基于7-羟基甲氨蝶呤血药浓度监测的大剂量化疗骨肉瘤患者肝功能损伤预测模型构建

目的：探讨甲氨蝶呤（MTX）代谢产物7-羟基甲氨蝶呤（7-OHMTX）血药浓度监测在接受大剂量甲氨蝶呤化疗（HD-MTX）的骨肉瘤患者肝功能损伤预测中的应用。方法：采用自建的高效液相色谱法同时测定患者不同时间点MTX及7-OHMTX血药浓度，收集患者相关信息，利用SPSS 22.0软件，考察性别、年龄、体质量、身高、体表面积、MTX剂量以及化疗后不同时间点MTX血药浓度、7-OHMTX血药浓度、7-OHMTX/MTX浓度比值与化疗所致急性肝功能损伤相关性。结果：在不干涉原治疗方案的情况下，有24例患者47例次行大剂量甲氨蝶呤化疗数据纳入分析。单因素分析结果显示，化疗引起的急性中重度肝功能损伤与7-OHMTX_{5 h}、7-OHMTX_{12 h}、7-OHMTX_{24 h}、7-OHMTX_{48 h}、7-OHMTX/MTX_{5 h}、7-OHMTX/MTX_{12 h}、7-OHMTX/MTX_{24 h}、7-OHMTX/MTX_{48 h}这8个指标正相关（P<0.05）；经过标准方案解救治疗的骨肉瘤患者，急性肝功能损伤与延迟排泄无显著相关性（P>0.05）。多因素Logistic回归分析显示，仅MTX化疗剂量及7-OHMTX血药浓度分别纳入5，12，24，48 h这4个时间点的回归方程，与中重度肝功能损伤呈正相关（P<0.01），肝功能损伤预测模型受试者工作曲线（ROC）曲线下面积（AUC）分别为0.795，0.861，0.780，0.789。结论：高剂量的MTX、高浓度7-OHMTX是HD-MTX肝功能损伤的独立危险因素，通过测定不同时间点（5，12，24，48 h）7-OHMTX浓度，均可以较好地预测中重度肝功能损伤。在其他指标不变的情况下，MTX剂量每增加1 g·m^-2，肝功能损伤风险增加2倍左右，7-OHMTX_{5 h}、7-OHMTX_{12 h}、7-OHMTX_{24 h}、7-OHMTX_{48 h}每增加1 μmol·L^-1，肝功能损伤风险分别增加1.070，1.058，1.131，1.866倍。5 h预测模型预警时间最早，12 h预测模型为最佳模型，7-OHMTX血药浓度5，12，24，48 h肝功能损伤预警值分别为20.36，33.37，4.54，0.47 μmol·L^-1。

Construction of liver damage prediction model for patients with osteosarcoma receiving high-dose chemotherapy based on 7-hydroxymethotrexate blood concentration monitoring

OBJECTIVE To investigate the application of serum concentration monitoring of 7-hydroxymethotrexate (7-OHMTX), a metabolite of methotrexate (MTX), in predicting liver damage in osteosarcoma patients treated with high-dose methotrexate chemotherapy (HD-MTX).METHODS The serum concentrations of MTX and 7-OHMTX at different timepoints were determined simultaneously by a self-built high performance liquid chromatography method. The relevant information of patients was collected, and the correlations between gender, age, weight, height, body surface area, MTX dose, serum concentration of MTX, serum concentration of 7-OHMTX, 7-OHMTX/MTX ratio and acute liver damage induced by HD-MTX were analyzed by SPSS 22.0 software.RESULTS The data from 47 cases of 24 patients who received HD-MTX were analyzed. Univariate analysis showed that acute moderate to severe liver damage caused by chemotherapy was positively correlated with 7-OHMTX_{5 h}, 7-OHMTX_{12 h}, 7-OHMTX_{24 h}, 7-OHMTX_{48 h}, 7-OHMTX/MTX_{5 h}, 7-OHMTX/MTX_{12 h}, 7-OHMTX/MTX_{24 h} and 7-OHMTX/MTX_{48 h} (P<0.05). There was no significant correlation between acute liver damage and delayed excretion in osteosarcoma patients rescued by regular treatment (P>0.05). Multivariate logistic regression analysis showed that only MTX dose and 7-OHMTX serum concentration were included in the regression equations at the time of 5, 12, 24 and 48 h, respectively, and were positively correlated with moderate to severe liver damage (P<0.01). The areas under receiver operator characteristic curve (ROC) of the liver damage prediction model were 0.795, 0.861, 0.780 and 0.789, respectively.CONCLUSION High-dose MTX and high-concentration 7-OHMTX are independent risk factors for liver damage caused by HD-MTX. Liver damage can be well predicted by measuring the concentration of 7-OHMTX at different time (5, 12, 24, 48 h after chemotherapy). The risk of liver damage increases about 2 times for each increase of 1 g·m^-2 MTX dose. The risk of liver damage increases 1.070, 1.058, 1.131 and 1.866 times for each increase of 1 μmol·L^-1 7-OHMTX_5h, 7-OHMTX_12h, 7-OHMTX_{24 h} and 7-OHMTX_{48 h}, respectively. The 5 h prediction model is the earliest warning time, and the 12 h prediction model is the best model. The liver damage warning values of 7-OHMTX serum concentration at 5, 12, 24 and 48 h are 20.36, 33.37, 4.54 and 0.47 μmol·L^-1, respectively.