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系统综述和meta分析

背景：研究证明三氧化二砷（arsenic trioxide, ATO）联合全反式维甲酸（all-trans retinoic acid, ATRA）在急性早幼粒细胞白血病（acute promyelocytic leukemia, APL）的治疗中通过不同的分子机制发挥作用，奠定了ATO和ATRA协同或相加作用的分子学基础，并且ATO联合ATRA方案在临床上也广为应用，但目前尚无明确的高级别循证医学证据证明其疗效和安全性。 目的：评价ATO联合ATRA方案治疗APL的疗效。 检索策略：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，检索时间截至2009年3月。 纳入标准：纳入研究ATO联合ATRA方案治疗APL疗效的随机对照试验文献。干预措施包括：（1）ATO联合ATRA方案与ATO单药比较；（2）ATO联合ATRA方案与ATRA单药比较；（3）ATO联合ATRA方案与ATRA联合化疗比较；④ATO联合ATRA方案与ATO＋ATRA＋化疗比较。 资料提取与分析：提取完全缓解率、总生存率、无病生存率、开始治疗到完全缓解的时间、复发率、病死率及相关副反应等结局评价指标的数据，按不同数据类型采用相应的统计方法，使用Cochrane协作网RevMan 5.0软件进行meta分析。 结果：共纳入9项随机对照试验，合并同类研究后，共7项研究纳被入分析，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联合蒽环类药物）比较的随机对照试验。Meta分析结果示，与ATO单药比较，ATO联合ATRA方案能够改善初治APL病人开始治疗到完全缓解的时间和复发率，对其余结局指标影响的差异无统计学意义，以受试者疾病状态（初治或复发）为划分标准对完全缓解率、无病生存率、病死率和肝功能异常发生率进行的敏感性分析结果与总的meta分析结果一致；与ATRA单药比较，ATO联合ATRA方案能够改善初治APL病人开始治疗到完全缓解的时间、无病生存率和复发率，但有可能导致水肿的发生率增加；与ATO＋ATRA＋化疗方案相比，ATO联合ATRA方案对初治APL患者完全缓解率、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。

Arsenic trioxide in combination with all-trans retinoic acid for acute promyelocytic leukemia: a systematic review and meta-analysis

Background： The studies have demonstrated that arsenic trioxide （ATO） in combination with all-trans retinoic acid （ATRA） takes effects in treatment of acute promyelocytic leukemia （APL） through different underlying mechanisms. This has established the molecular foundation of ATO plus ATRA therapy. Currently, ATO plus ATRA has also been widely used in clinical practice.
Objective： To assess the efficacy and safety of ATO in combination with ATRA for APL.
Search strategy： 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）, CNKI （from 1994 to December 2008）, 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 authors also hand-searched Chinese periodicals potentially related to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clinical Hematology.
Inclusion criteria： All randomized controlled trials comparing ATO plus ATRA with other regimens for the treatment of APL were included. Intervention and comparison regimens include： 1） ATO plus ATRA vs ATO monotherapy; 2） ATO plus ATRA vs ATRA monotherapy; 3） ATO plus ATRA vs ATRA plus chemotherapy; 4） ATO plus ATRA vs ATO＋ATRA＋chemotherapy.
Data extraction and analysis： Related data concerning complete remission rate, overall survival rate, and disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions were extracted independently by two reviewers. The different statistical methods were applied according to different data type with RevMan 5.0 software.
Results： After merging of the included trials, seven eligible randomized controlled trials with 392 cases were analyzed, among which 6 RCTs were methodologically graded as middle and one as of high risk of bias. The control therapies included ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA. Compared with ATO monotherapy, ATO plus ATRA could improve time to complete remission and relapse rate of newly diagnosed APL, but could not improve the complete remission rate, disease free survival rate, mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis. Compared with ATRA monotherapy, ATO plus ATRA shortened the time to complete remission, improved the disease free survival rate and relapse rate, but increased the incidence of edema during the treatment. Compared with chemotherapy with ATO plus ATRA, ATO plus ATRA could improve the complete remission rate, relapse rate, mortality and adverse reactions.
Conclusion： For newly diagnosed APL, ATO plus ATRA is superior to ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA, but due to the lack of data about comparison with the current standard treatment regimen （ATRA plus chemotherapy）, it is not enough to recommend ATO plus ATRA as a frontline therapy. For relapsed APL, ATO plus ATRA is not superior to ATO monotherapy, and ATRA plus ATO is not a supportive therapy. Due to limitation of sample size and risk of bias from the included trials, the effects of ATO plus ATRA need to be confirmed by large and high-quality randomized controlled trials.