Craniocerebral radiotherapy for EGFR‑mutant non‑small cell lung cancer with brain metastasis: Current evidence and future perspectives on therapeutic strategies (Review)

Luo,Yijun; Lei,Wenqian; Wang,Xiaoli

doi:10.3892/mco.2025.2891

Craniocerebral radiotherapy for EGFR‑mutant non‑small cell lung cancer with brain metastasis: Current evidence and future perspectives on therapeutic strategies (Review)

Authors:
- Yijun Luo
- Wenqian Lei
- Xiaoli Wang
View Affiliations

Affiliations: Department of Oncology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330000, P.R. China, Department of Oncology, Hejiang County People's Hospital, Luzhou, Sichuan 646200, P.R. China
Published online on: August 20, 2025 https://doi.org/10.3892/mco.2025.2891
Article Number: 96
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Brain metastases (BMs) frequently occur in non‑small cell lung cancer (NSCLC) and are associated with a poor prognosis. Epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) have shown notable potential in treating patients with NSCLC and BMs due to their enhanced ability to cross the blood‑brain barrier. However, failure pattern analyses reveal that initial disease progression (PD) in most patients primarily occurs in the brain, with >50% of cranial PD occurring exclusively at the original metastatic sites. This highlights the potential clinical importance of craniocerebral radiotherapy. Nevertheless, current clinical research indicates that not all patients with BMs will benefit from combined craniocerebral radiotherapy. Therefore, a comprehensive evaluation of relevant clinical factors is essential before selecting the most suitable treatment approach for these patients.

View Figures

View References

1	Ganti AK, Klein AB, Cotarla I, Seal B and Chou E: Update of incidence, prevalence, survival,and initial treatment in patients with non-small cell lung cancer in the US. JAMA Oncol. 7:1824–1832. 2021.PubMed/NCBI View Article : Google Scholar
2	Wang M, Herbst RS and Boshoff C: Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 27:1345–1356. 2021.PubMed/NCBI View Article : Google Scholar
3	Zhou F, Guo H, Xia Y, Le X, Tan D, Ramalingam SS and Zhou C: The changing treatment landscape of EGFR-mutant non-small-cell lung cancer. Nat Rev Clin Oncol. 22:95–116. 2025.PubMed/NCBI View Article : Google Scholar
4	Mizuno T, Konno H, Nagata T, Isaka M and Ohde Y: Osteogenic and brain metastases after non-small cell lung cancer resection. Int J Clin Oncol. 26:1840–1846. 2021.PubMed/NCBI View Article : Google Scholar
5	Popat S, Ahn MJ, Ekman S, Leighl NB, Ramalingam SS, Reungwetwattana T, Siva S, Tsuboi M, Wu YL and Yang JC: Osimertinib for EGFR-mutant non-small-cell lung cancer central nervous system metastases: Current evidence and future perspectives on therapeutic strategies. Target Oncol. 18:9–24. 2023.PubMed/NCBI View Article : Google Scholar
6	Li Z, Wang J, Deng L, Zhai Y, Zhang T, Bi N, Wang J, Wang X, Liu W, Xiao Z, et al: Hippocampal avoidance whole-brain radiotherapy with simultaneous integrated boost in lung cancer brain metastases and utility of the Hopkins verbal learning test for testing cognitive impairment in Chinese patients: A prospective phase II study. BMC Cancer. 24(899)2024.PubMed/NCBI View Article : Google Scholar
7	Gaebe K, Li AY, Park A, Parmar A, Lok BH, Sahgal A, Chan K, Erickson AW and Das S: Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: A systematic review and meta-analysis. Lancet Oncol. 23:931–939. 2022.PubMed/NCBI View Article : Google Scholar
8	Le Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, Galldiks N, de Azambuja E, Berghoff AS, Metellus P, et al: EANO-ESMO Clinical practice guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 32:1332–1347. 2021.PubMed/NCBI View Article : Google Scholar
9	Vogelbaum MA, Brown PD, Messersmith H, Brastianos PK, Burri S, Cahill D, Dunn IF, Gaspar LE, Gatson N, Gondi V, et al: Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol. 40:492–516. 2022.PubMed/NCBI View Article : Google Scholar
10	Colclough N, Chen K, Johnström P, Strittmatter N, Yan Y, Wrigley GL, Schou M, Goodwin R, Varnäs K, Adua SJ, et al: Preclinical comparison of the blood-brain barrier permeability of osimertinib with other EGFR TKIs. Clin Cancer Res. 27:189–201. 2021.PubMed/NCBI View Article : Google Scholar
11	Hayman JA, Dekker A, Feng M, Keole SR, McNutt TR, Machtay M, Martin NE, Mayo CS, Pawlicki T, Smith BD, et al: Minimum data elements for radiation oncology: An American society for radiation oncology consensus paper. Pract Radiat Oncol. 9:395–401. 2019.PubMed/NCBI View Article : Google Scholar
12	Tozuka T, Noro R, Mizutani H, Kurimoto F, Hakozaki T, Hisakane K, Naito T, Takahashi S, Taniuchi N, Yajima C, et al: Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-mutant non-small cell lung cancer. Lung Cancer. 191(107540)2024.PubMed/NCBI View Article : Google Scholar
13	Tsai PF, Yang CC, Chuang CC, Huang TY, Wu YM, Pai PC, Tseng CK, Wu TH, Shen YL and Lin SY: Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: A prospective study. Radiat Oncol. 10(253)2015.PubMed/NCBI View Article : Google Scholar
14	Hanna N, Johnson D, Temin S, Baker S Jr, Brahmer J, Ellis PM, Giaccone G, Hesketh PJ, Jaiyesimi I, Leighl NB, et al: Systemic therapy for stage IV non-small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 35:3484–3515. 2017.PubMed/NCBI View Article : Google Scholar
15	Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, Peters S, Planchard D, Smit EF, Solomon BJ, et al: Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 34:358–376. 2023.PubMed/NCBI View Article : Google Scholar
16	Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V and Yang JCH: First-Line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 11:380–390. 2016.PubMed/NCBI View Article : Google Scholar
17	Yang JJ, Zhou C, Huang Y, Feng J, Lu S, Song Y, Huang C, Wu G, Zhang L, Cheng Y, et al: Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): A multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 5:707–716. 2017.PubMed/NCBI View Article : Google Scholar
18	Jung HA, Woo SY, Lee SH, Ahn JS, Ahn MJ, Park K and Sun JM: The different central nervous system efficacy among gefitinib, erlotinib and afatinib in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Transl Lung Cancer Res. 9:1749–1758. 2020.PubMed/NCBI View Article : Google Scholar
19	Peng W, Pu X, Jiang M, Wang J, Li J, Li K, Xu Y, Xu F, Chen B, Wang Q, et al: Dacomitinib induces objective responses in metastatic brain lesions of patients with EGFR-mutant non-small-cell lung cancer: A brief report. Lung Cancer. 152:66–70. 2021.PubMed/NCBI View Article : Google Scholar
20	Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, et al: CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 28(JCO2018783118)2018.PubMed/NCBI View Article : Google Scholar
21	Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, et al: Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 382:41–50. 2020.PubMed/NCBI View Article : Google Scholar
22	Cheng Y, He Y, Li W, Zhang HL, Zhou Q, Wang B, Liu C, Walding A, Saggese M, Huang X, et al: Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China, A randomized study. Target Oncol. 16:165–176. 2021.PubMed/NCBI View Article : Google Scholar
23	Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, Ji Y, Wang Z, Shi J, Lu J, et al: AENEAS: A randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastaticnon-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations. J Clin Oncol. 40:3162–3171. 2022.PubMed/NCBI View Article : Google Scholar
24	Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, et al: Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): A multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 10:1019–1028. 2022.PubMed/NCBI View Article : Google Scholar
25	Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, Liu C, Zhu S, Zhang X, Li Y, et al: Central nervous system efficacy of furmonertinib (AST2818) versus gefitinib as first-line treatment for EGFR-mutated NSCLC: Results from the FURLONG study. J Thorac Oncol. 17:1297–1305. 2022.PubMed/NCBI View Article : Google Scholar
26	Xu ST, Xi JJ, Zhong WZ, Mao WM, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, et al: The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy: A post hoc analysis of the ADJUVANT trial (CTONG 1104). J Thorac Oncol. 14:503–512. 2019.PubMed/NCBI View Article : Google Scholar
27	Patel SH, Rimner A, Foster A, Zhang Z, Woo KM, Yu HA, Riely GJ and Wu AJ: Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib. Lung Cancer. 108:109–114. 2017.PubMed/NCBI View Article : Google Scholar
28	Zhou Y, Wang B, Qu J, Yu F, Zhao Y, Li S, Zeng Y, Yang X, Chu L, Chu X, et al: Survival outcomes and symptomatic central nervous system (CNS) metastasis in EGFR-mutant advanced non-small cell lung cancer without baseline CNS metastasis: Osimertinib vs. first-generation EGFR tyrosine kinase inhibitors. Lung Cancer. 150:178–185. 2020.PubMed/NCBI View Article : Google Scholar
29	Zhao Y, Li S, Yang X, Chu L, Wang S, Tong T, Chu X, Yu F, Zeng Y, Guo T, et al: Overall survival benefit of osimertinib and clinical value of upfront cranial local therapy in untreated EGFR-mutant nonsmall cell lung cancer with brain metastasis. Int J Cancer. 150:1318–1328. 2022.PubMed/NCBI View Article : Google Scholar
30	Zeng Y, Su X, Zhao Y, Zhou Y, Guo T, Chu X, Chu L, Yang X, Ni J and Zhu Z: Rationale and value of consolidative cranial local therapy in EGFR-mutant non-small cell lung cancer patients with baseline brain metastasis treated with first-line EGFR-TKIs. Ther Adv Med Oncol. 15(17588359231169975)2023.PubMed/NCBI View Article : Google Scholar
31	Arvanitis CD, Ferraro GB and Jain RK: The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 20:26–41. 2020.PubMed/NCBI View Article : Google Scholar
32	Tanaka H, Karita M, Ueda K, Ono T, Kajima M, Manabe Y, Fujimoto K, Yuasa Y and Shiinoki T: Differences in radiosensitivity according to egfr mutation status in non-small cell lung cancer: A clinical and in vitro study. J Pers Med. 14(25)2023.PubMed/NCBI View Article : Google Scholar
33	Pawlik TM and Keyomarsi K: Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 59:928–942. 2004.PubMed/NCBI View Article : Google Scholar
34	Willers H, Azzoli CG, Santivasi WL and Xia F: Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer. Cancer J. 19:200–207. 2013.PubMed/NCBI View Article : Google Scholar
35	Chen H, Wu A, Tao H, Yang D, Luo Y, Li S, Yang Z and Chen M: Concurrent versus sequential whole brain radiotherapy and TKI in EGFR-mutated NSCLC patients with brain metastasis: A single institution retrospective analysis. Medicine (Baltimore). 97(e13014)2018.PubMed/NCBI View Article : Google Scholar
36	Du XJ, Pan SM, Lai SZ, Xu XN, Deng ML, Wang XH, Yao DC and Wu SX: Upfront cranial radiotherapy vs. EGFR tyrosine kinase inhibitors alone for the treatment of brain metastases from non-small-cell lung cancer: A meta-analysis of 1465 patients. Front Oncol. 8(603)2018.PubMed/NCBI View Article : Google Scholar
37	Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, et al: Management of brain metastases in tyrosine kinase inhibitor-naïve epidermal growth factor receptor-mutant non-small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol. 35:1070–1077. 2017.PubMed/NCBI View Article : Google Scholar
38	Tancherla A, Wijovi F, Hariyanto TI, Kurniawan A and Giselvania A: 142P EGFR-TKI plus radiotherapy versus EGFR-TKI only in non-small cell lung cancer patients with brain metastasis: A systematic review and meta-analysis of observational studies. J Thorac Oncol. 16(S774)2021.
39	Miyawaki E, Kenmotsu H, Mori K, Harada H, Mitsuya K, Mamesaya N, Kawamura T, Kobayashi H, Nakashima K, Omori S, et al: Optimal sequence of local and EGFR-TKI therapy for EGFR-mutant non-small cell lung cancer with brain metastases stratified by number of brain metastases. Int J Radiat Oncol Biol Phys. 104:604–613. 2019.PubMed/NCBI View Article : Google Scholar
40	Goldstein IM, Roisman LC, Keren-Rosenberg S, Dudnik J, Nechushtan H, Shelef I, Fuchs V, Kian W and Peled N: Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases. Neurooncol Adv. 1(vdaa125)2020.PubMed/NCBI View Article : Google Scholar
41	Yu F, Ni J, Zeng W, Zhou Y, Guo T, Zeng Y, Zhao Y, Li S, Li Y, Yang X, et al: Clinical value of upfront cranial radiation therapy in osimertinib-treated epidermal growth factor receptor-mutant non-small cell lung cancer with brain metastases. Int J Radiat Oncol Biol Phys. 111:804–815. 2021.PubMed/NCBI View Article : Google Scholar
42	Zhou J, Zhou Y, Sun Y, Xiao L, Lu H, Yin X and Fan K: The efficacy of upfront craniocerebral radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors in patients with epidermal growth factor receptor-positive non-small cell lung cancer with brain metastases. Front Oncol. 13(1259880)2023.PubMed/NCBI View Article : Google Scholar
43	Chen JY, Zhang H, Wang B, Wen J, Xu XY, Li H and Fan M: 18P Stereotactic radiotherapy (SRT) in combination with aumolertinib to treat intracranial oligometastatic non-small cell lung cancer (NSCLC): An update of the phase II, prospective study. J Thorac Oncol. 18(S51)2023.