OBJECTIVE： To systematically evaluate the efficacy and safety for different infusion schemes of large-dose （＞500 mg/m2） 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/m2 group were significantly lower than 10 g/m2 group. Results of descriptive analysis showed that when both groups were given 8 g/m2， 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 thrombo- cytopenia in 8 g/m2 group was significantly lower than 10 g/m2 group. CONCLUSIONS： In the treatment of osteosarcoma with high-dose of methotrexate， appropriate dosage reduction （e.g. 8 g/m2） and appropriate prolongation of infusion time   （e.g. 6 h） may lead to a better efficacy and safety.

Objeoctive To evaluate the association between blood methotrexate concentrations at 24 hours (C24 h) after the initiation of high-dose methotrexate (HDMTX) infusion and clinical outcomes in patients with hematologic neoplasm.Methods The literature on C24 h after the initiation of HDMTX treatment and clinical outcomes in MEDLINE (Ovid),EMBASE (Ovid),Clinical Trials.gov,CNKI,WanFang Data,and SinoMed databases up to March 2018 were retrieved (the outcome indicators mainly included safety indicators,such as adverse event incidence and effectiveness indicators,such as complete remission rate).The quality of the enrolled literature was evaluated by Newcastle-Ottawa Scale (NOS) and related outcome indicators were analyzed by meta-analysis or descriptive analysis.Results A total of 6 studies were enrolled,including 4 with high quality (NOS scores were 7-9) and 2 with medium quality (both of NOS scores were 6).All the subjects in the 6 studies were children with acute lymphoblastic leukemia (ALL),aged 0.4 to 17.0 years,and a total of 516 HDMTX treatments were given to them.Five studies reported the association between methotrexate C24 h and safety outcomes and 1 reported the association between methotrexate C24 h and effectiveness outcomes.For safety outcomes,compared with C24 h ＜ 10 μ mol/L,methotrexate C24 h ＞ 10 μmol/L might increase the risk of hematological toxicity (OR =4.17,95％ CI:1.17-14.90) rather than the risks of gastrointestinal toxicity (OR =2.22,95％ CI:0.97-5.04),renal toxicity (P =0.130),oral mucositis (P =0.166),or dermal toxicity (P =0.227).Compared with C24 h ＜40 μmol/L,methotrexate C24 h ＞40 μmol/L might increase the risks of hepatotoxicity (OR =16.64,95％ CI:6.35-43.64),oral mucositis (OR =31.73,95％ CI:12.37-81.41),severe oral mucositis (P =0.002),and gastrointestinal toxicity (P =0.003).For effectiveness outcomes,the single study suggested that methotrexate C24 h ＞ 16 μmol/L could increase the complete and partial remission rates (P ＜ 0.05 for both) and decrease the 1.5 year-recurrence rate (P =0.006).Conclusions There was a significant association between methotrexate C24 h and clinical outcomes in children with ALL.Methotrexate C24 h ＞16 μmol/L was significantly associated with a favorable clinical outcome while C24 h ＞ 40 μmol/L was significantly associated with increased risks of hepatotoxicity,oral mucositis,and gastrointestinal toxicity.

Objeoctive To evaluate the association between blood methotrexate concentrations at 24 hours (C24 h) after the initiation of high-dose methotrexate (HDMTX) infusion and clinical outcomes in patients with hematologic neoplasm.Methods The literature on C24 h after the initiation of HDMTX treatment and clinical outcomes in MEDLINE (Ovid),EMBASE (Ovid),Clinical Trials.gov,CNKI,WanFang Data,and SinoMed databases up to March 2018 were retrieved (the outcome indicators mainly included safety indicators,such as adverse event incidence and effectiveness indicators,such as complete remission rate).The quality of the enrolled literature was evaluated by Newcastle-Ottawa Scale (NOS) and related outcome indicators were analyzed by meta-analysis or descriptive analysis.Results A total of 6 studies were enrolled,including 4 with high quality (NOS scores were 7-9) and 2 with medium quality (both of NOS scores were 6).All the subjects in the 6 studies were children with acute lymphoblastic leukemia (ALL),aged 0.4 to 17.0 years,and a total of 516 HDMTX treatments were given to them.Five studies reported the association between methotrexate C24 h and safety outcomes and 1 reported the association between methotrexate C24 h and effectiveness outcomes.For safety outcomes,compared with C24 h ＜ 10 μ mol/L,methotrexate C24 h ＞ 10 μmol/L might increase the risk of hematological toxicity (OR =4.17,95％ CI:1.17-14.90) rather than the risks of gastrointestinal toxicity (OR =2.22,95％ CI:0.97-5.04),renal toxicity (P =0.130),oral mucositis (P =0.166),or dermal toxicity (P =0.227).Compared with C24 h ＜40 μmol/L,methotrexate C24 h ＞40 μmol/L might increase the risks of hepatotoxicity (OR =16.64,95％ CI:6.35-43.64),oral mucositis (OR =31.73,95％ CI:12.37-81.41),severe oral mucositis (P =0.002),and gastrointestinal toxicity (P =0.003).For effectiveness outcomes,the single study suggested that methotrexate C24 h ＞ 16 μmol/L could increase the complete and partial remission rates (P ＜ 0.05 for both) and decrease the 1.5 year-recurrence rate (P =0.006).Conclusions There was a significant association between methotrexate C24 h and clinical outcomes in children with ALL.Methotrexate C24 h ＞16 μmol/L was significantly associated with a favorable clinical outcome while C24 h ＞ 40 μmol/L was significantly associated with increased risks of hepatotoxicity,oral mucositis,and gastrointestinal toxicity.