三氧化二砷治疗急性早幼粒细胞白血病疗效的系统综述和meta分析

目的：评价三氧化二砷（arsenic trioxide, ATO）治疗急性早幼粒细胞白血病（acute promyelocytic leukemia, APL）的疗效与安全性。方法：采用Cochrane系统综述方法，检索Cochrane图书馆及其对照试验注册资料库（Cochrane Central Register of Controlled Trials, CENTRAL）、MEDLINE、EMBASE、中国生物医学文献数据库、中国期刊网专题全文数据库和中国医学学术会议论文数据库，并辅以手工检索和附加检索，检索时间截止至2009年3月。获取比较含与不含ATO的治疗方案对APL疗效的随机对照试验（randomized controlled trial, RCT）文献，以完全缓解率、总生存率、无病生存率、开始治疗到获得完全缓解的时间、复发率、病死率及治疗相关副反应等为评价指标，采用Cochrane协作网RevMan 5.0软件进行meta分析。结果：纳入9项RCT，合并后共5项RCT，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完全缓解的时间影响的效应统计量均数差（mean difference, MD）及其95％可信区间（confidence interval , CI）为－1.20 ［－1.68，－0.72］；对两年无病生存率影响的效应统计量风险比率（hazard ratio, HR）及其95％CI为8.64 ［1.66，45.00］；对复发率、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0.21 ［0.09，0.47］、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完全缓解的时间，提高无病生存率，降低复发率，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。

Efficacy of arsenic trioxide for acute promyelocytic leukemia: a systematic review and meta-analysis

Objective： To systematically review the efficacy and safety of arsenic trioxide （ATO） in treatment of acute promyelocytic leukemia （APL）.
Methods： The Cochrane Library （Issue 1, 2009）, Cochrane Central Register of Controlled Trials （from 1970 to January 2009）, MEDLINE （from 1978 to October 2008）, EMBASE （from 1950 to March 2009）, Chinese Biological Medical Literature Database （from 1978 to December 2008）, China National Knowledge Infrastructure （CNKI, from 1994 to December 2008）, and China Medical Academic Conference Database （from 1994 to December 2008） were electronically searched. We also searched the Meta-Register of controlled trials, Conference Proceedings of American Society of Hematology （from 1946 to December 2008） and Conference Proceedings of American Society of Clinical Oncology （from 1946 to December 2008） on the internet for grey literature. The related journals in the library of Third Military Medical University were hand-searched. The randomized controlled trials （RCTs） of ATO in treatment of APL were included. We adopted complete remission, overall survival rate, disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions as outcome indicators. Data were entered and analyzed with the Cochrane review manager software 5.0 （RevMan 5.0）.
Results： After merger of the included trials, five eligible RCTs with 328 cases were included. All the RCTs focused on the comparison of all-trans retinoic acid （ATRA） plus ATO regimen with ATRA monotherapy. Meta-analysis showed that the effect indexes for time to complete remission, two-year disease free survival rate, relapse rate, incidence of edema and incidence rate of QT interval prolongation were -1.20 [-1.68, -0.72], 8.64 [1.66,45.00], 0.21 [0.09,0.47], 4.16 [1.46,11.79] and 22.10 [2.75,177.49], respectively. The influences on other outcome indicators such as complete remission and leukocytosis were statistically non-significant.
Conclusion： ATO can prolong disease free survival and reduce the time to complete remission and relapse rate of newly diagnosed APL patients, and increase the incidence of edema and prolongation of corrected QT interval during the treatment. Due to limitation of the included trials, this conclusion needs to be validated by further studies.