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目的:回顾性分析2010年6月-2012年1月来自于多家医疗中心的69例进展期结直肠癌接受以伊立替康(irinotecan,CPT-11)为基础的二线联合化疗患者的尿苷二磷酸葡醛酰转移酶1A1(uridine diphosphate glucuronosyl transferase1A1,UGT1A1)*28基因多态性的表达情况,探讨UGT1A1*28(TA)6/(TA)6和(TA)6/(TA)7型患者接受CPT-11治疗后的葡萄糖醛酸化SN-38(SN-38 glucuronide,SN-38G)峰浓度和谷浓度与不良反应和疗效之间的关系。方法:这是一项多中心的回顾性研究。研究对象为2010年6月—2012年1月接受以CPT-11为基础的二线联合化疗的69例进展期结直肠癌患者。化疗之前,检测UGT1A1基因多态性;在CPT-11化疗1.5和49.0h时,应用高效液相色谱法检测SN-38血药浓度。观察近期疗效和不良反应,采用逐步回归分析法分析不同的UGT1A1*28基因型患者SN-38血药浓度与近期疗效和不良反应的关系。结果:69例患者中,(TA)6/(TA)6型45例(65.22%),(TA)6/(TA)7型24例(34.78%),未发现(TA)7/(TA)7型。CPT-11治疗后,(TA)6/(TA)7型患者的SN-38平均峰浓度和谷浓度均高于(TA)6/(TA)6型患者(P=0.001,P=0.000)。逐步回归分析结果显示,(TA)6/(TA)6型患者的SN-38峰浓度与无病生存期相关,SN-38谷浓度与近期疗效相关;而(TA)6/(TA)7型患者的SN-38峰浓度与骨髓抑制相关,SN-38谷浓度与治疗后血浆总胆红素水平和迟发性腹泻相关。(TA)6/(TA)6型患者SN-38峰浓度>43.20ng/mL和谷浓度>9.41ng/mL的中位无进展生存期优于SN-38峰浓度≤43.20ng/mL(6.0和4.6个月,χ2=25.57,P=0.00)和谷浓度≤9.41ng/mL的患者(6.0和5.2个月,χ2=6.81,P=0.01)。(TA)6/(TA)7型患者SN-38峰浓度>50.60ng/mL和谷浓度>16.29ng/mL的中位无进展生存期并不明显优于SN-38峰浓度≤50.60ng/mL(7.0和6.0个月,χ2=0.18,P=0.67)和谷浓度≤16.29ng/mL的患者(6.0和7.3个月,χ2=0.56,P=0.46),而骨髓抑制发生率(P=0.02,P=0.02)和迟发性腹泻发生率(P=0.04,P=0.03)较高。结论:进展期结直肠癌患者以UGT1A1*28(TA)6/(TA)6型和(TA)6/(TA)7型占绝大多数。对于(TA)6/(TA)6型患者,如果CPT-11化疗后SN-38峰浓度≤43.20ng/mL或谷浓度≤9.41ng/mL,可逐步增加CPT-11剂量以提高治疗效果;对于(TA)6/(TA)7型患者,如果CPT-11化疗后SN-38峰浓度>50.60ng/mL或谷浓度>16.29ng/mL者,可适当减少CPT-11剂量以减轻不良反应,而不影响化疗效果。
PURPOSE: To retrospectively analyze the clinical data of 69 patients with advanced colorectal cancer who received irinotecan (CPT-11) -based second-line combination chemotherapy from June 2010 to January 2012. Uridine (TA) 6 / (TA) 6 and (TA) 6 / (TA) 7 polymorphisms in uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) The relationship between the peak concentration and trough concentration of glucuronidase SN-38 (SN-38 glucuronide, SN-38G) and the adverse reactions and effects in patients receiving CPT-11. Method: This is a multi-center retrospective study. The study population was 69 patients with advanced colorectal cancer who received second-line combination chemotherapy based on CPT-11 from June 2010 to January 2012. Before chemotherapy, UGT1A1 gene polymorphism was detected. At 1.5 and 49.0 hours of CPT-11 chemotherapy, the plasma concentration of SN-38 was detected by high performance liquid chromatography. To observe the short-term curative effect and adverse reaction, and to analyze the relationship between the SN-38 blood concentration and the short-term curative effect and adverse reactions in different UGT1A1 * 28 genotypes by stepwise regression analysis. Results: Among the 69 patients, there were 24 cases (34.78%) of (TA) 6 / (TA) 6 type (45.22% ) 7 type. The mean peak concentration and trough concentration of SN-38 in (TA) 6 / (TA) 7 patients after CPT-11 treatment were higher than those in TA 6 / TA patients (P = 0.001, P = 0.000) . Stepwise regression analysis showed that SN-38 peak concentration in (TA) 6 / (TA) 6 patients was associated with disease-free survival, while SN-38 trough concentration was associated with short-term efficacy; Patients with SN-38 peak concentration and myelosuppression related, SN-38 trough concentration and plasma total bilirubin levels and delayed diarrhea related. The median progression-free survival (SN-38) peak concentration> 43.20 ng / mL and trough concentration> 9.41 ng / mL for patients with type 6 TA (TA) 6 / And 4.6 months, χ2 = 25.57, P = 0.00) and trough concentrations ≤ 9.41 ng / mL (6.0 and 5.2 months, χ2 = 6.81, P = 0.01). The median progression-free survival (SN-38) peak concentration> 50.60 ng / mL and the trough concentration> 16.29 ng / mL in patients with TA type 6 / (TA) 7 were not significantly better than those with SN-38 peak concentrations ≤50.60 ng / (6.0 and 7.3 months, χ2 = 0.56, P = 0.46), while the incidence of myelosuppression (P = 0.46, P = 0.02, P = 0.02) and the incidence of delayed diarrhea (P = 0.04, P = 0.03). Conclusion: The majority of patients with advanced colorectal cancer have UGT1A1 * 28 (TA) 6 / (TA) 6 and (TA) 6 / (TA) 7. For patients with (TA) 6 / (TA) type 6, the CPT-11 dose may be increased gradually to increase the therapeutic effect if the peak concentration of SN-38 is ≤43.20 ng / mL or the trough concentration is lower than 9.41 ng / mL after CPT- For patients with (TA) 6 / (TA) type 7, the CPT-11 dose may be appropriately reduced to reduce adverse reactions if peak concentration of SN-38> 50.60 ng / mL or trough concentration> 16.29 ng / mL after CPT-11 chemotherapy , Without affecting the effect of chemotherapy.