晚期胆道癌吉西他滨为基础化疗方案临床疗效Meta分析
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摘要
目的以吉西他滨(gemcitabine,GEM)为基础化疗方案治疗晚期胆道癌临床疗效尚不确定,本研究通过Meta分析综合评估以GEM为基础化疗方案治疗晚期胆道癌临床疗效,探讨其作为晚期胆道癌一线治疗方案可行性。方法检索PubMed、EMbase、MEDLINE、Ovid、EBSCO和Cochrane数据库自建库至2016-10发表的GEM为基础化疗方案治疗晚期胆道癌的前瞻性随机对照试验和文献,并进行文献筛选和提取资料。评估指标包括总生存期(overall survival,OS)、无进展生存期(progression-free survival,PFS)、完全缓解(complete remission,CR)、部分缓解(partial remission,PR)、疾病稳定(stability of the disease,SD)、客观缓解率(objective response rate,ORR)、临床受益率(clinical benefit rate,CBR)和不良反应。纳入研究的结果采用Review Manager 5.3软件进行Meta分析。结果共纳入9篇研究,包括906例病例。按照化疗方案进行分组,即GEM为基础的化疗方案(GC组)和不联合GEM为基础的化疗方案(包括GEM组和单独GEM组2个亚组)。总分析结果显示,GC组OS(HR=0.75,95%CI=0.65～0.87,P<0.001)、PFS(HR=0.75,95%CI=0.57～0.99,P=0.04)和ORR(OR=1.55,95%CI=1.07～2.25,P=0.02)优于不联合GEM为基础的化疗方案。亚组分析结果显示,GC组OS(HR=0.76,95%CI=0.64～0.90,P=0.002)和ORR(OR=1.70,95%CI=1.02～2.83,P=0.04)优于单独GEM组;GC组OS(HR=0.74,95%CI=0.57～0.95,P=0.02)和PFS(HR=0.58,95%CI=0.43～0.78,P<0.001)优于GEM组。总分析结果显示,GC组和不联合GEM为基础的化疗方案3或4级血液学不良反应发生率比较,包括白细胞减少症(OR=2.74,95%CI=1.86～4.03,P<0.001)、中性粒细胞减少症(OR=2.37,95%CI=1.21～4.66,P=0.01)、贫血(OR=3.61,95%CI=2.12～6.16,P<0.001)和血小板减少症(OR=1.92,95%CI=1.25～2.95,P=0.003),差异有统计学意义。结论 GEM为基础的联合化疗是一种潜在的一线治疗晚期胆道癌的有效方案,但不良反应增加。
OBJECTIVE The clinical efficacy of gemcitabine-based chemotherapy for advanced biliary tract cancer(BTC)remains uncertain.This study assessed the clinical efficacy of gemcitabine-based chemotherapy for advanced BTC by meta-analysis and explored its feasibility as a first-line treatment for advanced BTC.METHODS PubMed,EMbase,MEDLINE,Ovid,EBSCO and Cochrane databases were searched until 2016-10,and literature screening and data extraction were carried out.Overall survival(OS),progression-free survival(PFS),complete remission(CR),partial remission(PR),stability of the disease(SD),objective response rate(ORR),clinical benefit rate(CBR)and adverse reactions were assessed.The results of the study were carried out by Review Manager 5.3 software for Meta analysis.RESULTS Nine trials including 906 patients were analyzed.The studies were divided into subgroups based on the chemotherapy regimen,including Gem-based(GC group)and non-Gem-based chemotherapy(including two subgroups of GEM and GEM alone).In overall analyses,patients treated with Gem-based combination chemotherapy had significantly improvement of overall survival(HR=0.75,95%CI=0.65-0.87,P<0.001),progression-free survival(HR=0.75,95%CI=0.57-0.99,P=0.04),overall response rate(OR=1.55,95%CI=1.07-2.25,P=0.02).In subgroup analysis,Gem-based combination chemotherapy,comparing Gem monotherapy,can significantly improve overall survival,overall response rate(HR=0.76,95%CI=0.64-0.90,P=0.002;OR=1.70,95%CI=1.02-2.83,P=0.04),in addition,Gem-based combination chemotherapy,comparing to non-Gem-based chemotherapy,had significantly improvement of overall survival,progressionfree survival(HR=0.74,95%CI=0.57-0.95,P=0.02;HR=0.58,95%CI=0.43-0.78,P<0.001).A higher incidence of Grade 3 or 4 hematological toxicities,including leukopenia(OR=2.74,95%CI=1.86-4.03,P<0.001),neutropenia(OR=2.37,95%CI=1.21-4.66,P=0.01),anemia(OR=3.61,95%CI=2.12-6.16,P<0.001)and thrombocytopenia(OR=1.92,95%CI=1.25-2.95,P=0.003)was found in the Gem-based combination chemotherapy group compared with no Gem-based combination chemotherapy group.CONCLUSION Our results confirmed that Gem-based combination chemotherapy is a potential first-line treatment for advanced biliary tract cancer,though with additional toxicity.
OBJECTIVE The clinical efficacy of gemcitabine-based chemotherapy for advanced biliary tract cancer(BTC)remains uncertain.This study assessed the clinical efficacy of gemcitabine-based chemotherapy for advanced BTC by meta-analysis and explored its feasibility as a first-line treatment for advanced BTC.METHODS PubMed,EMbase,MEDLINE,Ovid,EBSCO and Cochrane databases were searched until 2016-10,and literature screening and data extraction were carried out.Overall survival(OS),progression-free survival(PFS),complete remission(CR),partial remission(PR),stability of the disease(SD),objective response rate(ORR),clinical benefit rate(CBR)and adverse reactions were assessed.The results of the study were carried out by Review Manager 5.3 software for Meta analysis.RESULTS Nine trials including 906 patients were analyzed.The studies were divided into subgroups based on the chemotherapy regimen,including Gem-based(GC group)and non-Gem-based chemotherapy(including two subgroups of GEM and GEM alone).In overall analyses,patients treated with Gem-based combination chemotherapy had significantly improvement of overall survival(HR=0.75,95%CI=0.65-0.87,P<0.001),progression-free survival(HR=0.75,95%CI=0.57-0.99,P=0.04),overall response rate(OR=1.55,95%CI=1.07-2.25,P=0.02).In subgroup analysis,Gem-based combination chemotherapy,comparing Gem monotherapy,can significantly improve overall survival,overall response rate(HR=0.76,95%CI=0.64-0.90,P=0.002;OR=1.70,95%CI=1.02-2.83,P=0.04),in addition,Gem-based combination chemotherapy,comparing to non-Gem-based chemotherapy,had significantly improvement of overall survival,progressionfree survival(HR=0.74,95%CI=0.57-0.95,P=0.02;HR=0.58,95%CI=0.43-0.78,P<0.001).A higher incidence of Grade 3 or 4 hematological toxicities,including leukopenia(OR=2.74,95%CI=1.86-4.03,P<0.001),neutropenia(OR=2.37,95%CI=1.21-4.66,P=0.01),anemia(OR=3.61,95%CI=2.12-6.16,P<0.001)and thrombocytopenia(OR=1.92,95%CI=1.25-2.95,P=0.003)was found in the Gem-based combination chemotherapy group compared with no Gem-based combination chemotherapy group.CONCLUSION Our results confirmed that Gem-based combination chemotherapy is a potential first-line treatment for advanced biliary tract cancer,though with additional toxicity.
引文
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[14]Morizane C,Okusaka T,Mizusawa J,et al.Randomized phaseⅡstudy of gemcitabine plus S-1versus S-1in advanced biliary tract cancer:a Japan Clinical Oncology Group trial(JCOG 0805)[J].Cancer Sci,2013,104(9):1211-1216.
[15]Kang MJ,Lee JL,Kim TW,et al.Randomized phaseⅡtrial of S-1and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma[J].Acta Oncol,2012,51(7):860-866.
[16]Kornek GV,Schuell B,Laengle F,et al.Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer:a randomised phaseⅡtrial[J].Ann Oncol,2004,15(3):478-483.
[17]Sharma A,Dwary AD,Mohanti BK,et al.Best supportive care compared with chemotherapy for unresectable gall bladder cancer:a randomized controlled study[J].J Clin Oncol,2010,28(30):4581-4586.
[18]吴燕丽,曾晖,王智勇.吉西他滨不同给药方案联合奥沙利铂治疗复发转移性胆管癌的临床观察[J].中国药房,2017,28(27):3794-3797.
[19]段方方,张彦华,孔天东,等.吉西他滨联合替吉奥治疗晚期胆囊癌的疗效及安全性[J].肿瘤基础与临床,2018,31(1):28-31.
[20]孙振.进展期胆囊癌患者术后应用替吉奥联合吉西他滨的临床疗效分析[D].郑州:郑州大学,2018.
[21]杜剑平,王峰,江丰收,等.吉西他滨联合洛铂治疗复发性难治性乳腺癌临床疗效观察[J].解放军医药杂志,2017,29(6):58-61.
[22]张艳艳.吉西他滨联合顺铂治疗晚期非小细胞肺癌患者的疗效及其对外周血T淋巴细胞亚群的影响[J].肿瘤基础与临床,2018(1):60-62.
[23]王小倩,刘丽英,卢辉.吉西他滨联合奥沙利铂二线治疗老年套细胞淋巴瘤临床观察[J].肿瘤基础与临床,2018(1):31-33.
[24]Valle JW,Furuse J,Jitlal M,et al.Cisplatin and gemcitabine for advanced biliary tract cancer:a meta-analysis of two randomised trials[J].Ann Oncol,2014,25(2):391-398.
[25]Liu H,Zhang QD,Li ZH,et al.Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer:a meta-analysis[J].World J Gastroenterol,2014,20(47):18001-18012.
[2]Ciombor KK,Goff LW.Advances in the management of biliary tract cancers[J].Clin Adv Hematol Oncol,2013,11(1):28-34.
[3]Gebbia V,Majello E,Testa A,et al.Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with5-fluorouracil,high dose levofolinic acid and oral hydroxyurea on a weekly schedule:G.O.I.M.[J].Cancer,1996,78(6):1300-1307.
[4]Smith GW,Bukowski RM,Hewlett JS,et al.Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma[J].Cancer,1984,54(8):1513-1516.
[5]Ducreux M,Rougier P,Fandi A,et al.Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin[J].Ann Oncol,1998,9(6):653-656.
[6]Patt YZ,Hassan MM,Lozano RD,et al.PhaseⅡtrial of cisplatin,interferon alpha-2b,doxorubicin,and 5-fluorouracil for biliary tract cancer[J].Clin Cancer Res,2001,7(11):3375-3380.
[7]Castro MP.Efficacy of gemcitabine in the treatment of patients with gallbladder carcinoma:a casereport[J].Cancer,1998,82(4):639-641.
[8]Park JS,Oh SY,Kim SH,et al.Single-agent gemcitabine in the treatment of advanced biliary tract cancers:aphaseⅡstudy[J].Jpn J Clin Oncol,2005,35(2):68-73.
[9]Okusaka T,Nakachi K,Fukutomi A,et al.Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer:a comparative multicentre study in Japan[J].Br J Cancer,2010,103(4):469-474.
[10]Sasaki T,Isayama H,Nakai Y,et al.A randomized phaseⅡstudy of gemcitabine and S-1combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer[J].Cancer Chemother Pharmacol,2013,71(4):973-979.
[11]Valle J,Wasan H,Palmer DH,et al.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer[J].N Engl J Med,2010,362(14):1273-1281.
[12]Moehler M,Maderer A,Schimanski C,et al.Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer:a double-blind placebo-controlled multicentre phaseⅡAIOstudy with biomarker and serum programme.[J].Eur J Cancer,2014,50(18):3125-3135.
[13]Santoro A,Gebbia V,Pressiani T,et al.A randomized,multicenter,phaseⅡstudy of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer:the VanGogh study[J].Ann Oncol,2015,26(3):542-547.
[14]Morizane C,Okusaka T,Mizusawa J,et al.Randomized phaseⅡstudy of gemcitabine plus S-1versus S-1in advanced biliary tract cancer:a Japan Clinical Oncology Group trial(JCOG 0805)[J].Cancer Sci,2013,104(9):1211-1216.
[15]Kang MJ,Lee JL,Kim TW,et al.Randomized phaseⅡtrial of S-1and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma[J].Acta Oncol,2012,51(7):860-866.
[16]Kornek GV,Schuell B,Laengle F,et al.Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer:a randomised phaseⅡtrial[J].Ann Oncol,2004,15(3):478-483.
[17]Sharma A,Dwary AD,Mohanti BK,et al.Best supportive care compared with chemotherapy for unresectable gall bladder cancer:a randomized controlled study[J].J Clin Oncol,2010,28(30):4581-4586.
[18]吴燕丽,曾晖,王智勇.吉西他滨不同给药方案联合奥沙利铂治疗复发转移性胆管癌的临床观察[J].中国药房,2017,28(27):3794-3797.
[19]段方方,张彦华,孔天东,等.吉西他滨联合替吉奥治疗晚期胆囊癌的疗效及安全性[J].肿瘤基础与临床,2018,31(1):28-31.
[20]孙振.进展期胆囊癌患者术后应用替吉奥联合吉西他滨的临床疗效分析[D].郑州:郑州大学,2018.
[21]杜剑平,王峰,江丰收,等.吉西他滨联合洛铂治疗复发性难治性乳腺癌临床疗效观察[J].解放军医药杂志,2017,29(6):58-61.
[22]张艳艳.吉西他滨联合顺铂治疗晚期非小细胞肺癌患者的疗效及其对外周血T淋巴细胞亚群的影响[J].肿瘤基础与临床,2018(1):60-62.
[23]王小倩,刘丽英,卢辉.吉西他滨联合奥沙利铂二线治疗老年套细胞淋巴瘤临床观察[J].肿瘤基础与临床,2018(1):31-33.
[24]Valle JW,Furuse J,Jitlal M,et al.Cisplatin and gemcitabine for advanced biliary tract cancer:a meta-analysis of two randomised trials[J].Ann Oncol,2014,25(2):391-398.
[25]Liu H,Zhang QD,Li ZH,et al.Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer:a meta-analysis[J].World J Gastroenterol,2014,20(47):18001-18012.