摘要
第一部分阿糖胞苷用药与否对急性早幼粒细胞白血病治疗作用的Cochrane系统评价
目的探讨阿糖胞苷(cytarabine,Ara-C)治疗急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)的疗效与安全性,评价Ara-C应用与否对APL治疗作用的影响。
资料和方法采用Cochrane系统评价方法,查阅国内外已公开发表或未发表的比较含与不含Ara-C的治疗方案对APL疗效的随机对照试验(randomized controlled trials,RCT)文献,以无事件生存(event free survival,EFS)、总生存期(overla survival,OS)、无病生存期(disease free survival,DFS)、完全缓解率(complete remission,CR)、诱导期内死亡率、化疗相关毒副反应、复发率(relapse rate,RR)等为评价指标,采用Cochrane协作网RevMan5.0软件进行Meta分析。
结果纳入3个RCT,共包括504例受试对象。结果表明,加用Ara-C对APL患者的EFS、OS和CR的影响差异无统计学意义,其效应统计量危险比及其95%可信区间分别为1.21(0.93,1.59)、1.02(0.80,1.31)和1.51(0.17,13.45);加用Ara-C对APL患者诱导期内病死率和化疗相关毒副反应的发生率的影响的差异也无统计学意义,其效应统计量比值比及其95%可信区间分别为1.26(0.70,2.29)和6.91(0.15,315.6);对DFS的影响亦不明显。而加用Ara-C对RR的影响尚存在争议。
结论根据3个RCT的meta分析结果,在APL化疗方案中应用Ara-C并没有显示提高疗效的证据。目前的证据尚不足以推荐Ara-C用于APL的常规化疗中。
第二部分三氧化二砷在急性早幼粒细胞白血病治疗中作用的Cochrane系统评价
第一节三氧化二砷单药治疗急性早幼粒细胞白血病疗效的Cochrane系统评价
目的评价三氧化二砷(arsenic trioxide, ATO)单药治疗APL的疗效与安全性。
资料和方法采用Cochrane系统评价方法,检索Cochrane图书馆及其对照试验注册资料库(Cochrane Central Register of Clinical Trials,CENTRAL)、MEDLINE、EMBASE、中国生物医学文献数据库(CBM)、中国期刊网专题全文数据库(CNKI)、中国医学学术会议论文数据库(CMAC),并辅以手工检索和附加检索,检索时间截至2009年3月。获取比较含与不含ATO的治疗方案对APL疗效的RCT文献,以CR、OS、DFS、开始治疗到获得CR的时间、RR、病死率及治疗相关副反应等为评价指标,采用Cochrane协作网Revman5.0软件进行meta分析。
结果纳入5项RCT,共包括328例APL患者,其中4项研究存在中度偏倚风险,1项研究存在高度偏倚风险。研究目的均为在全反式维甲酸(all-trans retinoic acid, ATRA)治疗基础上联用ATO与ATRA单药的比较,未能检索到ATO与安慰剂或空白观察进行对比的RCT。结果表明,加用ATO对初治APL病人开始治疗到获得CR的时间影响的效应统计量均数差(mean difference,MD)及其95%CI为-1.20天(-1.68,-0.72);对两年DFS影响的效应统计量风险比率(hazard ratio,HR)及其95%CI为8.37(1.64,42.60);对RR、治疗期间病人水肿发生率和对心电图校正后的QT间期延长发生率影响的效应统计量比值比(odds ratio,OR)及其95%CI分别为0.19(0.08,0.49)、4.16(1.46,11.79)和22.10 (2.75,177.49);其余结局指标的meta分析结果差异均无明显统计学意义。
结论与ATRA单药治疗方案相比,加用ATO可以缩短初治APL病人开始治疗到获得CR的时间、改善DFS、降低RR,但是有可能导致治疗期间病人水肿和心电图校正后的QT间期延长发生率的增加。由于纳入试验质量和病例数目的限制,该结论需要进一步的研究证实。
第二节三氧化二砷和全反式维甲酸治疗急性早幼粒细胞白血病疗效比较的Cochrane系统评价
目的比较ATO与ATRA治疗APL的疗效与安全性。
资料和方法采用Cochrane系统评价方法,检索Cochrane图书馆及CENTRAL、MEDLINE、EMBASE、CBM、CNKI和CMAC,并辅以手工检索和附加检索,检索时间截至2009年3月。获取比较ATO和ATRA治疗APL疗效的RCT文献,以CR、OS、DFS、治疗开始到获得CR的时间、RR、病死率及治疗相关副反应为结局评价指标,使用Cochrane协作网Revman5.0软件进行Meta分析。
结果共鉴定并纳入4项RCTs,共包括243例APL患者,研究的偏倚风险评估全部为中等程度偏倚,研究目的均为比较ATO与ATRA治疗APL的疗效和副反应发生情况。Meta分析结果显示,ATO与ATRA初治治疗APL比较,针对CR、复发率、病死率等结局指标差异无统计学意义,以上各结局指标OR值及其95%CI分别为0.96(0.50,1.86),0.86(0.45,1.63)和1.15(0.45,2.95);开始治疗到获得CR的时间结局指标差异无统计学意义,MD及其95%CI为0.60 d(-12.34,13.53);DFS的比较差异也无统计学意义,HR及其95%CI为2.76(0.71,10.66)。针对肝功能异常发生率结局指标比较的OR值及其95%CI为3.03(1.25,7.37),差异有统计学意义。
结论Meta分析结果提示,采用ATO与ATRA治疗初治APL患者从CR、RR、病死率及DFS等指标比较疗效相当,但ATO可能导致肝功能异常的发生率增加。
第三节三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病疗效的Cochrane系统评价
目的评价ATO联合ATRA治疗APL的疗效。
资料和方法采用Cochrane系统评价方法,检索Cochrane图书馆及CENTRAL、MEDLINE、EMBASE、CBM、CNKI和CMAC,并辅以手工检索和附加检索,检索时间截至2009年3月。获取研究ATO联合ATRA方案治疗APL疗效的RCT文献,以CR、OS、DFS、开始治疗到CR的时间、RR、病死率及相关副反应等为结局评价指标,使用Cochrane协作网Revman5.0软件进行meta分析。
结果共纳入7项RCT,包括392例受试者。其中6项研究存在中度偏倚风险,1项研究存在高度偏倚风险。研究方案包括ATO联合ATRA方案与ATO单药、ATRA单药和ATO+ATRA+化疗方案的比较,未能检索到与目前的首选方案(ATRA+蒽环类药物)比较的RCT。Meta分析结果示,与ATO单药比较,联合方案能够改善初治APL病人开始治疗到CR的时间和RR,对其余结局指标的影响无明显统计学意义,以受试者疾病状态(初治或复发)为划分标准对CR、DFS、病死率和肝功能异常发生率进行的敏感性分析,结果总的meta分析结果一致;与ATRA单药比较,联合方案能够改善初治APL病人开始治疗到CR的时间、DFS和RR,但有可能导致水肿的发生率增加;与ATO+ATRA+化疗方案相比,联合方案对初治APL患者CR、复发率、病死率及治疗相关副反应等结局指标均有一定的改善。
结论针对初治APL病人,ATO联合ATRA方案疗效优于ATO单药、ATRA单药和ATO+ATRA+化疗方案,但是由于缺乏与目前初治APL病人标准疗法(ATRA+蒽环类药物)比较的数据,尚不足以推荐ATO联合ATRA方案应用于初治APL病人的治疗中。针对复发APL病人,ATO联合ATRA方案并不优于ATO单药,即目前证据尚不支持在ATO单药治疗的基础上加用ATRA。由于纳入研究的质量、病例数等的限制,对该结论的解析需持谨慎的态度,并亟需进一步的研究来检验。
PART I Role of cytarabine in acute promyelocytic leukemia(APL) treatment: a cochrane systematic review
Objectives This systematic review assesses the efficacy and safety of cytarabine (Ara-C) for the treatment of acute promyelocytic leukemia(APL).
Methods We searched the Cochrane Library (Issue 3, 2008), Cochrane Register of Clinical Trials(CENTRAL,1970-2008.8), Medline(1978-2008.4), EMBASE(1990-2008.8), CBM(1978-2008), CNKI(1994-2008),VIP(1989-2008),CMAC(1994-2008).We also seached the Current Controlled Trials,the the National Research Register,Conference Proceedings of American Society of Hematology(2004-2007) and American Society of Clinical Oncology(2005-2007), OpenSIGLE、HMIC and NTIS on the internet.We handsearched the related journals in the library of Third Military Medical University. We included randomized clinical trials(RCT), which studied the efficacy and safety of Ara-C in APL treatment, by comparison of therapeutical strategy with Ara-C and treatment strategy without. The include trials were graded methodologically. Two authors at least, indenpdently selected studies and extracted data. The data was input and analysed with the latest Cochrane review manager software(RevMan 5.0).
Results Three eligible RCTs were included (N=504 ). Meta analysis showed that adding Ara-C to the treatment of APL had no statistically significant effects on event free survival (EFS) (HR 1.21,95%CI 0.93,1.59), overall survival(OS)(HR1.02,95%CI 0.80,1.31) and disease free survival(DFS). Ara-C for the treatment of APL also had no significant influences on complete remission(CR), induction death, toxic and adverse reaction. The influence of adding Ara-c to relapse rate(RR) is still controversial.
Conclusion This systematic review found that adding Ara-C for the treatment of APL was not beneficial based on the currently available data.
PART II Role of arsenic trioxide in APL treatment: Cochrane systematic reviews
SectionⅠArsenic trioxide(ATO) monotherapy for APL treatment:a cochrane systematic review
Objectives This systematic review is aiming to assess the efficacy and safety of ATO monotherapy for the treatment of APL.
Methods We searched the Cochrane Library (Issue 1, 2009), CENTRAL(1970-2009.1), Medline(1978-2008.10),EMBASE(1950-2009.3), CBM(1978-2008), CNKI(1994-2008) ,CMAC(1994-2008).We also seached the metaregister,Conference Proceedings of American Society of Hematology(1946-2008) and Conference Proceedings of American Society of Clinical Oncology(2004-2008) on the internet for grey literature.We handsearched the related journals in the library of Third Military Medical University. We included RCT which compared regimen containing ATO with regimen without ATO for the treatment of APL. We adopt CR,OS,DFS,time to CR, RR,mortality and adverse reactions as result indicators. Data was input and analysed with the Cochrane review manager software 5.0(RevMan 5.0).
Results Five eligible RCTs were included (N=328). All the RCTs were mainly focusing on the comparison of ATRA plus ATO regimen with ATRA monotherapy. Meta analysis showed that effect index for time to CR, 2-year DFS,RR and incidence of edema were-1.20 days(-1.68,-0.72), 8.37(1.64,42.60),0.20(0.08,0.52)and 4.16(1.46,11.79), respectively. The influence on other reslult indicators such as CR, leukocytosis , et al are statistically non-significant.
Conclusion: ATO can improve DFS and reduce the time to CR and RR of newly diagnosed APL patients, but it will increase the incidence of edema during treatment. Due to limitation of the included trials, this conclusion need to be validated by further studies.
SectionⅡComparison of efficacy of ATO versus ATRA for APL treatment: a Cochrane systematic review
Objectives This systematic review compares the efficacy and safety of ATO with ATRA for the treatment of APL.
Methods We searched the Cochrane Library (Issue 1, 2009), CENTRAL(1970-2009.1), Medline(1978-2008.10),EMBASE(1950-2009.3), CBM(1978-2008), CNKI(1994-2008) ,CMAC(1994-2008); We also seached the metaregister,Conference Proceedings of American Society of Hematology(1946-2008) and American Society of Clinical Oncology(2004-2008) on the internet for grey literature.We handsearched the related journals in the library of Third Military Medical University. We included RCTs which compared ATO with ATRA for the treatment of APL. We adopt CR,OS,DFS,time to CR, RR,mortality and adverse reactions as result indicators. Data was imput and analysed with the Cochrane review manager software(RevMan 5.0).
Results Four eligible RCTs were included (N=243). All the RCTs were methodologically graded as B. They all are focusing on the comparison of ATO monotherapy with ATRA monotherapy in treating newly diagnosed APL patients. Meta analysis showed that effect index for CR, 2-year DFS,time to CR,RR and mortality is 0.96(0.50,1.86),2.76(0.71,10.66),-1.30days(-1.83,-0.78), 0.86(0.45,1.63),1.15(0.45,2.95),respectively,all indicate no statisticaly significant difference. Effect index for incidence of liver dysfunction is 3.03(1.25,7.37),which shows statistically significant difference between ATO group and ATRA group..
Conclusion ATO is not superior to ATRA in treating newly diagnosed APL patients regarding CR,DFS,time to CR,RR and mortality. What is worse, it will increase the incidence of liver dysfunction during treatment. Due to limitation of included trials, this comclusion need to be validated by further studies.
SectionⅢATO in combination with ATRA for APL treatment: a cochrane systematic review
Objective To assess the efficacy and safety of ATO in combination with ATRA for the treatment of APL.
Methods Cochrane Library (Issue 1, 2009), CENTRAL(1970-2009.1), Medline (1978-2008.10), EMBASE(1950-2009.3), CBM(1978-2008), CNKI(1994-2008), CMAC(1994-2008) were searched. the metaregister, Conference Proceedings of American Society of Hematology(1946-2008) and American Society of Clinical Oncology(2004-2008) on the internet were also searched for grey literature. The authors also hand-searched Chinsese periodicals potentially realated to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clincal Hematology. All randomizde controlled trials comparing ATO+ATRA with other regimens for the treatment of APL were included. Two reviewers selected studies,appraised the quality of studies, and extracted the data independently. The eligible studies were evaluated and extracted data was analysed with Cochrane Review Manager 5.0.
Results Seven eligible RCTs were included (N=392). Six RCTs were methodologically graded as middle and one as high risk of bias. The control group include ATO monotherapy, ATRA monotherapy and ATO+ATRA+chemotherapy. Compared with ATO monotherapy, ATO+ATRA combination can improve time to CR and RR of newly diagnosed APL,but can not improve CR rate,DFS,mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis; Compared with ATRA monotherapy, ATO+ATRA combination can improve time to CR, DFS and RR, but may increase the incidence of edema during treatment; Compared with ATO+ATRA+chemotherapy, ATO+ATRA can impove CR, RR, mortality and adverse reactions.
Conclusion The reslults of meta-analysis and sensitivity analysis indicate that:①For newly diagnosed APL, ATO+ATRA combination is superior to ATO monotherapy, ATRA monotherapy and ATO+ATRA+chemotherapy, but due to the lack of data about comparison with the current standard treatment regimen(ATRA+chemotherapy), it is not enough to recommend ATO+ATRA as frontline therap;②For relapsed APL, ATO+ATRA combination is not superior to ATO monotherapy, it is not supportive of adding ATRA to ATO monotherapy. But due to limitation of sample size and risk of bias of included trials, the effect of ATO+ATRA combination need to be confirmed by large and high-quality RCTs.
引文
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[4] Tallman MS,Andersen JW,Schiffer CA,Appelbaum FR,Feusner JH,Ogden A,Shepherd L,Willman C,Bloomfield CD,Rowe JM,Wiernik PH.. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med, 1997;337(15): 1021-1028.
[5] Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood, 2008;111(5): 2505-2015.
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[7] Douer D,Tallman MS.. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol, 2005;23(10): 2396-2410.
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[9] Davison K,Mann KK,Miller WH. Arsenic trioxide: mechanisms of action. Semin hematol, 2002;39(2 Suppl 1): 3-7.
[10] Zheng PZ,Wang KK,Zhang QY,Huang QH,Du YZ,Zhang QH,Xiao DK,Shen SH,Imbeaud S,Eveno E,Zhao CJ,Chen YL,Fan HY,Waxman S,Auffray C,Jin G,Chen SJ,Chen Z,Zhang J.. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A, 2005; 102(21): 7653-7658.
[11] Zhou GB,Zhang J,Wang ZY,Chen SJ,Chen Z.. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci, 2007;362(1482): 959-971.
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