Skip to main content
Top
Published in: Radiation Oncology 1/2019

Open Access 01-12-2019 | Magnetic Resonance Imaging | Research

Whole brain radiation therapy does not improve the overall survival of EGFR-mutant NSCLC patients with leptomeningeal metastasis

Authors: Weiwei Yan, Yang Liu, Ji Li, Anqin Han, Li Kong, Jinming Yu, Hui Zhu

Published in: Radiation Oncology | Issue 1/2019

Login to get access

Abstract

Background

Leptomeningeal metastasis (LM) is a devastating and terminal complication of advanced non-small-cell lung cancer (NSCLC), especially in patients harboring epidermal growth factor receptor (EGFR) mutations. The role of whole brain radiation therapy (WBRT) in the treatment of EGFR-mutant NSCLC patients with LM is not conclusive. Therefore, we conducted a retrospective study to evaluate the therapeutic effect of WBRT in this setting.

Methods

EGFR-mutant NSCLC patients with LM, who had previously received treatment at the Shandong Cancer Hospital and Institute from July 2014 to March 2018 were reviewed retrospectively. LM was diagnosed by positive CSF cytology and/or leptomeningeal-enhanced magnetic resonance imaging (MRI). Survival was estimated using the Kaplan-Meier method.

Results

In total, 51 EGFR-mutated NSCLC patients with LM were eligible for analysis, subdivided into 26 in the WBRT group and 25 in the non-WBRT group. No significant differences were observed in intracranial ORR (15.4% vs. 16%, p = 0.952) and DCR (34.7% vs. 28%, p = 0.611) between the two groups. The median iPFSLM and OSLM for the entire cohort were 3.3 months (95% CI: 2.77–3.83) and 12.6 months (95% CI: 9.66–15.54), respectively. No difference in iPFSLM was observed between the WBRT and non-WBRT groups (median 3.9 vs. 2.8 months; HR = 0.506, p = 0.052). The median OSLM was 13.6 months in the WBRT group, compared with 5.7 months in the non-WBRT group (HR = 0.454, p = 0.022). Multivariate analyses of OSLM showed that KPS ≥ 80 at the time of LM diagnosis (HR = 0.428, 95% CI: 0.19–0.94; p = 0.034) and the administration of EGFR-TKIs (HR = 0.258, 95% CI: 0.11–0.58; p = 0.001) were independent predictors of survival, but WBRT (HR = 0.49, 95% CI: 0.24–1.01; p = 0.54) was not. Toxicities associated with WBRT or other treatment were rare.

Conclusion

For EGFR-mutated NSCLC patients with LM, WBRT did not improve intracranial treatment response and survival statistically.
Literature
1.
go back to reference Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: a continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017;53:128–37.CrossRef Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: a continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017;53:128–37.CrossRef
2.
go back to reference Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018;19(1):e43–55.CrossRef Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018;19(1):e43–55.CrossRef
3.
go back to reference Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol. 2010;22(6):627–35.CrossRef Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol. 2010;22(6):627–35.CrossRef
4.
go back to reference Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ. Leptomeningeal metastasis: clinical experience of 519 cases. Eur J Cancer. 2016;56:107–14.CrossRef Hyun JW, Jeong IH, Joung A, Cho HJ, Kim SH, Kim HJ. Leptomeningeal metastasis: clinical experience of 519 cases. Eur J Cancer. 2016;56:107–14.CrossRef
5.
go back to reference Li YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, et al. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol. 2016;11(11):1962–9.CrossRef Li YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, et al. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol. 2016;11(11):1962–9.CrossRef
6.
go back to reference Liao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol. 2015;10(12):1754–61.CrossRef Liao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol. 2015;10(12):1754–61.CrossRef
7.
go back to reference Lee Y, Han JY, Kim HT, Yun T, Lee GK, Kim HY, et al. Impact of EGFR tyrosine kinase inhibitors versus chemotherapy on the development of leptomeningeal metastasis in never smokers with advanced adenocarcinoma of the lung. J Neuro-Oncol. 2013;115(1):95–101.CrossRef Lee Y, Han JY, Kim HT, Yun T, Lee GK, Kim HY, et al. Impact of EGFR tyrosine kinase inhibitors versus chemotherapy on the development of leptomeningeal metastasis in never smokers with advanced adenocarcinoma of the lung. J Neuro-Oncol. 2013;115(1):95–101.CrossRef
8.
go back to reference Lee SJ, Lee JI, Nam DH, Ahn YC, Han JH, Sun JM, et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013;8(2):185–91.CrossRef Lee SJ, Lee JI, Nam DH, Ahn YC, Han JH, Sun JM, et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013;8(2):185–91.CrossRef
9.
go back to reference Wu YL, Zhao Q, Deng L, Zhang Y, Zhou XJ, Li YY, et al. Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer. Lung Cancer. 2019;127:1–5.CrossRef Wu YL, Zhao Q, Deng L, Zhang Y, Zhou XJ, Li YY, et al. Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer. Lung Cancer. 2019;127:1–5.CrossRef
10.
go back to reference Riess JW, Nagpal S, Iv M, Zeineh M, Gubens MA, Ramchandran K, et al. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung Cancer. 2014;15(3):202–6.CrossRef Riess JW, Nagpal S, Iv M, Zeineh M, Gubens MA, Ramchandran K, et al. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung Cancer. 2014;15(3):202–6.CrossRef
11.
go back to reference Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group. Lung Cancer. 2012;77(1):134–9.CrossRef Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung cancer study group. Lung Cancer. 2012;77(1):134–9.CrossRef
12.
go back to reference Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012;7(2):382–5.CrossRef Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012;7(2):382–5.CrossRef
13.
go back to reference Xu Y, Hu M, Zhang M, Zhong W, Yin X, Sun Y, et al. Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy. Lung Cancer. 2018;125:142–9.CrossRef Xu Y, Hu M, Zhang M, Zhong W, Yin X, Sun Y, et al. Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy. Lung Cancer. 2018;125:142–9.CrossRef
14.
go back to reference Gwak HS, Joo J, Kim S, Yoo H, Shin SH, Han JY, et al. Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. J Thorac Oncol. 2013;8(5):599–605.CrossRef Gwak HS, Joo J, Kim S, Yoo H, Shin SH, Han JY, et al. Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. J Thorac Oncol. 2013;8(5):599–605.CrossRef
15.
go back to reference Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer. 2012;76(3):387–92.CrossRef Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer. 2012;76(3):387–92.CrossRef
16.
go back to reference Kuiper JL, Bahce I, Voorhoeve C, Yaqub M, Heideman DA, Thunnissen E, et al. Detecting resistance in EGFR-mutated non-small-cell lung cancer after clonal selection through targeted therapy. Pers Med. 2015;12(2):63–6.CrossRef Kuiper JL, Bahce I, Voorhoeve C, Yaqub M, Heideman DA, Thunnissen E, et al. Detecting resistance in EGFR-mutated non-small-cell lung cancer after clonal selection through targeted therapy. Pers Med. 2015;12(2):63–6.CrossRef
17.
go back to reference Kuiper JL, Hendriks LE, van der Wekken AJ, de Langen AJ, Bahce I, Thunnissen E, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer. 2015;89(3):255–61.CrossRef Kuiper JL, Hendriks LE, van der Wekken AJ, de Langen AJ, Bahce I, Thunnissen E, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer. 2015;89(3):255–61.CrossRef
18.
go back to reference Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004–14.CrossRef Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004–14.CrossRef
19.
go back to reference Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Saito T. Patient outcomes of whole brain radiotherapy for brain metastases versus leptomeningeal metastases: a retrospective study. Asia Pac J Clin Oncol. 2017;13(5):e449–e57.CrossRef Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Saito T. Patient outcomes of whole brain radiotherapy for brain metastases versus leptomeningeal metastases: a retrospective study. Asia Pac J Clin Oncol. 2017;13(5):e449–e57.CrossRef
20.
21.
go back to reference Chamberlain MC, Eaton K. Is there a role for whole brain radiotherapy in the treatment of leptomeningeal metastases? J Thorac Oncol. 2012;7(7):1204; author reply -5.CrossRef Chamberlain MC, Eaton K. Is there a role for whole brain radiotherapy in the treatment of leptomeningeal metastases? J Thorac Oncol. 2012;7(7):1204; author reply -5.CrossRef
22.
go back to reference Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer. 2009;65(1):80–4.CrossRef Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer. 2009;65(1):80–4.CrossRef
23.
go back to reference So T, Inoue M, Chikaishi Y, Nose N, Sugio K, Yasumoto K. Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: report of two cases. Surg Today. 2009;39(7):598–602.CrossRef So T, Inoue M, Chikaishi Y, Nose N, Sugio K, Yasumoto K. Gefitinib and a ventriculo-peritoneal shunt to manage carcinomatous meningitis from non-small-cell lung cancer: report of two cases. Surg Today. 2009;39(7):598–602.CrossRef
24.
go back to reference Chen Y, Yang J, Li X, Hao D, Wu X, Yang Y, et al. 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. 2016;107(12):1800–5.CrossRef Chen Y, Yang J, Li X, Hao D, Wu X, Yang Y, et al. 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. 2016;107(12):1800–5.CrossRef
25.
go back to reference Lu Y, Fan Y. Combined action of EGFR tyrosine kinase inhibitors and whole-brain radiotherapy on EGFR-mutated non-small-cell lung cancer patients with brain metastasis. Onco Targets Ther. 2016;9:1135–43.CrossRef Lu Y, Fan Y. Combined action of EGFR tyrosine kinase inhibitors and whole-brain radiotherapy on EGFR-mutated non-small-cell lung cancer patients with brain metastasis. Onco Targets Ther. 2016;9:1135–43.CrossRef
26.
go back to reference Zeng YD, Zhang L, Liao H, Liang Y, Xu F, Liu JL, et al. 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. 2012;13(3):909–14.CrossRef Zeng YD, Zhang L, Liao H, Liang Y, Xu F, Liu JL, et al. 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. 2012;13(3):909–14.CrossRef
27.
go back to reference Zhou L, He J, Xiong W, Liu Y, Xiang J, Yu Q, et al. Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: results of phase I dose-escalation study. Lung Cancer. 2016;96:93–100.CrossRef Zhou L, He J, Xiong W, Liu Y, Xiang J, Yu Q, et al. Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: results of phase I dose-escalation study. Lung Cancer. 2016;96:93–100.CrossRef
28.
go back to reference Borghetti P, Bonu ML, Giubbolini R, Levra NG, Mazzola R, Perna M, et al. Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group. Radiol Med. 2019;124(7):662–70.CrossRef Borghetti P, Bonu ML, Giubbolini R, Levra NG, Mazzola R, Perna M, et al. Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group. Radiol Med. 2019;124(7):662–70.CrossRef
29.
go back to reference Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, et al. Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol. 2013;8(8):1069–74.CrossRef Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, et al. Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol. 2013;8(8):1069–74.CrossRef
30.
go back to reference Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;70(3):399–405.CrossRef Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;70(3):399–405.CrossRef
31.
go back to reference Tamiya A, Tamiya M, Nishihara T, Shiroyama T, Nakao K, Tsuji T, et al. Cerebrospinal fluid penetration rate and efficacy of Afatinib in patients with EGFR mutation-positive non-small cell lung cancer with leptomeningeal carcinomatosis: a multicenter prospective study. Anticancer Res. 2017;37(8):4177–82.PubMed Tamiya A, Tamiya M, Nishihara T, Shiroyama T, Nakao K, Tsuji T, et al. Cerebrospinal fluid penetration rate and efficacy of Afatinib in patients with EGFR mutation-positive non-small cell lung cancer with leptomeningeal carcinomatosis: a multicenter prospective study. Anticancer Res. 2017;37(8):4177–82.PubMed
32.
go back to reference Gong L, Xiong M, Huang Z, Miao L, Fan Y. Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations. Lung Cancer. 2015;89(3):268–73.CrossRef Gong L, Xiong M, Huang Z, Miao L, Fan Y. Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations. Lung Cancer. 2015;89(3):268–73.CrossRef
33.
go back to reference Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016;93:59–68.CrossRef Tan CS, Cho BC, Soo RA. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. Lung Cancer. 2016;93:59–68.CrossRef
34.
go back to reference Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of Osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.CrossRef Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of Osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.CrossRef
35.
go back to reference Yang JC-H, Cho BC, Kim D-W, Kim S-W, Lee J-S, Su W-C, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study. J Clin Oncol. 2017;35(15_suppl):2020.CrossRef Yang JC-H, Cho BC, Kim D-W, Kim S-W, Lee J-S, Su W-C, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study. J Clin Oncol. 2017;35(15_suppl):2020.CrossRef
36.
go back to reference Saboundji K, Auliac JB, Perol M, Francois G, Janicot H, Marcq M, et al. Efficacy of Osimertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastases pretreated with EGFR-tyrosine kinase inhibitors. Target Oncol. 2018;13(4):501–7.CrossRef Saboundji K, Auliac JB, Perol M, Francois G, Janicot H, Marcq M, et al. Efficacy of Osimertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastases pretreated with EGFR-tyrosine kinase inhibitors. Target Oncol. 2018;13(4):501–7.CrossRef
Metadata
Title
Whole brain radiation therapy does not improve the overall survival of EGFR-mutant NSCLC patients with leptomeningeal metastasis
Authors
Weiwei Yan
Yang Liu
Ji Li
Anqin Han
Li Kong
Jinming Yu
Hui Zhu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2019
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-019-1376-z

Other articles of this Issue 1/2019

Radiation Oncology 1/2019 Go to the issue