血清药物浓度监测下大剂量甲氨蝶呤治疗儿童恶性骨肿瘤

Serum Concentration Monitoring and High-Dose Methotrexate Chemotherapy for Osteosarcoma in Children

目的探讨甲氨蝶呤(MTX)剂量与恶性骨肿瘤患儿血清药物浓度、疗效、不良反应的关系。方法恶性骨肿瘤患儿24例。其中男20例,女4例;年龄9.5(7～16)岁。大剂量(HD)-MTX(8g/m2组、10g/m2组、12g/m2组)滴注12h后开始甲酰四氢叶酸钙(CF)解救,术前2个疗程,术后6～8个疗程化疗,其中术前HD-MTX化疗48例次,术后HD-MTX化疗156例次,总疗程204例次。每次给药后的第0、24h、48h及72h分别取静脉血,离心后取上清,采用荧光偏振免疫分析法检测不同剂量MTX治疗时的血清药物浓度,并观察HD-MTX化疗的临床不良反应及其程度。结果给药后第0h,MTX血清药物浓度随剂量增加而增加,第24、48h的血清药物浓度与HD-MTX给药剂量无显著性差异,可能与机体的内环境、水化碱化及CF解救等有关;MTX的不良反应与MTX第24h、48h的血清药物浓度有关,第24h、48h的血清药物浓度超过安全范围(24hMTX血清药物浓度>8.5μmol/L,48hMTX血清药物浓度>1.0μmol/L)时,MTX的不良反应显著增加,最常见的不良反应是胃肠道症状及白细胞降低;12g/m2组患儿口腔黏膜损害加重。结论MTX血清药物浓度监测是临床实施合理的HD-MTX个体化治疗的客观依据。

Objective To investigate the relationship between methotrexate （MTX） dosage and serum concentration, clinical efficacy, side effects for osteosarcoma in children. Methods Twenty male and 4 female children with osteosarcoma were studied. The age was from 7 to 16 years （median age was 9.5 year）. After different dosages of MTX （8 g/m2 group, 10 g/m^2 group,and 12 g/m^2 group）were injected 12 hours later, calcium formyltetrahydrofolate （CF） was used to rescue ,2 pre - operative courses and 6 to 8 postoperative courses of chemotherapy were executed. Total 204 cases were studied ,48 cases before operation and 156 cases after operation. At each time after the administration of high - dose （HD）MTX,venous blood was draw at 0,24 h ,48 h and 72 h, respectively. After centrifugation, the supernatant was chosen, and MTX concentration was measured by a flurorescence polarization immunoassay. The toxicity and side effects of MTX were analyzed combined with clinical manifestations. Results The MTX serum concentration at 0 hours increased with the increasing doses of MTX, while the concentration at 24 and 48 h had no significant difference. It might be related with the body internal environment, hydration and alkalization, or rescue with CF. The toxicity of HD - MTX was relevant with the serum concentration at 24 and 48 h. When the serum drug concentrations of 24 h or 48 h were above the safety margin （ 24 hours serum MTX concentrations 〉 8. 5 μmol/L; 48 hours, serum MTX concentrations 〉 1.0 μmol/L）, the toxicity and side effects of MTX increased significantly. The most common drug side effects were gastrointestinal symptoms and leucopenia. The oral mucosal lesions became worse in 12 g/m^2 group. Conclusion The monitoring of HD - MTX plasma concentration provides an objective clinical basis for the individualized chemotherapy.