The first generation EGFR-TKIs <i>versus</i> pemetrexed as second-line treatment for advanced non-small cell lung cancer: a meta-analysis _Chinese Journal of Evidence-Based Medicine

Authors：

CHENG Xiangsong , LIU Haiyang , SONG Yongan , XU Zhiwei ,  ZHANG Xiaoju

Department of Respiratory and Critical Care Medicine, Henan Province People’s Hospital, Zhengzhou, 450003, P.R.China;

Corresponding author：

ZHANG Xiaoju, Email: 15837101166@163.com

Keywords：

Gefitinib; Erlotinib; Icotinib; Pemetrexed; Non-small cell lung cancer; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.201708048

Video：

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ObjectivesTo systematically review the efficacy and safety of the first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced non-small cell lung cancer (NSCLC).MethodsDatabases including PubMed, EMbase, The Cochrane Library, CNKI, WanFang Data and CBM were searched to collect randomized controlled trials (RCTs) about the first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced NSCLC from inception to June 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 20 RCTs involving 2 242 patients were finally included. The results of meta-analysis showed that: the rate of progression free survival (PFS) in the EGFR-TKI group was superior to the pemetrexed group (HR=0.78, 95%CI 0.58 to 0.99, P<0.000 1) with significant difference. However, there was no significant difference between two groups in complete remission rate (RR=1.81, 95%CI 0.65 to 5.07,P=0.26), partial remission rate (RR=0.93, 95%CI 0.78 to 1.11, P=0.44), stable disease rate (RR=0.92, 95%CI 0.82 to 1.03, P=0.16), progression disease rate (RR=1.09, 95%CI 0.99 to 1.20, P=0.09), overall response rate (RR=0.97, 95%CI 0.72 to 1.30, P=0.84), disease control rate (RR=0.93, 95%CI 0.87 to 1.01, P=0.07) and overall survival rate (HR=0.89, 95%CI 0.74 to 1.04, P<0.572). The incidences of skin rash (RR=12.43, 95%CI 3.98 to 38.84,P<0.01) and diarrhea (RR=3.94, 95%CI 2.32 to 6.70,P<0.01) were significantly higher in the EGFR-TKI group, but the incidences of leukopenia (RR=0.19, 95%CI 0.09 to 0.41,P<0.01 ), anemia (RR=0.40, 95%CI 0.17 to 0.92,P=0.03), thrombocytopenia (RR=0.37, 95%CI 0.14 to 0.97, P=0.04), nausea and vomiting (RR=0.50, 95%CI 0.28 to 0.87, P=0.01), constipation (RR=0.30, 95%CI 0.14 to 0.64, P=0.002) were significant lower in the EGFR-TKI group than that of the pemetrexed group.ConclusionGefitinib shows some superiority to pemetrexed in second-line treatment for NSCLC, and it can be used as the second-line drug for advanced NSCLC. Due to the limited quality and quantity of included studies, more high quality studies are needed to verify the above conclusion.

Citation： CHENG Xiangsong, LIU Haiyang, SONG Yongan, XU Zhiwei, ZHANG Xiaoju. The first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced non-small cell lung cancer: a meta-analysis . Chinese Journal of Evidence-Based Medicine, 2018, 18(4): 326-332. doi: 10.7507/1672-2531.201708048 Copy

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2.	韩忠辉. 医院 2005～2009 年恶性肿瘤住院病例统计分析. 现代医药卫生, 2011, 27(7): 1017-1018.
3.	Passaro A, Cortesi E, De Marinis F. Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors? Expert Rev Anticanc, 2011, 11(10): 1587-1597.
4.	Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol, 2009, 4(2): 243-250.
5.	石远凯, 孙燕, 于金明, 等. 中国晚期原发性肺癌诊治专家共识 (2016 年版). 中国肺癌杂志, 2016, 19(1): 1-15.
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7.	陈红娜, 张明智. 吉非替尼与培美曲塞二线治疗晚期非小细胞肺癌临床对比研究. 河南医学研究, 2016, 25(12): 2207-2208.
8.	赵利红, 汪海岩, 张德芳. 培美曲塞与吉非替尼二线治疗晚期非小细胞肺癌的临床对比分析. 中国肿瘤临床与康复, 2013, 20(11): 1235-1238.
9.	虞泽. 一线化疗失败晚期非小细胞肺癌应用培美曲塞和吉非替尼治疗对比分析. 北方药学, 2016, 13(9): 37.
10.	王美清, 何立香, 彭大为, 等. 培美曲塞与吉非替尼二线治疗晚期 NSCLC 的对比研究. 中国热带医学, 2012, 12(11): 1361-1363.
11.	王守忠. 晚期非小细胞肺癌二线化疗疗效及生存分析. 沈阳: 辽宁医学院, 2015.
12.	戴宏宇, 徐玲, 夏春伟, 等. 吉非替尼对比培美曲塞二线治疗晚期非鳞型非小细胞肺癌的随机对照临床研究. 中国肺癌杂志, 2013, 16(8): 405-410.
13.	张静, 刘素勤, 张洁, 等. 晚期非小细胞肺癌二线治疗不同方案的疗效及成本效益分析. 临床肿瘤学杂志, 2012, 17(10): 908-911.
14.	张定国, 阮秀丽. 吉非替尼对比培美曲塞二线治疗晚期非小细胞肺癌的临床研究. 癌症进展, 2016, 14(1): 78-80, 86.
15.	张宇卉, 王海宾. 吉非替尼和培美曲塞治疗晚期复发非小细胞肺癌的临床研究. 临床合理用药杂志, 2009, 2(18): 14-16.
16.	宋霆婷, 盖慧荣, 李伟, 等. 吉非替尼治疗晚期非小细胞肺癌的疗效观察. 疑难病杂志, 2015, 14(8): 778-781.
17.	刘文霞. 培美曲塞对比吉非替尼二线治疗晚期非小细胞肺癌的临床观察. 南宁: 广西医科大学, 2011.
18.	刘孝民. 吉非替尼对比培美曲塞治疗晚期非鳞非小细胞肺癌的临床疗效及安全性评价. 中国临床药理学杂志, 2015, 31(24): 2393-2395.
19.	Zhou Q, Cheng Y, Yang JJ, et al. Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. Ann Oncol, 2014, 25(12): 2385-2391.
20.	Kim YS, Cho K, Woo H S, et al. Randomized phase II study of pemetrexed versus gefitinib in previously treated patients with advanced non-small cell lung cancer. Cancer Res Treat, 2016, 48(1): 80.
21.	Xu YH, Mei JS, Zhou J. Randomized study of gefitinib versus pemetrexed as maintenance treatment in patients with advanced glandular non-small cell lung cancer. Int J Clin Exp Med, 2015, 8(4): 6242.
22.	Fiala O, Pesek M, Finek J, et al. Pemetrexed versus erlotinib in the second-line treatment of patients with advanced-stage non-squamous NSCLC harboring wild-type EGFR gene. Anticancer Res, 2016, 36(1): 447-453.
23.	Li N, Ou W, Yang H, et al. A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Cancer, 2014, 120(9): 1379-1386.
24.	Lin L, Zhao J, Hu J, et al. Comparison of the efficacy and tolerability of gefitinib with pemetrexed maintenance after first-line platinum-based doublet chemotherapy in advanced lung adenocarcinoma: single-center experience. Onco Targets Ther, 2016, 9: 6305-6314.
25.	Sun JM, Lee KH, Kim S, et al. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01). Cancer, 2012, 118(24): 6234-6242.
26.	Karampeazis A, Voutsina A, Souglakos J, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer, 2013, 119(15): 2754-2764.
27.	Ohe Y. Chemoradiotherapy for lung cancer. Expert Opin Pharmacother, 2005, 6(16): 2793-2804.
28.	Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol, 2004, 22(9): 1589-1597.
29.	陈闪闪, 冯奉仪. 培美曲塞在非小细胞肺癌治疗中的研究进展. 肿瘤学杂志, 2007, 13(1): 22-25.
30.	Clarke SJ, Abratt R, Goedhals L, et al. Phase II trial of pemetrexed disodium (ALIMTA®, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. Ann Oncol, 2002, 13(5): 737-741.
31.	Rusthoven JJ, Eisenhauer E, Butts C, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. J Clin Oncol, 1999, 17(4): 1194-1194.
32.	Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. New Engl J Med, 2005, 353(2): 123-132.
33.	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 randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 2005, 366(9496): 1527-1537.
34.	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. Anticancer Drugs, 2006, 17(4): 401-409.

1. Zheng R, Zeng H, Zuo T, et al. Lung cancer incidence and mortality in China, 2011. Thorac Cancer, 2016, 7(1): 94-99.
2. 韩忠辉. 医院 2005～2009 年恶性肿瘤住院病例统计分析. 现代医药卫生, 2011, 27(7): 1017-1018.
3. Passaro A, Cortesi E, De Marinis F. Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors? Expert Rev Anticanc, 2011, 11(10): 1587-1597.
4. Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol, 2009, 4(2): 243-250.
5. 石远凯, 孙燕, 于金明, 等. 中国晚期原发性肺癌诊治专家共识 (2016 年版). 中国肺癌杂志, 2016, 19(1): 1-15.
6. 曾宪涛, 包翠萍, 曹世义, 等. Meta 分析系列之三: 随机对照试验的质量评价工具. 中国循证心血管医学杂志, 2012, 4(3): 183-185.
7. 陈红娜, 张明智. 吉非替尼与培美曲塞二线治疗晚期非小细胞肺癌临床对比研究. 河南医学研究, 2016, 25(12): 2207-2208.
8. 赵利红, 汪海岩, 张德芳. 培美曲塞与吉非替尼二线治疗晚期非小细胞肺癌的临床对比分析. 中国肿瘤临床与康复, 2013, 20(11): 1235-1238.
9. 虞泽. 一线化疗失败晚期非小细胞肺癌应用培美曲塞和吉非替尼治疗对比分析. 北方药学, 2016, 13(9): 37.
10. 王美清, 何立香, 彭大为, 等. 培美曲塞与吉非替尼二线治疗晚期 NSCLC 的对比研究. 中国热带医学, 2012, 12(11): 1361-1363.
11. 王守忠. 晚期非小细胞肺癌二线化疗疗效及生存分析. 沈阳: 辽宁医学院, 2015.
12. 戴宏宇, 徐玲, 夏春伟, 等. 吉非替尼对比培美曲塞二线治疗晚期非鳞型非小细胞肺癌的随机对照临床研究. 中国肺癌杂志, 2013, 16(8): 405-410.
13. 张静, 刘素勤, 张洁, 等. 晚期非小细胞肺癌二线治疗不同方案的疗效及成本效益分析. 临床肿瘤学杂志, 2012, 17(10): 908-911.
14. 张定国, 阮秀丽. 吉非替尼对比培美曲塞二线治疗晚期非小细胞肺癌的临床研究. 癌症进展, 2016, 14(1): 78-80, 86.
15. 张宇卉, 王海宾. 吉非替尼和培美曲塞治疗晚期复发非小细胞肺癌的临床研究. 临床合理用药杂志, 2009, 2(18): 14-16.
16. 宋霆婷, 盖慧荣, 李伟, 等. 吉非替尼治疗晚期非小细胞肺癌的疗效观察. 疑难病杂志, 2015, 14(8): 778-781.
17. 刘文霞. 培美曲塞对比吉非替尼二线治疗晚期非小细胞肺癌的临床观察. 南宁: 广西医科大学, 2011.
18. 刘孝民. 吉非替尼对比培美曲塞治疗晚期非鳞非小细胞肺癌的临床疗效及安全性评价. 中国临床药理学杂志, 2015, 31(24): 2393-2395.
19. Zhou Q, Cheng Y, Yang JJ, et al. Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. Ann Oncol, 2014, 25(12): 2385-2391.
20. Kim YS, Cho K, Woo H S, et al. Randomized phase II study of pemetrexed versus gefitinib in previously treated patients with advanced non-small cell lung cancer. Cancer Res Treat, 2016, 48(1): 80.
21. Xu YH, Mei JS, Zhou J. Randomized study of gefitinib versus pemetrexed as maintenance treatment in patients with advanced glandular non-small cell lung cancer. Int J Clin Exp Med, 2015, 8(4): 6242.
22. Fiala O, Pesek M, Finek J, et al. Pemetrexed versus erlotinib in the second-line treatment of patients with advanced-stage non-squamous NSCLC harboring wild-type EGFR gene. Anticancer Res, 2016, 36(1): 447-453.
23. Li N, Ou W, Yang H, et al. A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Cancer, 2014, 120(9): 1379-1386.
24. Lin L, Zhao J, Hu J, et al. Comparison of the efficacy and tolerability of gefitinib with pemetrexed maintenance after first-line platinum-based doublet chemotherapy in advanced lung adenocarcinoma: single-center experience. Onco Targets Ther, 2016, 9: 6305-6314.
25. Sun JM, Lee KH, Kim S, et al. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01). Cancer, 2012, 118(24): 6234-6242.
26. Karampeazis A, Voutsina A, Souglakos J, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer, 2013, 119(15): 2754-2764.
27. Ohe Y. Chemoradiotherapy for lung cancer. Expert Opin Pharmacother, 2005, 6(16): 2793-2804.
28. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol, 2004, 22(9): 1589-1597.
29. 陈闪闪, 冯奉仪. 培美曲塞在非小细胞肺癌治疗中的研究进展. 肿瘤学杂志, 2007, 13(1): 22-25.
30. Clarke SJ, Abratt R, Goedhals L, et al. Phase II trial of pemetrexed disodium (ALIMTA®, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. Ann Oncol, 2002, 13(5): 737-741.
31. Rusthoven JJ, Eisenhauer E, Butts C, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. J Clin Oncol, 1999, 17(4): 1194-1194.
32. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. New Engl J Med, 2005, 353(2): 123-132.
33. 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 randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 2005, 366(9496): 1527-1537.
34. 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. Anticancer Drugs, 2006, 17(4): 401-409.

Chinese Journal of Evidence-Based Medicine

The first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced non-small cell lung cancer: a meta-analysis

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