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目的通过总结四肢骨肉瘤化疗的随机对照多中心临床研究中大剂量甲氨蝶呤(high dose methotrexate,HD-MTX)的应用,为临床安全应用HD-MTX提供依据。方法收集2009年2月至2010年12月国内五所医院的63例骨肉瘤患者(分为实验组32例、对照组31例)。对随机对照多中心的研究中的实验组与对照组合并分析,根据实验设计行统一、规范给药并进行血药浓度监测及相应实验室检查,对HD-MTX应用的相关并发症及毒性反应进行了回顾分析。不良反应采用(the national cancer institute common terminology criteria for adverse event,CTCAE)v4.0评分系统评价肝、肾、血液学及黏膜毒性反应等。结果 63例中HD-MTX治疗共计60例,共给药186个周期,平均给药剂量为7.45 g/m2。血药浓度给药后24 h>20μm占27.9%,48 h后占1%。两组总无进展生存率为37.0%(20/54),总生存率为66.7%(36/54)。谷丙转氨酶最大值2133 mmol/L,>800 mmol/L共发生4例次(CTCAE 4度),200~800 mmol/L(CTCAE 3度)发生15例次;肌酐最大值190 mmol/L(CTCAE 2度),肾功能异常4例次(CTCAE 2度)。严重肝损害发生率为4.8%(9/186),严重肾功能损害发生率为2.2%(4/186)。死亡1例,除死亡病例外无不可逆肝肾损害发生。最早出现的不良反应为给药后1~24 h出现皮肤过敏反应,在有记录的病例中发生率为18.8%(6/32),而其余28例中I~II度骨髓抑制发生率为45%,IV度骨髓抑制发生率12%,口腔炎发生率为13.5%。出现过敏反应后的肝肾损害和骨髓抑制并发症的发生率及程度,较没有过敏反应的病例无差别。呕吐、腹胀、腹泻等不同程度胃肠道反应发生率>90%(CTCAE 1~4度)。结论本研究充分地反映了使用HD-MTX的现状,为今后更加合理应用提供了有利的数据支持,也为临床应用的安全性的提高提供了依据。
Objective To summarize the application of high-dose methotrexate (HD-MTX) in the randomized controlled multicenter clinical study of salivary osteosarcoma in the extremities to provide a basis for clinical application of HD-MTX. Methods Sixty-three patients with osteosarcoma from five hospitals in China from February 2009 to December 2010 were divided into experimental group (32 cases) and control group (31 cases). In the randomized, multicenter study, the experimental group and the control group were combined and analyzed. According to the experimental design, uniform, standardized administration and plasma concentration monitoring and corresponding laboratory tests were performed. The complication and toxicity of HD-MTX Conducted a review and analysis. Adverse reactions The liver, kidney, hematology and mucosal toxicities were evaluated using the national cancer institute common terminology criteria for adverse event (CTCAE) v4.0 scoring system. Results 63 cases of HD-MTX treatment a total of 60 cases, a total of 186 cycles of administration, the average dose of 7.45 g / m2. Serum concentration of 24 h> 20μm accounted for 27.9%, 48% after 1%. The overall progression-free survival rate was 37.0% (20/54) in both groups and the overall survival rate was 66.7% (36/54). A maximum of 2133 mmol / L of alanine aminotransferase (ALT) occurred in 4 cases (CTCAE 4 degrees)> 800 mmol / L and 15 cases of 200 mmol / L to 800 mmol / L CTCAE 2 degrees), renal dysfunction in 4 cases (CTCAE 2 degrees). The incidence of severe liver damage was 4.8% (9/186) and severe renal damage was 2.2% (4/186). 1 case of death, in addition to death, no irreversible liver and kidney damage occurred. The earliest adverse reactions occurred in 1 ~ 24 h after the administration of skin allergies, the incidence of recorded cases was 18.8% (6/32), while the remaining 28 cases of I ~ II degree of myelosuppression was 45 %, IV degrees of bone marrow suppression incidence of 12%, stomatitis incidence of 13.5%. The incidence and extent of liver and kidney damage and myelosuppression complications after anaphylactic reaction were no different from those without anaphylaxis. Vomiting, bloating, diarrhea and other varying degrees of gastrointestinal reaction rate> 90% (CTCAE 1 ~ 4 degrees). Conclusion This study fully reflects the current status of the use of HD-MTX, providing more favorable data support for more reasonable application in the future, and providing a basis for improving the safety of clinical applications.