大剂量甲氨蝶呤不同输注方案治疗骨肉瘤疗效和安全性的Meta分析

Efficacy and Safety of Different Infusion Schedules of High-dose Methotrexate in the Treatment of Osteosarcoma:A Meta-analysis

目的:系统评价大剂量(>500 mg/m^2)甲氨蝶呤不同输注方案治疗骨肉瘤的疗效和安全性,为临床治疗提供循证参考。方法:计算机检索Medline、Embase、clinicaltrials.gov、中国期刊全文数据库、万方数据和中国生物医学文献数据库,检索时限为自建库起至2018年3月纳入大剂量甲氨蝶呤不同输注方案(不同剂量和输注时间)治疗骨肉瘤的疗效和安全性的观察性研究和随机/非随机对照试验,进行资料提取并采用纽卡斯尔-渥太华量表、Cochrane系统评价员手册5.1.0和非随机对照试验方法学评价指标进行质量评价后,采用Rev Man 5.3软件对血药浓度(c)、相关毒性(如肝毒性发生率、血液毒性发生率)进行Meta分析或描述性分析。结果:共纳入5项研究,合计310例患者。Meta分析结果显示,8 g/m^2组患者c0 h[MD=-240.11,95%CI(-271.47,-208.75),P<0.001]、c24 h[MD=-0.09,95%CI(-0.11,0.08),P<0.001]、c48 h[MD=-0.07,95%CI(-0.10,-0.05),P<0.001]、c72 h[MD=-0.05,95%CI(-0.06,-0.03),P<0.001]以及肝毒性发生率[OR=0.26,95%CI(0.10,0.67),P<0.005]均显著低于10 g/m^2组患者;描述性分析结果显示,均给予8 g/m^2时,输注时间为2、4 h患者的c24 h显著低于输注6 h患者,8 g/m^2组患者白细胞减少和血小板减少的发生率显著低于10 g/m^2组患者。结论:用大剂量甲氨蝶呤治疗骨肉瘤时,适当降低给药剂量(如8 g/m^2)和适当延长输注时间(如6 h)可能获得较理想的疗效和安全性。

OBJECTIVE:To systematically evaluate the efficacy and safety for different infusion schemes of large-dose(>500 mg/m^2)of methotrexate in the treatment of osteosarcoma,and to provide evidence-based reference for clinical treatment.METHODS:Retrieved from Medline,Embase,clinicaltrials.gov,CJFD,Wanfang database and CBM database,observational studies and randomized/non-randomized controlled trials about therapeutic efficacy and safety for different infusion schemes(different doses and infusion time)of large-dose of methotrexate in the treatment of osteosarcoma were included during the establishment of the database to Mar.2018.After data extraction and quality evaluation with methodological evaluation index of the Newcastle-Ottawa scale,Cochrane 5.1.0 bias risk evaluation tool and non-randomized controlled trials,Meta-analysis or descriptive analysis for blood drug concentration(c),related toxicity(e.g.incidence of hepatotoxicity,incidence of hemotoxicity)were performed by using Rev Man 5.3 software.RESULTS:Totally 5 studies were included,involving 310 cases.Results of Meta-analyses indicated c0 h[MD=-240.11,95%CI(-271.47,-208.75),P<0.001],c24 h[MD=-0.09,95%CI(-0.11,0.08),P<0.001],c48 h[MD=-0.07,95%CI(-0.10,-0.05),P<0.001],c72 h[MD=-0.05,95%CI(-0.06,-0.03),P<0.001]and the incidence of liver toxicity[OR=0.26,95%CI(0.10,0.67),P<0.005]in 8 g/m^2 group were significantly lower than 10 g/m^2 group.Results of descriptive analysis showed that when both groups were given 8 g/m^2,c24 h of patients with 2 and 4 h infusion time was significantly lower than that of patients with 6 h infusion time.The incidence of leukopenia and thrombocytopenia in 8 g/m^2 group was significantly lower than 10 g/m^2 group.CONCLUSIONS:In the treatment of osteosarcoma with high-dose of methotrexate,appropriate dosage reduction(e.g.8 g/m^2)and appropriate prolongation of infusion time(e.g.6 h)may lead to a better efficacy and safety.