吉非替尼和厄洛替尼治疗非小细胞肺癌优势人群筛选的系统评价
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摘要
背景与目的
表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKIs)吉非替尼和厄洛替尼,是新型非小细胞肺癌(NSCLC)分子靶向治疗药。有研究证明具有某些生物学和临床特性的患者对吉非替尼和厄洛替尼有更大的生存获益,但这些研究所得结论并不一致。本研究将收集所有吉非替尼和厄洛替尼与安慰剂对比治疗NSCLC的随机对照试验(RCT),并对数据进行Meta-分析,以评估生物学和临床特性对吉非替尼和厄洛替尼疗效的影响,筛选出优势人群。
材料与方法
计算机检索Cochrane图书馆临床对照试验库、Pubmed、Embase、CBM、CNKI、Wanfang Date等电子数据库,手工检索肿瘤相关的国内外会议论文集。对符合纳入标准的RCT进行质量评价和资料提取,采用Stata10软件进行统计分析。
结果
纳入8个RCT研究。从不吸烟者对吉非替尼和厄洛替尼有较大获益[生存期MST,不吸烟者：HR=0.52,95%CI(0.31,0.86)；吸烟者：HR=0.91,95%CI(0.81,1.02)；疾病进展期PFS,不吸烟者：HR=0.55,95%CI(0.42,0.72)；吸烟者：HR=0.89,95%CI(0.78,1.01)；肿瘤反应率RR,不吸烟者：OR=27.58,95%CI(5.40,140.72)；吸烟者：OR=4.57,95%CI(2.07,10.07)]; EGFR基因表达阳性者实验组死亡风险低于对照组[MST,HR=0.79,95%CI(0.65,0.97)]; EGFR基因拷贝数高的患者,实验组的疾病进展风险低于对照组[HR=0.55,95%CI(0.40,0.75)]；EGFR(19,20)基因突变者在肿瘤反应率上有明显优势[RR,OR=4.08,95%CI(1.14,14.68)]；K-ras突变者实验组的死亡风险[HR=1.97,95%CI(1.16,3.33)]和疾病进展风险[HR=1.90,95%CI(1.05,3.44)]均高于对照组。
结论
基于目前可获得的证据,只能证明不吸烟者是吉非替尼和厄洛替尼的优势人群,而K-ras突变者不适合接受吉非替尼和厄洛替尼治疗。对吉非替尼和厄洛替尼优势人群的筛选,仍需大量的前瞻性研究来证明。
Epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors(TKIs)-gefitinib and erlotinib is a targeted therapy drug for non-small cell lung cancer(NSCLC). There was evidence of a greater survival benefit from gefitinib and erlotinib in patients with certain molecular and clinical features, but results are conflicting. The aim of this study is to assess the role of these factors in gefitinib and erlotinib efficacy.
Materials and methods
A systematic review of all the relevant randomized(RCTs) was performed. Searches were applied to the following electronic database:Cochrane Library, Pubmed, Embase, CBM, CNKI and Wanfang Date, and add hand search. The included studies, we performed assessment of studies quality and data extraction. StatalO software was used for meta-analysis.
Results
Eight RCTs were analyzed. Non-smokers get more benefit from gefitinib and erlotinib [Median Survival Time(MST), Non smokers:HR=0.52,95%CI(0.31,0.86); Smokers:HR=0.91,95%CI(0.81,1.02);Progression-free survival(PFS), Non smokers: HR=0.55,95%CI(0.42,0.72); Smokers:HR=0.89,95%CI(0.78,1.01); Reponse Rate(RR), Non smokers:OR=27.58,95%CI(5.40,140.72); Smokers:OR=4.57, 95%CI(2.07,10.07)]; Patients with positive EGFR expression had a lower relative risk of death[MST, HR=0.79,95%CI(0.65,0.97)]; There was a positive effect of TKIs on PFS in patients whose tumours had a high EGFR gene copy number[HR=0.55, 95%CI(0.40,0.75)]; Patients with positive EGFR(19,21) mutations are benefit on RR[OR=4.08,95%CI(1.14,14.68)]; K-ras mutations are unfit for TKIs [MST, K-ras+ HR=1.97,95%CI(1.16,3.33);PFS,K-ras+:HR=1.90,95%CI(1.05,3.44)].
Conclusion
Based on the present evidence, non-smokers get more benefit from gefitinib and erlotinib, and K-ras mutations are unfit for gefitinib and erlotinib. Results of prospective randomized trials are awaited.
表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKIs)吉非替尼和厄洛替尼,是新型非小细胞肺癌(NSCLC)分子靶向治疗药。有研究证明具有某些生物学和临床特性的患者对吉非替尼和厄洛替尼有更大的生存获益,但这些研究所得结论并不一致。本研究将收集所有吉非替尼和厄洛替尼与安慰剂对比治疗NSCLC的随机对照试验(RCT),并对数据进行Meta-分析,以评估生物学和临床特性对吉非替尼和厄洛替尼疗效的影响,筛选出优势人群。
材料与方法
计算机检索Cochrane图书馆临床对照试验库、Pubmed、Embase、CBM、CNKI、Wanfang Date等电子数据库,手工检索肿瘤相关的国内外会议论文集。对符合纳入标准的RCT进行质量评价和资料提取,采用Stata10软件进行统计分析。
结果
纳入8个RCT研究。从不吸烟者对吉非替尼和厄洛替尼有较大获益[生存期MST,不吸烟者：HR=0.52,95%CI(0.31,0.86)；吸烟者：HR=0.91,95%CI(0.81,1.02)；疾病进展期PFS,不吸烟者：HR=0.55,95%CI(0.42,0.72)；吸烟者：HR=0.89,95%CI(0.78,1.01)；肿瘤反应率RR,不吸烟者：OR=27.58,95%CI(5.40,140.72)；吸烟者：OR=4.57,95%CI(2.07,10.07)]; EGFR基因表达阳性者实验组死亡风险低于对照组[MST,HR=0.79,95%CI(0.65,0.97)]; EGFR基因拷贝数高的患者,实验组的疾病进展风险低于对照组[HR=0.55,95%CI(0.40,0.75)]；EGFR(19,20)基因突变者在肿瘤反应率上有明显优势[RR,OR=4.08,95%CI(1.14,14.68)]；K-ras突变者实验组的死亡风险[HR=1.97,95%CI(1.16,3.33)]和疾病进展风险[HR=1.90,95%CI(1.05,3.44)]均高于对照组。
结论
基于目前可获得的证据,只能证明不吸烟者是吉非替尼和厄洛替尼的优势人群,而K-ras突变者不适合接受吉非替尼和厄洛替尼治疗。对吉非替尼和厄洛替尼优势人群的筛选,仍需大量的前瞻性研究来证明。
Epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors(TKIs)-gefitinib and erlotinib is a targeted therapy drug for non-small cell lung cancer(NSCLC). There was evidence of a greater survival benefit from gefitinib and erlotinib in patients with certain molecular and clinical features, but results are conflicting. The aim of this study is to assess the role of these factors in gefitinib and erlotinib efficacy.
Materials and methods
A systematic review of all the relevant randomized(RCTs) was performed. Searches were applied to the following electronic database:Cochrane Library, Pubmed, Embase, CBM, CNKI and Wanfang Date, and add hand search. The included studies, we performed assessment of studies quality and data extraction. StatalO software was used for meta-analysis.
Results
Eight RCTs were analyzed. Non-smokers get more benefit from gefitinib and erlotinib [Median Survival Time(MST), Non smokers:HR=0.52,95%CI(0.31,0.86); Smokers:HR=0.91,95%CI(0.81,1.02);Progression-free survival(PFS), Non smokers: HR=0.55,95%CI(0.42,0.72); Smokers:HR=0.89,95%CI(0.78,1.01); Reponse Rate(RR), Non smokers:OR=27.58,95%CI(5.40,140.72); Smokers:OR=4.57, 95%CI(2.07,10.07)]; Patients with positive EGFR expression had a lower relative risk of death[MST, HR=0.79,95%CI(0.65,0.97)]; There was a positive effect of TKIs on PFS in patients whose tumours had a high EGFR gene copy number[HR=0.55, 95%CI(0.40,0.75)]; Patients with positive EGFR(19,21) mutations are benefit on RR[OR=4.08,95%CI(1.14,14.68)]; K-ras mutations are unfit for TKIs [MST, K-ras+ HR=1.97,95%CI(1.16,3.33);PFS,K-ras+:HR=1.90,95%CI(1.05,3.44)].
Conclusion
Based on the present evidence, non-smokers get more benefit from gefitinib and erlotinib, and K-ras mutations are unfit for gefitinib and erlotinib. Results of prospective randomized trials are awaited.
引文
1 Jemal A, Siegel R, Ward E, et al. Cancer Statistics,2008.CA Cancer J Clin,2008,58(2):71-96.
2 Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(INTEREST):a randomized phase Ⅲ trial.Lancet,2008,372(22):1809-18.
3 Maruyama R, Nishiwaki Y, Tamura T, et al. Phase ⅢStudy,V-15-32,of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients With Non-Small-Cell Lung Cancer. J Clin Oncol,2008,26(26):4244-4252.
4 Giaccone G, Herbst RS, Manegold, et al. Gefitinib in Combination With Gemcitabine and Cisplatin in Advanced Non-Small-Cell Lung Cancer:A Phase Ⅲ Trial-INTACT1. J Clin Oncol, 2004,22(5):777-784.
5 Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non-Small-Cell Lung Cancer:A Phase Ⅲ Trial-INTACT2. J Clin Oncol,2004,22(5):785-794.
6 Herbst RS, Prager D, Hermann R, et al. TRIBUTE:a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol,2005,23(25):5892-5899.
7 Gatzemeier U, Pluzanska A, Szczesna A,et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer:The Tarceva lung cancer investigation trial. J Clin Oncol,2007,25(12):1545-1552.
8 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med,2004,350(21):2129-2139.
9 Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst,2005,97(9):643-655.
10 Miller VA, Zakowski M, Riely GJ, et al. EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC):Results of a prospective phase II trial. J Clin Oncol,2006,24:364s.
11 Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol,2005,23(25):5900-5909.
12 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst,2000,92(3):205-216.
13 Juni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ,2001,323 (7303):42-46.
14 Higgins JPT, Thompson SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11);1539-1558.
15 Parmar MK, Torri V, Swart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med,1998,17(24):2815-2834.
16 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med,2005,353(2):123-132.
17 Goss G, Ferry D, Wierzbicki R,et al. Randomized Phase Ⅱ Study of gefitinib Compared With Placebo in Chemotherapy-Naive Patients With Advanced Non-Small-Cell Lung Cancer and Poor Performance Status. J Clin Oncol,2009,27.
18 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomized, placebo-controlled, multicentre study(Iressa Survival Evaluation in Lung Cancer). Lancet, 2005,366:1527-1537.
19 Kelly K,Chansky K,Gaspar LE,et al. Phase III Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage III Non-Small-Cell Lung Cancer:SWOG S0023. J Clin Oncol,2008,26:2450-2456.
20 Hirsch FR,Varella-Garcia M,Dziadziuszko R,et al. Fluorescence in situ hybridization subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in non-small cell lung cancer. Clin Cancer Res,2008,14(19):6317-23.
21 Eberhard DA, Johnson BE, Amler LC,et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol,2005, 23(25):5900-9.
22 Hirsch FR, Varella-Garcia M, Bunn PA Jr,et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol, 2006,24(31):5034-42.
23 Tsao MS, Sakurada A, Cutz JC,et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med,2005,353(2):133-44.
24 Shepherd FA,Ding K,Sakurada A,et al. Updated molecular analyses of the epidermal growth factor receptor(EGFR) gene and codon 12 and 13 of the k-ras gene in non-small cell lung cancer patients treated with erlotinib in National Cancer Institute. J Clin Oncol,2007,25:18s (abstr 7571).
25 Bell DW, Lynch TJ, Haserlat SM, et al.Epidermal growth factor receptor mutations and gene amplification in non-small cell lung cancer:Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol,2005,23(31):8081-8092.
26 Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy:case closed or is the jury still out? J Clin Oncol,2005,23(25):5856-8.
27 Baselga J. Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer:how do we go from INTACT to impact? J Clin Oncol,2004,22(5):759-61.
28 Johnson DH. Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin Cancer Res.2006,12(14 Pt 2):4451s-4457s.
29 Xu JM.Azzariti A,Severino M,et al. Characterization of sequence-dependent synergy between ZD1839 ("Iressa") and oxaliplatin. Biochem Pharmacol.2003,66(4):551-563.
30 Solit DB, She Y, Lobo J,et al. Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res,2005,11 (5):1983-9.
31 Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res,2004,15;64(20):7241-4.
32 Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer? Lancet Oncol,2006,7(6):499-507.
33 Mencoboni M, Bergaglio M, Serra M, et al.Maintenance therapy with gefitinib afer first-line chemotherapy in patients affected by advanced non-small cell lung cancer. Anticancer Res, 2007,27(6C):4425-9.
34 Mok T, Wu YL, Thongprasent S, et al. Phase Ⅲ randomized open-label first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer(IPASS). J Clin Oncol,2009,27(15s)(suppl; abstr 8044).
1 Jemal A, Siegel R, Ward E, et al. Cancer statistic,2006. CA Cancer J Clin,2006,56(2): 106-30.
2 Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin,2005, 55(2):74-108.
3 Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years:analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol,2006,24(28):4539-44.
4 Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med,2004, 350(4):379-92.
5 Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med,2002,3 46(2):92-8.
6 Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase Ⅲ study of docetaxel plusplatium combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer:the TAX 326 study group. J Clin Oncol,2003,21(16):3016-24.
7 Kelly K, Crowley J, Bunn PA Jr, et al. Randomized phase Ⅲ trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer:a Southwest Oncology Group trial. J Clin Oncol,2001,19(13):3210-8.
8 Figlin RA, Crowley JJ, Jacobs EL, et al. Evaluation of cisplatin,carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase Ⅱ study of the Southwest Oncology Group. Cancer,1996,78(5):998-1003.
9 Zheng BX. Molecular targeted therapies in non-small-cell lung cancer. Journal of Modern Clinical Medicine,2008,34(3):234-235.[郑碧霞.非小细胞肺癌分子靶向治疗的研究现状.现代临床医学,2008,34(3)：234-235.]
10 Cohen MH, Williams GA, Sridhara R, et al. United States Food and Drug Administration Drug Approval summary:Gefitinib (ZD1839;Iressa) tablets. Clin Cancer Res 2004; 10(4):1212-8.
11 Fukuoka M, Yano S, Giaccone G, et al. Multi-insitution a randomized phase II trail of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL 1 Trial). J Clin Oncol,2003,21(12):2237-46.
12 Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib,an inhibitor of the epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small-cell lung cancer: a randomized trial. JAMA,2003,290(16):2149-2158.
13 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomized, placebo-controlled, multicentre study(Iressa Survival Evaluation in Lung Cancer). Lancet, 2005,366:1527-1537.
14 Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol, 2004,22(6):1103-1109.
15 Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer:a phase Ⅱ study. Clin Cancer Res,2006,12(20 Pt 1): 6049-55.
16 Gu D, Scaringe WA, Li K, et al. Database of somatic mutations in EGFRwith analyses revealing indel hotspots but no smokingassociated signature. Hum Mutat,2007,28(8):760-70.
17 Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res,2004,10(24):8195-203.
18 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 2004,350(21):2129-2139.
19 Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004,304(5676):1497-500.
20 Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res,2004,64(20):7241-7244.
21 Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non small-cell lung cancer. J Natl Cancer Inst,2005,97(9):643-655.
22 Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med,2005,2(1):e17.
23 Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med,2005,352(8):786-92.
24 Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med,2005, 2(3):e73.
25 BalakMN, Gong Y, Riely GJ, et al. Novel D761Y and commonsecondary T790M mutations in epidermal growth factor receptormutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res,2006,12(21):6494-501.
26 Lin WC, Chiu CH, Liou JL, et al. Gefitinib as front-line treatment in Chinese patients with advanced non-small-cell lung cancer. Lung Cancer,2006,54(2):193-9.
27 Kimura H, Kasahara K, Shibata K, et al. EGFR mutation of tumor and serum in gefitinib-treated patients with chemotherapy-naive non-small cell lung cancer. J Thorac Oncol, 2006,1(3):260-7.
28 Suzuki R, Hasegawa Y, Baba K, et al. A phase Ⅱ study of singleagent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer. Br J Cancer,2006, 94(11):1599-603.
29 Reck M, Buchholz E, Romer KS, et al. Gefitinib monotherapy in chemotherapy-naive patients with inoperable stage Ⅲ/Ⅳnon-small-cell lung cancer. Clin Lung Cancer,2006,7(6): 406-411.
30 D'Addario G, Rauch D, Stupp R.et al. Multicenter phase Ⅱ trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC):SAKK protocol 19/03. Ann Oncol,2008,19(4):739-45.
31 Maruyama R, Nishiwaki Y, Tamura T, et al. Phase Ⅲstudy, Ⅴ-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol, 2008,26(26):4244-4255.
32 Cufer T, Vrdoljak E, Gaafar R, et al. Phase Ⅱ, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage Ⅲb or Ⅳ) non-small-cell lung cancer. Anti-cancer drugs,2006,17(4):401-409.
33 Douillard JY, Kim E, Hirsh V, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(INTEREST):a randomized Phase Ⅲ trial. Lancet,2008,372(9652): 1809-18.
34 Kelly K, Chansky K, Gaspar LE, et al. Phase Ⅲ Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage Ⅲ Non-Small-Cell Lung Cancer:SWOG S0023. J Clin Oncol,2008,26(15):2450-6.
35 Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gencitabine and cisplatin in advanced non-small-cell lung cancer:A phase Ⅲ trial(INTACT1). J Clin Oncol, 2004,22(5):777.
36 Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer:a phase III trial-INTACT 2. J Clin Oncol, 2004,22(5):785-794.
37 Lee DH, Han JY, Lee HG, et al. A phase Ⅱ study of gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in lifetime non-smokers. J Clin Oncol, 2005,23(16S):Abstract 7072.
38 Cappuzzo F, Ligorio C, Janne PA, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridizationpositive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer:the ONCOBELL trial. J Clin Oncol, 2007,25(16):2248-2255.
39 Cappuzzo F, Magrini E, Ceresoli GL, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst,2004, 96(15):1133-1141.
40 ClinicalTrials.gov:http://www.clinicaltrials.gov/ct2/show/NCT00322452. Accessioned May 5, 2006
41 Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase Ⅱ study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol,2006,24(21):3340-6.
42 Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer,2006,95(8):998-1004.
43 Tamura K. Okamoto I, Kashii T. et al. Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations:results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer,2008,98(5): 907-14.
44 Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol,2008,26(15): 2442-9.
45 ClinicalTrials.gov:www.clinicaltrials.gov. Accessioned October 26,2007.
46 Chen YM, Liu JM, Chou TY, et al. Phase II randomized study of daily gefitinib treatment alone or with vinorelbine every 2 weeks in patients with adenocarcinoma of the lung who failed at least 2 regimens of chemotherapy. Cancer,2007,109(9):1821-8.
47 Miller VA, Hirsch FR, Johnson DH. Systemic therapy of advanced bronchioloalveolar cell carcinoma:challenges and opportunities. J Clin Oncol,2005,23(14):3288-3293.
48 West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced bronchioloalveolar carcinoma:Southwest Oncology Group Study S0126. J Clin Oncol,2006,24(12):1807-1813.
49 Bearz A, Talamini R, Vaccher E, et al. Ca-15.3 antigen as predictor of response to EGFR inhibitors in patients with bronchio-alveolar carcinoma. J Clin Oncol,2007,25(18S):Abstract 18151.
50 Cadranel J, Quoix E, Debove P, et al. IFCT0401 trial:Phase Ⅱ study of gefitinib administered as first line treatment in non-resectable pneumonic-type adenocarcinoma (P-ADC). J Clin Oncol,2006,24(18S):Abstract 7186.
51 Crino L, Zatloukal P, Reck M, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE):a randomized,Phase Ⅱ study. J Clin Oncol 2008,26(26):4253-60.
52 Swinson D, Williams S, Beddard K, et al. Phase Ⅱ trial of first-line gefitinib in patients unsuitable for chemotherapy with stage Ⅲ/Ⅳ non-small-cell lung cancer. J Clin Oncol,2005, 23(16S):Abstract 7256.
53 Ebi N, Semba H, Tokunaga SJ, et al. A phase Ⅱ trial of gefitinib monotherapy in chemotherapy-naive patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol,2008,3(10):1166-71.
54 Spigel DR, Hainsworth JD, Burkett ER, et al. Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status:a Minnie Pearl Cancer Research Network Phase Ⅱ Trial. Clin Lung Cancer,2005,7(2):127-132.
2 Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(INTEREST):a randomized phase Ⅲ trial.Lancet,2008,372(22):1809-18.
3 Maruyama R, Nishiwaki Y, Tamura T, et al. Phase ⅢStudy,V-15-32,of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients With Non-Small-Cell Lung Cancer. J Clin Oncol,2008,26(26):4244-4252.
4 Giaccone G, Herbst RS, Manegold, et al. Gefitinib in Combination With Gemcitabine and Cisplatin in Advanced Non-Small-Cell Lung Cancer:A Phase Ⅲ Trial-INTACT1. J Clin Oncol, 2004,22(5):777-784.
5 Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non-Small-Cell Lung Cancer:A Phase Ⅲ Trial-INTACT2. J Clin Oncol,2004,22(5):785-794.
6 Herbst RS, Prager D, Hermann R, et al. TRIBUTE:a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol,2005,23(25):5892-5899.
7 Gatzemeier U, Pluzanska A, Szczesna A,et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer:The Tarceva lung cancer investigation trial. J Clin Oncol,2007,25(12):1545-1552.
8 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med,2004,350(21):2129-2139.
9 Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst,2005,97(9):643-655.
10 Miller VA, Zakowski M, Riely GJ, et al. EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC):Results of a prospective phase II trial. J Clin Oncol,2006,24:364s.
11 Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol,2005,23(25):5900-5909.
12 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst,2000,92(3):205-216.
13 Juni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ,2001,323 (7303):42-46.
14 Higgins JPT, Thompson SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11);1539-1558.
15 Parmar MK, Torri V, Swart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med,1998,17(24):2815-2834.
16 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med,2005,353(2):123-132.
17 Goss G, Ferry D, Wierzbicki R,et al. Randomized Phase Ⅱ Study of gefitinib Compared With Placebo in Chemotherapy-Naive Patients With Advanced Non-Small-Cell Lung Cancer and Poor Performance Status. J Clin Oncol,2009,27.
18 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomized, placebo-controlled, multicentre study(Iressa Survival Evaluation in Lung Cancer). Lancet, 2005,366:1527-1537.
19 Kelly K,Chansky K,Gaspar LE,et al. Phase III Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage III Non-Small-Cell Lung Cancer:SWOG S0023. J Clin Oncol,2008,26:2450-2456.
20 Hirsch FR,Varella-Garcia M,Dziadziuszko R,et al. Fluorescence in situ hybridization subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in non-small cell lung cancer. Clin Cancer Res,2008,14(19):6317-23.
21 Eberhard DA, Johnson BE, Amler LC,et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol,2005, 23(25):5900-9.
22 Hirsch FR, Varella-Garcia M, Bunn PA Jr,et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol, 2006,24(31):5034-42.
23 Tsao MS, Sakurada A, Cutz JC,et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med,2005,353(2):133-44.
24 Shepherd FA,Ding K,Sakurada A,et al. Updated molecular analyses of the epidermal growth factor receptor(EGFR) gene and codon 12 and 13 of the k-ras gene in non-small cell lung cancer patients treated with erlotinib in National Cancer Institute. J Clin Oncol,2007,25:18s (abstr 7571).
25 Bell DW, Lynch TJ, Haserlat SM, et al.Epidermal growth factor receptor mutations and gene amplification in non-small cell lung cancer:Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol,2005,23(31):8081-8092.
26 Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy:case closed or is the jury still out? J Clin Oncol,2005,23(25):5856-8.
27 Baselga J. Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer:how do we go from INTACT to impact? J Clin Oncol,2004,22(5):759-61.
28 Johnson DH. Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin Cancer Res.2006,12(14 Pt 2):4451s-4457s.
29 Xu JM.Azzariti A,Severino M,et al. Characterization of sequence-dependent synergy between ZD1839 ("Iressa") and oxaliplatin. Biochem Pharmacol.2003,66(4):551-563.
30 Solit DB, She Y, Lobo J,et al. Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res,2005,11 (5):1983-9.
31 Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res,2004,15;64(20):7241-4.
32 Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer? Lancet Oncol,2006,7(6):499-507.
33 Mencoboni M, Bergaglio M, Serra M, et al.Maintenance therapy with gefitinib afer first-line chemotherapy in patients affected by advanced non-small cell lung cancer. Anticancer Res, 2007,27(6C):4425-9.
34 Mok T, Wu YL, Thongprasent S, et al. Phase Ⅲ randomized open-label first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer(IPASS). J Clin Oncol,2009,27(15s)(suppl; abstr 8044).
1 Jemal A, Siegel R, Ward E, et al. Cancer statistic,2006. CA Cancer J Clin,2006,56(2): 106-30.
2 Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin,2005, 55(2):74-108.
3 Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years:analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol,2006,24(28):4539-44.
4 Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med,2004, 350(4):379-92.
5 Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med,2002,3 46(2):92-8.
6 Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase Ⅲ study of docetaxel plusplatium combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer:the TAX 326 study group. J Clin Oncol,2003,21(16):3016-24.
7 Kelly K, Crowley J, Bunn PA Jr, et al. Randomized phase Ⅲ trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer:a Southwest Oncology Group trial. J Clin Oncol,2001,19(13):3210-8.
8 Figlin RA, Crowley JJ, Jacobs EL, et al. Evaluation of cisplatin,carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase Ⅱ study of the Southwest Oncology Group. Cancer,1996,78(5):998-1003.
9 Zheng BX. Molecular targeted therapies in non-small-cell lung cancer. Journal of Modern Clinical Medicine,2008,34(3):234-235.[郑碧霞.非小细胞肺癌分子靶向治疗的研究现状.现代临床医学,2008,34(3)：234-235.]
10 Cohen MH, Williams GA, Sridhara R, et al. United States Food and Drug Administration Drug Approval summary:Gefitinib (ZD1839;Iressa) tablets. Clin Cancer Res 2004; 10(4):1212-8.
11 Fukuoka M, Yano S, Giaccone G, et al. Multi-insitution a randomized phase II trail of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL 1 Trial). J Clin Oncol,2003,21(12):2237-46.
12 Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib,an inhibitor of the epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small-cell lung cancer: a randomized trial. JAMA,2003,290(16):2149-2158.
13 Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomized, placebo-controlled, multicentre study(Iressa Survival Evaluation in Lung Cancer). Lancet, 2005,366:1527-1537.
14 Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol, 2004,22(6):1103-1109.
15 Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer:a phase Ⅱ study. Clin Cancer Res,2006,12(20 Pt 1): 6049-55.
16 Gu D, Scaringe WA, Li K, et al. Database of somatic mutations in EGFRwith analyses revealing indel hotspots but no smokingassociated signature. Hum Mutat,2007,28(8):760-70.
17 Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res,2004,10(24):8195-203.
18 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 2004,350(21):2129-2139.
19 Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004,304(5676):1497-500.
20 Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res,2004,64(20):7241-7244.
21 Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non small-cell lung cancer. J Natl Cancer Inst,2005,97(9):643-655.
22 Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med,2005,2(1):e17.
23 Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med,2005,352(8):786-92.
24 Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med,2005, 2(3):e73.
25 BalakMN, Gong Y, Riely GJ, et al. Novel D761Y and commonsecondary T790M mutations in epidermal growth factor receptormutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res,2006,12(21):6494-501.
26 Lin WC, Chiu CH, Liou JL, et al. Gefitinib as front-line treatment in Chinese patients with advanced non-small-cell lung cancer. Lung Cancer,2006,54(2):193-9.
27 Kimura H, Kasahara K, Shibata K, et al. EGFR mutation of tumor and serum in gefitinib-treated patients with chemotherapy-naive non-small cell lung cancer. J Thorac Oncol, 2006,1(3):260-7.
28 Suzuki R, Hasegawa Y, Baba K, et al. A phase Ⅱ study of singleagent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer. Br J Cancer,2006, 94(11):1599-603.
29 Reck M, Buchholz E, Romer KS, et al. Gefitinib monotherapy in chemotherapy-naive patients with inoperable stage Ⅲ/Ⅳnon-small-cell lung cancer. Clin Lung Cancer,2006,7(6): 406-411.
30 D'Addario G, Rauch D, Stupp R.et al. Multicenter phase Ⅱ trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC):SAKK protocol 19/03. Ann Oncol,2008,19(4):739-45.
31 Maruyama R, Nishiwaki Y, Tamura T, et al. Phase Ⅲstudy, Ⅴ-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol, 2008,26(26):4244-4255.
32 Cufer T, Vrdoljak E, Gaafar R, et al. Phase Ⅱ, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage Ⅲb or Ⅳ) non-small-cell lung cancer. Anti-cancer drugs,2006,17(4):401-409.
33 Douillard JY, Kim E, Hirsh V, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(INTEREST):a randomized Phase Ⅲ trial. Lancet,2008,372(9652): 1809-18.
34 Kelly K, Chansky K, Gaspar LE, et al. Phase Ⅲ Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage Ⅲ Non-Small-Cell Lung Cancer:SWOG S0023. J Clin Oncol,2008,26(15):2450-6.
35 Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gencitabine and cisplatin in advanced non-small-cell lung cancer:A phase Ⅲ trial(INTACT1). J Clin Oncol, 2004,22(5):777.
36 Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer:a phase III trial-INTACT 2. J Clin Oncol, 2004,22(5):785-794.
37 Lee DH, Han JY, Lee HG, et al. A phase Ⅱ study of gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in lifetime non-smokers. J Clin Oncol, 2005,23(16S):Abstract 7072.
38 Cappuzzo F, Ligorio C, Janne PA, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridizationpositive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer:the ONCOBELL trial. J Clin Oncol, 2007,25(16):2248-2255.
39 Cappuzzo F, Magrini E, Ceresoli GL, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst,2004, 96(15):1133-1141.
40 ClinicalTrials.gov:http://www.clinicaltrials.gov/ct2/show/NCT00322452. Accessioned May 5, 2006
41 Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase Ⅱ study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol,2006,24(21):3340-6.
42 Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer,2006,95(8):998-1004.
43 Tamura K. Okamoto I, Kashii T. et al. Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations:results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer,2008,98(5): 907-14.
44 Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol,2008,26(15): 2442-9.
45 ClinicalTrials.gov:www.clinicaltrials.gov. Accessioned October 26,2007.
46 Chen YM, Liu JM, Chou TY, et al. Phase II randomized study of daily gefitinib treatment alone or with vinorelbine every 2 weeks in patients with adenocarcinoma of the lung who failed at least 2 regimens of chemotherapy. Cancer,2007,109(9):1821-8.
47 Miller VA, Hirsch FR, Johnson DH. Systemic therapy of advanced bronchioloalveolar cell carcinoma:challenges and opportunities. J Clin Oncol,2005,23(14):3288-3293.
48 West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced bronchioloalveolar carcinoma:Southwest Oncology Group Study S0126. J Clin Oncol,2006,24(12):1807-1813.
49 Bearz A, Talamini R, Vaccher E, et al. Ca-15.3 antigen as predictor of response to EGFR inhibitors in patients with bronchio-alveolar carcinoma. J Clin Oncol,2007,25(18S):Abstract 18151.
50 Cadranel J, Quoix E, Debove P, et al. IFCT0401 trial:Phase Ⅱ study of gefitinib administered as first line treatment in non-resectable pneumonic-type adenocarcinoma (P-ADC). J Clin Oncol,2006,24(18S):Abstract 7186.
51 Crino L, Zatloukal P, Reck M, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE):a randomized,Phase Ⅱ study. J Clin Oncol 2008,26(26):4253-60.
52 Swinson D, Williams S, Beddard K, et al. Phase Ⅱ trial of first-line gefitinib in patients unsuitable for chemotherapy with stage Ⅲ/Ⅳ non-small-cell lung cancer. J Clin Oncol,2005, 23(16S):Abstract 7256.
53 Ebi N, Semba H, Tokunaga SJ, et al. A phase Ⅱ trial of gefitinib monotherapy in chemotherapy-naive patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol,2008,3(10):1166-71.
54 Spigel DR, Hainsworth JD, Burkett ER, et al. Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status:a Minnie Pearl Cancer Research Network Phase Ⅱ Trial. Clin Lung Cancer,2005,7(2):127-132.