盐酸埃克替尼联合全脑放疗治疗非小细胞肺癌脑转移的随机对照研究
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摘要
目的探讨全脑放疗联合盐酸埃克替尼治疗非小细胞肺癌(NSCLC)脑转移的疗效及安全性。方法选取2013年6月～2017年6月共44例脑转移的NSCLC患者,随机分为联合治疗组与单纯放疗组,比较两组间疗效及安全性。结果中位随访18.5个月,联合治疗组及单纯放疗组的mPFS分别为9.3个月及6.6个月(log-rank P=0.006);联合治疗组EGFR突变者及野生型者的mPFS分别为12.2个月和6.5个月(log-rank P=0.002),单纯放疗组EGFR突变者及野生型者的mPFS分别为6.4个月和6.8个月(log-rank P=0.933)。联合治疗组及单纯放疗组的mOS分别为14.2个月及12.6个月(log-rank P=0.035);联合治疗组中EGFR突变者及野生型者的mOS分别为19.1个月和12.7个月(log-rank P=0.006),单纯放疗组EGFR突变者及野生型者的mOS分别为12.6个月和10.4个月(log-rank P=0.449)。两组间的ORR分别为78.3%及47.6%(log-rank P=0.035),DCR分别为91.3%及85.7%(χ2=0.341,P=0.560)。不良反应方面,联合组的皮疹发生率为56.5%,其中3例为3～4级;两组乏力、恶心呕吐、腹泻肝肾损伤、白细胞减少等不良反应均为1～2级,且两组比较差异无统计学意义。结论盐酸埃克替尼联合全脑放疗可提高非小细胞肺癌脑转移患者的客观缓解率,延长中位局部无进展生存期及中位总生存期,患者的不良反应耐受性良好。
Objective To investigate the efficacy and safety of whole brain radiotherapy combined with ectatinib hydrochloride in the treatment of non-small cell lung cancer(NSCLC) brain metastases. Methods A total of 44 patients with brain metastases from NSCLC from June 2013 to June 2017 were randomly divided into combination therapy group and radiotherapy group. The efficacy and safety between the two groups were compared. Results The median follow-up was 18.5 months. The mPFS of the combination therapy group and the radiotherapy group were 9.3 months and 6.6 months, respectively(log-rank P=0.006). The mPFS of the EGFR mutant and wild type in the combination group were12.2 months and 6.5 months(log-rank P=0.002). The mPFS of EGFR mutants and wild-type patients in the radiotherapy group were 6.4 months and 6.8 months, respectively(log-rank P=0.933). The mOS in the combination therapy group and the radiotherapy group were 14.2 months and 12.6 months, respectively(log-rank P=0.035). The mOS of the EGFR mutant and wild type in the combination group were 19.1 months and 12.7 months, respectively(log-rank P=0.006). The mOS of EGFR mutants and wild-type patients in the radiotherapy group were 12.6 months and 10.4 months, respectively(log-rank P=0.449).The ORR of the two groups was 78.3% and 47.6%, respectively(log-rank P=0.035), and the DCR was 91.3% and 85.7%, respectively(χ2=0.341, P=0.560).In terms of adverse reactions,the incidence of rash in the combined group was 56.5%, of which 3 cases were grade 3-4. The adverse reactions such as fatigue, nausea and vomiting,diarrhea,liver and kidney damage, and leukopenia were all grade 1-2, and there was no statistically significant difference between the two groups. Conclusion Ectinib hydrochloride combined with whole brain radiotherapy can improve the objective response rate of patients with non-small cell lung cancer with brain metastases, prolong the median local progression-free survival and median overall survival, and the patient's adverse reaction tolerance is good.
Objective To investigate the efficacy and safety of whole brain radiotherapy combined with ectatinib hydrochloride in the treatment of non-small cell lung cancer(NSCLC) brain metastases. Methods A total of 44 patients with brain metastases from NSCLC from June 2013 to June 2017 were randomly divided into combination therapy group and radiotherapy group. The efficacy and safety between the two groups were compared. Results The median follow-up was 18.5 months. The mPFS of the combination therapy group and the radiotherapy group were 9.3 months and 6.6 months, respectively(log-rank P=0.006). The mPFS of the EGFR mutant and wild type in the combination group were12.2 months and 6.5 months(log-rank P=0.002). The mPFS of EGFR mutants and wild-type patients in the radiotherapy group were 6.4 months and 6.8 months, respectively(log-rank P=0.933). The mOS in the combination therapy group and the radiotherapy group were 14.2 months and 12.6 months, respectively(log-rank P=0.035). The mOS of the EGFR mutant and wild type in the combination group were 19.1 months and 12.7 months, respectively(log-rank P=0.006). The mOS of EGFR mutants and wild-type patients in the radiotherapy group were 12.6 months and 10.4 months, respectively(log-rank P=0.449).The ORR of the two groups was 78.3% and 47.6%, respectively(log-rank P=0.035), and the DCR was 91.3% and 85.7%, respectively(χ2=0.341, P=0.560).In terms of adverse reactions,the incidence of rash in the combined group was 56.5%, of which 3 cases were grade 3-4. The adverse reactions such as fatigue, nausea and vomiting,diarrhea,liver and kidney damage, and leukopenia were all grade 1-2, and there was no statistically significant difference between the two groups. Conclusion Ectinib hydrochloride combined with whole brain radiotherapy can improve the objective response rate of patients with non-small cell lung cancer with brain metastases, prolong the median local progression-free survival and median overall survival, and the patient's adverse reaction tolerance is good.
引文
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[6]郭丽丽,李明智,唐俊舫,等.厄洛替尼治疗EGFR突变的晚期非小细胞肺癌临床疗效分析[J].医学研究杂志,2017,46(3):138-140.
[7]王银叶,朱波,贾美莹.吉非替尼与多西他赛治疗晚期非小细胞肺癌的临床效果比较[J].实用癌症杂志,2017,32(12):1978-1980.
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[11]杨妤,杨新辉,苏加利.替莫唑胺联合全脑放疗治疗非小细胞肺癌脑转移瘤的疗效[J].广东医学,2013,34(7):1115-1117.
[12]Eisenhauer EA,Therasse P,Bogaerts J,et al.New response evaluation criteria in solid tumours:Revised RE-CIST guideline(version 1.1)[J].Eur J Cancer,2009,45(2):228-247.
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[14]Cux JD,Stetz J,Pajak TF.Toxcicity criteria of the radiation therapy oncology group(RTOG)and the european organization for research and treatment of cancer(EORTC)[J].Int J Radiat Oncol Biol Phys,1995,31(5):1341-1346.
[15]Yosuke Togashi,Katsuhiro Masago,Masahide Fukudo,et al.Cerebrospinal fluid concentration oferlotinib and its active metabolite OSI-420 in patients with central nervous systemmetastases of non-small cell lung cancer[J].JThorac Oncol,2010,5(7):950-955.
[16]Weber Britta,Winterdahl Michael,Memon Ashfaque,et al.Erlotinib accumulation in brain metastases from nonsmall cell lung cancer:Visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor[J].J Thorac Oncol,2011,6(7):1287-1289.
[17]储建华,徐杰,沈预程.全脑放疗序贯吉非替尼治疗老年非小细胞肺癌伴脑转移的临床观察[J].临床肿瘤学杂志,2013,18(7):656-658.
[18]Welsh James W,Komaki Ritsuko,Amini Arya,et al.Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer[J].J Clin Oncol,2013,31(7):895-902.
[19]Zhuang Hongqing,Yuan Zhiyong,Wang Jun,et al.Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma[J].Drug Des Devel Ther,2013,7:1179-1186.
[20]Shi Yuankai,Zhang Li Liu,Xiaoqing,et al.Icotinib versus gefitinib in previously treated advanced non-smallcell lung cancer(ICOGEN):A randomised,double-blind phase 3 non-inferiority trial[J].Lancet Oncol,2013,14(10):953-961.
[21]Gong Lei,Xiong Ming,Huang Zhiyu,et al.Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations[J].Lung Cancer,2015,89(3):268-273.
[22]郭红云,贾亚森.埃克替尼联合放疗治疗晚期非小细胞肺癌的研究进展[J].中国临床新医学,2017,10(5):491-494.
[23]Li Jin-Rui,Zhang Ye,Zheng Jia-Lian.Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation[J].J Thorac Dis,2016,8(7):1504-1512.
[2]Barnholtz-Sloan Jill S,Sloan Andrew E,Davis Faith G,et al.Incidence proportions of brain metastases in patients diagnosed(1973 to 2001)in the Metropolitan Detroit Cancer Surveillance System[J].J Clin Oncol,2004,22(14):2865-2872.
[3]冯宇,胡兴胜.非小细胞肺癌脑转移治疗的研究进展[J].中国肿瘤临床,2018,45(7):331-338.
[4]Mulven na P,Nankivell M,Barton R,et al.Dexamethasone and supportive care with or without whole brain radiotherapy in treatingpatients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy(QUARTZ):Results from a phase3,non-inferiority,randomized trial[J].Lancet,2016,388(10055):2004-2014.
[5]郭芷汛,刘欢,李艳,等.表皮生长因子受体-酪氨酸激酶抑制剂在治疗非小细胞肺癌方面的研究进展[J].实用医院临床杂志,2018,15(1):208-210.
[6]郭丽丽,李明智,唐俊舫,等.厄洛替尼治疗EGFR突变的晚期非小细胞肺癌临床疗效分析[J].医学研究杂志,2017,46(3):138-140.
[7]王银叶,朱波,贾美莹.吉非替尼与多西他赛治疗晚期非小细胞肺癌的临床效果比较[J].实用癌症杂志,2017,32(12):1978-1980.
[8]Park SJ,Kim HT,Lee DH,et al.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[J].Lung Cancer,2012,77(3):556-560.
[9]Chinnaiyan Prakash,Huang Shyhmin,Vallabhaneni Geetha,et al.Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib(Tarceva)[J].Cancer Res,2005,65(8):3328-3335.
[10]Tanaka Toshimitsu,Munshi Anupama,Brooks Colin,et al.Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity[J].Clin Cancer Res,2008,14(4):1266-1273.
[11]杨妤,杨新辉,苏加利.替莫唑胺联合全脑放疗治疗非小细胞肺癌脑转移瘤的疗效[J].广东医学,2013,34(7):1115-1117.
[12]Eisenhauer EA,Therasse P,Bogaerts J,et al.New response evaluation criteria in solid tumours:Revised RE-CIST guideline(version 1.1)[J].Eur J Cancer,2009,45(2):228-247.
[13]Common Terminology Criteria for Adverse Events,Version 3.0.http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf.
[14]Cux JD,Stetz J,Pajak TF.Toxcicity criteria of the radiation therapy oncology group(RTOG)and the european organization for research and treatment of cancer(EORTC)[J].Int J Radiat Oncol Biol Phys,1995,31(5):1341-1346.
[15]Yosuke Togashi,Katsuhiro Masago,Masahide Fukudo,et al.Cerebrospinal fluid concentration oferlotinib and its active metabolite OSI-420 in patients with central nervous systemmetastases of non-small cell lung cancer[J].JThorac Oncol,2010,5(7):950-955.
[16]Weber Britta,Winterdahl Michael,Memon Ashfaque,et al.Erlotinib accumulation in brain metastases from nonsmall cell lung cancer:Visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor[J].J Thorac Oncol,2011,6(7):1287-1289.
[17]储建华,徐杰,沈预程.全脑放疗序贯吉非替尼治疗老年非小细胞肺癌伴脑转移的临床观察[J].临床肿瘤学杂志,2013,18(7):656-658.
[18]Welsh James W,Komaki Ritsuko,Amini Arya,et al.Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer[J].J Clin Oncol,2013,31(7):895-902.
[19]Zhuang Hongqing,Yuan Zhiyong,Wang Jun,et al.Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma[J].Drug Des Devel Ther,2013,7:1179-1186.
[20]Shi Yuankai,Zhang Li Liu,Xiaoqing,et al.Icotinib versus gefitinib in previously treated advanced non-smallcell lung cancer(ICOGEN):A randomised,double-blind phase 3 non-inferiority trial[J].Lancet Oncol,2013,14(10):953-961.
[21]Gong Lei,Xiong Ming,Huang Zhiyu,et al.Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non-small cell lung cancer with sensitive EGFR mutations[J].Lung Cancer,2015,89(3):268-273.
[22]郭红云,贾亚森.埃克替尼联合放疗治疗晚期非小细胞肺癌的研究进展[J].中国临床新医学,2017,10(5):491-494.
[23]Li Jin-Rui,Zhang Ye,Zheng Jia-Lian.Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation[J].J Thorac Dis,2016,8(7):1504-1512.