n=363) with severe methodological limitations. Upfront cranial radiotherapy results in similar intracranial disease ORR (relative risk (RR) 0.93, 95% confidence interval (CI) 0.82-1.06; interaction p value (p)=0.53), improved four-month intracranial disease PFS (RR 1.06, 95% CI 1.00-1.12; p=0.03), improved two-year OS (RR 1.33, 95% CI 1.00-1.77; p=0.05) but caused more neurological AEs than TKIs alone.Conclusion There is evidence, albeit of low quality, that upfront cranial radiotherapy may improve intracranial disease control and survival outcomes compared with TKI alone.

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Role of osimertinib plus brain radiotherapy versus osimertinib single therapy in EGFR-mutated non-small-cell lung cancer with brain metastases: A meta-analysis and systematic review
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Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis
Taslimi, S., Brar, K., Ellenbogen, Y., Deng, J., Hou, W., de Moraes, F. Y., Glantz, M., Zacharia, B. E., Tan, A. C., Ahluwalia, M. S., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.739765 · Cited by 12
Role of Epidermal Growth Factor Receptor (EGFR) Inhibitors and Radiation in the Management of Brain Metastases from EGFR Mutant Lung Cancers
Khandekar, M. J., Piotrowska, Z., Willers, H., & Sequist, L. V. D. (2018) · The Oncologist · doi:10.1634/theoncologist.2017-0557 · Cited by 13
“A systematic review and meta-analysis from 2015 examined 12 studies including 363 patients with EGFR BMs who received TKI,WBRT, SRS, or some combination [52].”
Background
Systemic Therapy of Lung Cancer CNS Metastases Using Molecularly Targeted Agents and Immune Checkpoint Inhibitors
O'Kane, G. M., & Leighl, N. B. (2018) · CNS Drugs · doi:10.1007/s40263-018-0526-4 · Cited by 12
Radiotherapy in combination with systemic therapies for brain metastases: current status and progress
Liu, L., Chen, W., Zhang, R., Wang, Y., Liu, P., Lian, X., Zhang, F., Wang, Y., & Ma, W. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0109 · Cited by 9
Concurrent Afatinib and Whole-Brain Radiotherapy in Exon 19-del-EGFR Mutant Lung Adenocarcinoma: A Case Report and Mini Review of the Literature
Eze, C., Schmidt-Hegemann, N.-S., Roengvoraphoj, O., Dantes, M., & Manapov, F. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00088 · Cited by 10
Treatment Patterns and Survival Outcomes of Non-Small Cell Lung Cancer Patients Initially Diagnosed With Brain Metastases in Real-World Clinical Practice
Chen, X., Hou, X., Dinglin, X.-X., Liu, Y., Li, Y., Zheng, W., Li, D., Chen, J., Wu, X., Wang, K., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.581729 · Cited by 10
Multiple treatment modalities for brain metastasis in patients with EGFR-mutant non-small-cell lung cancer
Wang, H., Yu, X., Fan, Y., & Jiang, Y. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s156570 · Cited by 9
“…patients with inoperable BMs. 8,9 10–16 In addition, some studies showed that the combination of RT and EGFR-TKIs produced superior outcomes for patients with EGFR mutations and BMs. 5,6,17,18 There are still several controversies concerning the management of EGFR-mutant NSCLC patients with BMs.”
Influential
Management of brain metastases in elderly patients with lung cancer
Socha, J., Rychter, A., & Kępka, L. (2021) · Journal of Thoracic Disease · doi:10.21037/jtd-2019-rbmlc-05 · Cited by 9
“However, there is some data, albeit of low quality, coming from a meta-analysis (58) and from a multiinstitutional retrospective analysis (59), that upfront cranial radiotherapy may improve intracranial disease control (58) and survival outcomes compared with TKI alone (58,59).”
A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases
Caponnetto, S., Cantale, O., Friedlaender, A., Gomes, F., Daryanani, S., Gelibter, A. J., Cortellini, A., Giuffrida, D., Addeo, A., & Banna, G. L. (2021) · Journal of Molecular Pathology · doi:10.3390/jmp2010001 · Cited by 9
Palliative radiotherapy: Evolving role and policy challenges
Aggarwal, A. K., & Hughes, S. R. (2016) · Journal of Cancer Policy · doi:10.1016/j.jcpo.2016.05.003 · Cited by 9
“comparing the use of EGFR tyrosine kinase inhibitors with cranial irradiation in patients with brain metastases secondary to EGFR mutant non-small cell lung cancer [113].”
Background
Upfront Advanced Radiotherapy and New Drugs for NSCLC Patients with Synchronous Brain Metastases: Is the Juice Worth the Squeeze? A Real-World Analysis from Lombardy, Italy
Corrao, G., Franchi, M., Zaffaroni, M., Vincini, M. G., de Marinis, F., Spaggiari, L., Orecchia, R., Marvaso, G., & Jereczek‐Fossa, B. A. (2023) · Cancers · doi:10.3390/cancers15041103 · Cited by 8
“similarly concluded that upfront radiotherapy improves OS in EGFR-mutant aNSCLC patients receiving TKI [35].”
Background
Radiotherapy in brain metastases from EGFR-mutated non-small cell lung cancer
Bhandari, S., Dunlap, N., & Kloecker, G. H. (2021) · Journal of Thoracic Disease · doi:10.21037/jtd-2019-rbmlc-04 · Cited by 8
“A 2015 meta-analysis of 12 observational studies exclusively including 363 patients with EGFR-mutant NSCLC with BMs found that, compared with upfront treatment with first-generation EGFR TKI, upfront cranial radiation results in similar overall intracranial response rate, improved 4-month intracranial PFS, improved 2-…”
Result
Cranial irradiation in patients with EGFR-mutant non-small cell lung cancer brain metastases.
Yang, J. T., & Wu, A. J.-C. (2016) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2016.01.08 · Cited by 7
“In a recent metaanalysis that included 12 non-comparative studies and 363 patients, upfront cranial radiation was found to improve intracranial disease control and survival outcomes compared to TKI alone (13).”
Background
Brain metastases from non-small cell lung carcinoma: an overview of classical and novel treatment strategies
Martín, M., Hernánz, R., Vallejo, C., Guerrero, L., Mielgo-Rubio, X., Martín, A. L., Trujillo-Reyes, J. C., & Couñago, F. (2022) · Reports of Practical Oncology & Radiotherapy · doi:10.5603/rpor.a2022.0050 · Cited by 7
Upfront osimertinib in EGFR-mutated non-small cell lung cancer: is brain still a sanctuary?
Leonetti, A., Facchinetti, F., & Tiseo, M. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.11.69 · Cited by 7
“Osimertinib more than doubled the ORR and PFS in CNS lesions previously met with platinum-based chemotherapy (24), and almost overtook the historical outcomes of highly effective stereotactic brain radiotherapy in this setting (25).”
Background
Management of medically inoperable and tyrosine kinase inhibitor-naïve early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: a retrospective multi-institutional analysis
Sun, Y., Wu, M., Zhou, M., Luo, X., Guo, Y. P., Bai, H., Zhang, Z., Tian, W., Wang, T., Bai, Y., et al. (2020) · BMC Cancer · doi:10.1186/s12885-020-07122-7 · Cited by 7
Brain metastases in patients with EGFR -mutant non-small-cell lung cancer
Rosell, R., & Karachaliou, N. (2017) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(17)30265-5 · Cited by 6
Management of patients with multiple brain metastases
Arnaout, M. M., Hoz, S. S., Lee, Á., & Taha, M. (2024) · The Egyptian Journal of Neurosurgery : the official publication of the Egyptian Society of Neurological Surgeons/Egyptian journal of neurosurgery · doi:10.1186/s41984-024-00321-5 · Cited by 6
“There hasn’t been a randomized trial comparing TKI therapy alone against TKI therapy followed by cranial irradiation [38–40].”
Background
Effects of EGFR-TKIs combined with intracranial radiotherapy in EGFR-mutant non-small cell lung cancer patients with brain metastases: a retrospective multi-institutional analysis
He, M., Wu, X., Li, L., Yi, G., Wang, Y., He, H., Ye, Y., Zhou, R., Xu, Z., & Yang, Z. (2025) · Radiation Oncology · doi:10.1186/s13014-024-02578-4 · Cited by 5
“Similarly, a meta-analysis involving 363 NSCLC patients with EGFR mutations and BMs found that upfront intracranial RT improved four-month iPFS and two-year OS compared to EGFR-TKIs alone [26].”
The Landscape and Management of Brain Parenchymal and Leptomeningeal Metastases in EGFR Mutated Non-Small Cell Lung Cancer
Hyak, J. M., & Rashdan, S. (2025) · Cancers · doi:10.3390/cancers17152434 · Cited by 5
“Soon et al. found, in their review of 12 first-line BM treatment studies, that, despite similar response rates between TKIs alone, WBRT with TKIs, WBRT alone, and SRS alone, survival was improved when adding WBRT to TKIs or sequencing SRS with a TKI versus a TKI alone [58].”
Stereotactic radiosurgery for brain metastases: A retrospective cohort study comparing treatment results between two lung cancer patient age groups, 75 years or older vs 65–74 years
Yamamoto, M., Serizawa, T., Sato, Y., Higuchi, Y., Kasuya, H., & Barfod, B. E. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.07.037 · Cited by 6
Brain surgery in combination with tyrosine kinase inhibitor and whole brain radiotherapy for epidermal growth factor receptor-mutant non-small-cell lung cancer with brain metastases
Lee, H.-H., Chen, C., Chuang, H., Huang, Y., & Huang, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-53456-z · Cited by 5
The efficacy of EGFR-tyrosine kinase inhibitor in non-small cell lung cancer patients with synchronous brain metastasis: a real-world study
Choi, J., Choi, Y. W., Lee, H. W., Kang, S. Y., Jeong, G. S., Ahn, M. S., Oh, Y., Noh, O. K., Kim, S.-H., Roh, T. H., et al. (2022) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2021.315 · Cited by 4
“Although many retrospective studies showed conflicting results [5-8,15-20], a few meta-analyses revealed better OS by addition of local treatment [2,21,22].”
BackgroundResultInfluential
The Effect of Epidermal Growth Factor Receptor Mutation on Intracranial Progression-Free Survival of Non-Small Cell Lung Cancer Patients with Brain Metastasis Underwent Gamma Knife Radiosurgery
Yang, S.-H., Kim, H. Y., Lee, S.-I., & Jin, S. J. (2020) · Brain Tumor Research and Treatment · doi:10.14791/btrt.2020.8.e15 · Cited by 3
“EGFR mutation has shown to be better prognostic factor in NSCLC patients when TKI was selected as a first-line chemotherapy [12-15].”
Background
Effect of Different Timing of Local Brain Radiotherapy on Survival of EGFR-Mutated NSCLC Patients with Limited Brain Metastases
Wang, Y., Wu, S., Li, J., Liang, X., & Zhou, X. (2023) · Brain Sciences · doi:10.3390/brainsci13091280 · Cited by 3
“reported the results from 12 non-comparative observational studies (n = 363) and found upfront cranial radiotherapy improved four-month intracranial disease PFS than TKIs alone [17].”
Result
Stereotactic radiosurgery in the era of novel systemic therapy for lung cancer brain metastases
Mudra, S. E., Bhandari, S., Tripathi, P., Dunlap, N., & Kloecker, G. H. (2019) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2019.09 · Cited by 3
“SRS followed by anti-EGFR TKI resulted in the longest overall survival, with WBRT followed by anti-EGFR TKI demonstrating intermediate overall survival and anti-EGFR TKI followed by SRS or WBRT at intracranial progression resulting in the shortest median overall survival([50,51]).”
Background
Upfront brain radiotherapy improves intracranial progression-free survival but not overall survival in lung adenocarcinoma patients with brain metastases: a retrospective, single-institutional analysis from China
Jiang, A., Ni, M., Li, L., Zhao, F., Yao, Y., Ding, X., Yu, Q., Zhang, L., & Yuan, S. (2022) · Journal of Cancer · doi:10.7150/jca.64335 · Cited by 3
“Several qualitative reviews have suggested that TKI therapy may be used first before BRT in EGFR+ NSCLC patients with asymptomatic BM [31-34].”
Background
ALK on my mind: alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements
Tran, P. N., & Klempner, S. J. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.03.47 · Cited by 4
“Meta analyses in EGFR mutant disease has suggested that cranial RT followed by erlotinib may be superior to upfront erlotinib in patient with CNS mets (22).”
Background
The optional approach of oncogene-addicted non-small cell lung cancer with brain metastases in the new generation targeted therapies era
Spagnuolo, A., Muto, M., Monaco, F., Colantuoni, G., & Gridelli, C. (2019) · Translational Lung Cancer Research · doi:10.21037/tlcr.2019.12.24 · Cited by 3
Efficacy and Safety of EGFR Tyrosine Kinase Inhibitors Combined with Cranial Radiotherapy for Brain Metastases from Non‐Small‐Cell Lung Cancer: A Protocol for a Systematic Review and Meta‐Analysis
Ge, Y., Xu, B., Wang, H., Gao, J., Zhang, X., Lu, T., Gao, R., & Li, J. (2022) · BioMed Research International · doi:10.1155/2022/6531748 · Cited by 2
“Two systematic reviews demonstrated that cranial RT with EGFR-TKIs might improve survival outcomes [28, 29].”
Radiotherapy of brain metastasis from lung cancer in limited resource settings
Agarwal, J. P., Tibdewal, A. R., Mohanty, S., & Mummudi, N. B. (2021) · Journal of Thoracic Disease · doi:10.21037/jtd-2019-rbmlc-02 · Cited by 2
“Retrospective studies and metaanalysis have shown inferior survival outcomes and shorter intracranial control rate with TKI alone than combination of cranial RT and TKI (33,34).”
Result
Efficacy and Safety of EGFR-TKI Combined With Early Brain Radiotherapy Versus TKI Alone in Patients With EGFR-Mutated NSCLC With Brain Metastases: A Systematic Review and Meta-Analysis
Zeng, Z., Feng, S., Gao, T., Chen, C., Chen, J., Chen, J., & Lian, Y. (2025) · Clinical Lung Cancer · doi:10.1016/j.cllc.2025.04.010 · Cited by 2
Treatment preferences for epidermal growth factor receptor mutation-positive non-small cell lung cancer with brain metastasis: a large-scale survey from Chinese oncologists
Yu, Y., Qian, J., Shen, L., Ji, W., & Lü, S. (2022) · Annals of Translational Medicine · doi:10.21037/atm-21-6413 · Cited by 2
“Also, TKIs might have radiosensitizing effects, and thus can potentialize the effect of RT when used in combination (33,34).”
Background
Comparative efficacy of osimertinib with and without radiation therapy in EGFR-mutated nonsmall cell lung cancer with brain metastases
Aibani, R., Collins, J. N., Amir-Kabirian, B., & Kamran, A. S. (2025) · Seminars in Oncology · doi:10.1016/j.seminoncol.2025.152436 · Cited by 1
Upfront radiation versus EGFR-TKI: which is the best approach for EGFR-mutated NSCLC patients with brain metastasis?
Passiglia, F., & Rolfo, C. D. (2017) · Translational Cancer Research · doi:10.21037/tcr.2017.04.08 · Cited by 1
“These data have been confirmed by a recent meta-analysis including 12 non-comparative trials and more than 300 EGFR-mutated NSCLC patients with BM revealing that WBRT improved both intracranial control and survival outcomes as compared to upfront EGFR-TKI monotherapy (21).”
Result
ZNS-Befall bei Patienten mit NSCLC
Reinmuth, N., & Würschmidt, F. (2018) · Im Focus Onkologie · doi:10.1007/s15015-018-3602-1 · Cited by 1
“Ähnliche Daten ergab auch eine Metaanalyse von zwölf prospektiven und retrospektiven Studien [48].”
Background
EGFR-Tyrosine Kinase Inhibitor Combined with Radiotherapy in 105 Patients of Lung Adenocarcinoma with Brain Metastasis: A Retrospective Study of Prognostic Factor Analysis
Yu, W., Yuan, X., Song, X. M., Li, T., & Zhang, M. (2024) · Oncology Research and Treatment · doi:10.1159/000541494 · Cited by 1
Non-small Cell Lung Cancer with Multiple Brain Metastases Treated with Radiosurgery and Erlotinib: A Case Report
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“Similarly, a metaanalysis of 12 studies reported that upfront radiotherapy, either WBRT or SRS, improved OS in EGFR-mutant NSCLC patients [8].”
Background
Combining Radiosurgery and Systemic Therapies for Treatment of Brain Metastases
Chiang, V., & Cheok, S. K. (2019) · Springer eBooks · doi:10.1007/978-3-030-23417-1_19 · Cited by 1
Brain Metastases
Vellayappan, B. A., Sahgal, A., Redmond, K. J., Halasz, L. M., Chang, E. L., & Lo, S. S.-M. (2017) · Medical radiology · doi:10.1007/174_2017_13 · Cited by 1
The systemic management of central nervous system metastases and leptomeningeal disease from advanced lung, melanoma, and breast cancer with molecular drivers: An Australian perspective
Senko, C., Gunjur, A., Balasubramanian, A., Gan, H. K., Parakh, S., & Cher, L. (2022) · Asia-Pacific Journal of Clinical Oncology · doi:10.1111/ajco.13759 · Cited by 1
METÁSTASIS CEREBRALES EN CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS CON MUTACION EGFR
Palomino, R. M., & Cárdenas-Agramonte, R. (2019) · Revista de la Facultad de Medicina Humana · doi:10.25176/rfmh.v19.n1.1798 · Cited by 1

Authors: Soon, Y. Y., Leong, C. N., Koh, W. Y., & Tham, I. W. K.
Affiliations: National University of Singapore (SG)
Corresponding author: Soon, Yu Yang
ORCID: Soon, Yu Yang
Leong, Cheng Nang
Koh, Wee Yao
Tham, Ivan Weng Keong
Venue: Radiotherapy and Oncology
Publisher: Elsevier BV
Published: 2015-02
Volume: 114
Issue: 2
Pages: 167-172
ISSN: 0167-8140 (ISSN-L)
DOI: 10.1016/j.radonc.2014.12.011
OpenAlex: W2021095467
Cited by: 110
References: 42
Citations by year: 2025: 5 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 10 · 2020: 13 · 2019: 15 · 2018: 12 · 2017: 21 · 2016: 16 · 2015: 1
FWCI: 2.95
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Radiotherapy and Oncology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Brain Metastases and Treatment
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Keywords: EGFR tyrosine kinase inhibitors, cranial irradiation, EGFR mutation, non-small cell lung cancer, brain metastases, intracranial disease control, progression-free survival, overall survival, neurological adverse events, upfront radiotherapy
MeSH terms: Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Cranial Irradiation, Disease-Free Survival, Protein Kinase Inhibitors, Chemoradiotherapy, ErbB Receptors

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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

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