晚期胃癌化疗中5-FU血药浓度及相关基因检测与疗效和不良反应的相关性研究

发布时间：2018-04-23 20:02

本文选题：胃癌 + 5-氟尿嘧啶　；参考：《山东大学》2017年硕士论文

【摘要】：目的:观察分析38例晚期胃癌患者经过FOLFOX 一线方案治疗后5-FU的血药浓度与疗效和不良反应的关系,同时分析其中25例晚期胃癌患者氟尿嘧啶类临床用药相关基因与血药浓度、不良反应的关系。研究方法:38例晚期胃癌患者均接受了 FOLFOX(奥沙利铂、亚叶酸钙和5-氟尿嘧啶)3周方案治疗,每个化疗周期在5-FU静脉微量泵入开始治疗后12h抽取外周血检测血药浓度,其中25例患者在首次治疗前抽取外周血检测5-FU相关基因,直至患者更改化疗方案或患者不可耐受或病人意愿终止参与本研究,血药浓度检测停止。根据5-FU血药浓度及AUC的分布四分位数将浓度分为≤45ng/ml、46～151ng/ml及151ng/ml 3个浓度组,分析5-FU血药浓度与晚期胃癌患者临床资料、治疗效果、不良反应、PFS、OS的相关性,5-FU相关基因与血药浓度、不良反应之间的相关性。采用单样本K-S验证正态分布,χ2检验或Fisher's精确概率计算法分析各组间的相关性,Kalplan-Meier法进行生存曲线的绘制,Log-rank检验比较分析生存曲线,Cox回归分析进行5-FU血药浓度与TNM分期、不良反应、疗效的多因素分析。P0.05则认为具有统计学意义。结果:38例晚期胃癌患者的5-FU平均血药浓度116.08ng/ml,中位血药浓度为92±106.5ng/ml,标准偏差为113.362ng/ml。5-FU血药浓度组与性别、年龄、TNM分期、骨髓抑制、胃肠道反应和手足综合征的相关性无明显统计学意义。5-FU血药浓度与化疗疗效之间不具有统计学意义(χ2=1.583,P=0.896)。5-FU血药浓度与皮肤及黏膜反应的不良反应发生率具有明显统计学(χ2=16.831,P=0.001),5-FU血药浓度≤45ng/ml的患者Ⅰ～Ⅱ级皮肤与黏膜反应的发生率增高,151ng/ml浓度的患者Ⅲ～Ⅳ皮肤与黏膜反应的发生率增高。5-FU血药浓度与21GSTP1、62ABCB1、68MTHFR、93MTHFR基因突变无明显统计学意义。68MTHFR基因突变与化疗药物不良反应具有明显统计学差异(χ2=27.227,P0.001),68MTHFR(667CT)基因的多态性中CC野生纯合型患者皮肤及黏膜反应、手足综合征的发生率高;TT突变纯合型患者骨髓抑制、胃肠道反应的不良反应发生率高;CT突变杂合型患者不良反应发生率介于CC与TT之间,骨髓抑制、胃肠道反应发生率在CT基因型的AGC患者仍具有一定的毒性风险。3组5-FU血药浓度的中位无进展生存期分别为4± 11.25个月、7±2个月、6.5±1.25个月;中位总生存期分别为8±11.25个月、8±3个月、7±3个月。3组5-FU血药浓度与PFS、OS的差异不具有统计学意义(/=0.984,P=0.611;χ2=0.693,P=0.707)。该结果表明基于BSA给予5-FU的化疗剂量未能提高晚期胃癌患者的无进展生存期及总生存期。Cox回归分析的结果说明5-FU血药浓度、TNM分期、不良反应、疗效不是影响AGC患者的独立预后因素(χ2=15.246,P=0.055)。结论:基于BSA的5-FU给药剂量方式,其5-FU血药浓度与FPS、OS的差异无统计学意义,可能不是最优的给药方式。基于PK对5-FU进行血药浓度检测可能是更有效的预测预后的方法。另一方面,5-FU的药物疗效和毒副作用与代谢酶基因多态性和表达水平相关。应紧密结合临床具体情况对5-FU相应基因型信息进行检测分析,同时对AGC患者进行5-FU血药浓度检测,加以实现基于PK以调整5-FU治疗剂量的给药模式,进行治疗效果的预测,避免药物浓度与基因突变而引起的毒性反应。
[Abstract]:Objective: To observe and analyze the relationship between the blood concentration of 5-FU in 38 patients with advanced gastric cancer after FOLFOX first line regimen, the relationship between the effect and the adverse reaction, and the relationship between the clinical drug related genes of fluorouracil and the drug concentration and the adverse reaction in 25 patients with advanced gastric cancer. The research method: 38 patients with advanced gastric cancer received FOL FOX (Asha Leigh Per, calcium folate, and 5- fluorouracil) was treated for 3 weeks, each chemotherapy cycle was treated with a 5-FU vein micropump for the beginning of treatment, and 12h was extracted from the peripheral blood to detect the blood drug concentration. 25 of the patients extracted the peripheral blood to detect the 5-FU related genes before the first treatment until the patient changed the chemotherapy or patient's intolerance or patient's wishes. At the end of the study, the blood concentration test stopped. According to the concentration of 5-FU blood and the four digits of AUC, the concentration was divided into 3 groups of less than 45ng/ml, 46 to 151ng/ml and 151ng/ml, to analyze the clinical data of the 5-FU blood concentration and the patients with advanced gastric cancer, the treatment effect, the adverse reaction, the correlation of PFS, OS, the 5-FU related genes and the concentration of blood drugs. The correlation between good reaction. A single sample K-S was used to verify the normal distribution, chi 2 test or Fisher's accurate probability calculation was used to analyze the correlation between each group. The survival curve was drawn by the Kalplan-Meier method, the survival curve was compared with the Log-rank test, and the Cox regression analysis was used to carry out the multiple factors of the 5-FU blood concentration and TNM staging, adverse reaction and curative effect. The analysis of.P0.05 was statistically significant. Results: the mean plasma concentration of 5-FU in 38 patients with advanced gastric cancer was 116.08ng/ml and the median blood concentration was 92 + 106.5ng/ml. The standard deviation was 113.362ng/ml.5-FU blood concentration group and sex, age, TNM staging, bone marrow depression, gastrointestinal reaction and hand foot syndrome. There was no statistical significance between the serum concentration of sense.5-FU and the curative effect of chemotherapy (x 2=1.583, P=0.896), the incidence of adverse reactions between.5-FU blood concentration and skin and mucous membrane reaction was statistically significant (x 2=16.831, P=0.001). The incidence of skin skin and mucosal reaction of grade I to grade II in patients with 5-FU plasma concentration less than 45ng/ml increased, and the concentration of 151ng/ml in patients with 5-FU was increased. The incidence of skin and mucous membrane reaction in the group III to IV increased.5-FU blood concentration and 21GSTP1,62ABCB1,68MTHFR, 93MTHFR gene mutation had no significant statistical significance,.68MTHFR mutation and chemotherapeutic drug adverse reactions were significantly different (x 2=27.227, P0.001), 68MTHFR (667CT) gene polymorphisms in the CC wild homozygous patients skin and The incidence of mucous reaction and hand foot syndrome was high; TT mutant homozygous patients had a high incidence of myelosuppression and gastrointestinal reactions; the incidence of adverse reactions in CT mutant heterozygous patients was between CC and TT, myelosuppression, and the incidence of gastrointestinal reaction in the CT genotype AGC patients still had a certain toxicity risk.3 group 5-FU blood concentration. The median progression free survival time was 4 + 11.25 months, 7 + 2 months, 6.5 + 1.25 months, the median total survival time was 8 + 11.25 months, 8 + 3 months, and the 5-FU blood concentration of group.3 was not statistically significant (/=0.984, P=0.611; P=0.611; P =0.707) in 7 + 3 months (/=0.984, P=0.611; P =0.707). The results showed that the dose of chemotherapy based on BSA given 5-FU was failed. The results of progression free survival and total survival.Cox regression analysis in advanced gastric cancer patients showed that 5-FU blood concentration, TNM staging, and adverse effects were not independent prognostic factors of AGC patients (x 2=15.246, P=0.055). Conclusion: there is no significant difference in 5-FU blood concentration from FPS, OS, based on BSA based 5-FU administration. It may not be the best way of drug delivery. The detection of 5-FU based on PK may be a more effective method to predict the prognosis. On the other hand, the efficacy and side effects of 5-FU are related to the gene polymorphism and expression level of metabolic enzymes. It should be closely combined with clinical specific information to detect and analyze the corresponding genotype information of the 5-FU. The blood concentration of 5-FU in AGC patients was detected to realize the drug delivery mode based on PK to adjust the dose of 5-FU, and to predict the effect of the treatment, and to avoid the toxic reaction caused by the drug concentration and gene mutation.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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