依据UGT1A1基因型调整伊立替康剂量对FOLFIRI方案治疗转移性结直肠癌的毒性和疗效影响的前瞻性临床研究

发布时间：2018-06-03 09:24

本文选题：伊立替康 + UGT1A1　；参考：《安徽医科大学》2017年硕士论文

【摘要】：研究背景与目的伊立替康(CPT-11)联合氟尿嘧啶,亚叶酸钙的FOLFIRI方案是目前治疗转移性结直肠癌的标准化疗方案之一。严重的中性粒细胞减少和迟发性腹泻限制了更广泛的应用。尿苷二磷酸葡糖醛酸转移酶1A1(UGT1A1)是参与CPT-11在人体内失活代谢的关键酶。在欧美高加索人种中,UGT1A1*28纯合变异的患者应用CPT-11发生严重不良反应的风险较大,需要减量,但具体减量标准目前尚无定论。在亚洲人种中UGT1A1*6与UGT1A1*28具有相似作用,我们课题组在研究中发现,UGT1A1*28和*6双位点突变患者体内AUCSN-38G/AUC SN-38的药物浓度大约为其他基因型患者的2倍。基于该研究,我们于2012年4月启动了一项前瞻性、全国多中心临床研究,依据UGT1A1基因型调整伊立替康剂量对FOLFIRI方案治疗转移性结直肠癌的毒性和疗效影响的前瞻性临床研究。方法在全国20家医院开展了这项多中心、前瞻性临床研究。选取经组织学证实的转移性结直肠癌患者,治疗前检测UGT1A1*28和*6基因型。根据UGT1A1*28和*6基因型将患者分为野生型(*1/*1)、单个位点突变型(*1/*28,*1/*6)、双位点突变型(*28/*28,*6/*6,*6/*28)。野生型及单个位点突变型采用标准剂量的FOLFIRI方案(A组),双位点突变型患者进行随机分组,一组采用调整剂量的FOLFIRI方案(CPT-11减量50%)(B组),另一组采用标准剂量的FOLFIRI方案(C组)。治疗持续至疾病进展或出现不可耐受的毒性。根据NCI-CTC3.0版评价不良反应。采用实体瘤疗效评价标准1.1(RECIST 1.1)评价疗效,并随访其疾病进展时间(PFS)和总生存期(OS)。分析三组间毒性和疗效的差异,评价根据3UGT1A1基因型进行CPT-11剂量调整的可行性。结果自2012年4月至2015年11月,共670例晚期结直肠癌患者参与筛选,最终入组患者579例,其中野生型268例(46.3%),单个位点突变型259(44.8%),双位点突变型52(9.0%)。最终有542例患者完成随机并接受至少一个周期的FOLFIRI方案治疗。其中A组497人,B组22人,C组23人,三组临床特征间差异均无统计学意义(P"g0.05)。A、B、C三组的3~4度中性粒细胞减少的发生率呈逐渐升高趋势(16.9%~21.7%,P=0.773)。其中C组的4度中性粒减少的发生率显著高于其他两组(4.0%vs 4.5%vs 17.4%,P=0.029)。三组患者的3~4度血小板减低的发生率分别为2.4%,4.5%和0%(P=0.483),3~4度血红蛋白减低的发生率分别1.8%,0%和4.3%(P=0.583)。三组患者间2~4度迟发性腹泻的发生率逐渐升高,但无统计学显著差异(P=0.805)。其中3~4度迟发性腹泻的发生率也无统计学差异(P=0.479)。三组间2~4度血清胆红素升高率分别为3.0%、9.0%、4.3%,无统计学差异(P=0.165)。三组间2~4度乏力的发生率呈逐渐升高趋势(三组分别为29.6%vs31.8%vs 34.8%,P=0.850),3~4乏力的发生率分别为11.5%、13.6%、21.7%,P=0.294。三组间2~4度恶心、呕吐的发生率依次为25.4%、18.2%、34.8%,P=0.434。A、B、C组的有效率(RR)分别为25.2%(125/497),22.7%(5/22)和9.1%(2/23)。虽然C组的有效率最低,但无统计学显著差异(P=0.197)。三组的中位PFS分别为6.13个月、6.83个月和5.53个月,P=0.975。OS分别为19.90个月、14.0个月和19.93个月,P=0.685。三组间均无统计学显著差异。研究对48例患者进行了药代动力学分析,其中A组34例,B组10例,C组4例。以AUCSN-38G/AUCSN-38作为CPT-11在体内失活代谢的评价指标,A组的AUCSN-38G/AUCSN-38是B组的3倍(3.01vs 1.01,P=0.027),而B组和C组的AUCSN-38G/AUCSN-38相似,分别为1.01、1.75,P=0.888。结论UGT1A1*6及*28双位点突变型患者采用标准FOLFIRI方案可导致4度中性粒细胞减低的风险显著增加,而采用CPT-11减半剂量能显著降低这一风险,同时并不影响疗效及预后。药代动力学分析提示,减量后对于双位点突变型患者CPT-11体内SN-38失活比例仍显著低于野生型和单个位点突变型患者,提示剂量调整仍需进一步研究。
[Abstract]:Background and objective CPT-11 combined fluorouracil, calcium folate FOLFIRI scheme is one of the current standard chemotherapy regimens for the treatment of metastatic colorectal cancer. Severe neutrophils and delayed diarrhea restrict the wider application. Uridine two phosphate glucuronotransferase 1A1 (UGT1A1) is involved in CPT-11 in human body The key enzyme of inactivation metabolism. In the American European and American Caucasus, the UGT1A1*28 homozygous variant has a greater risk of using CPT-11 for severe adverse reactions and needs a reduction, but the specific decrement standard is still undecided. In Asian races, UGT1A1*6 and UGT1A1*28 have similar effects. In our study group, we found UGT1A1*28 and *6 double. The drug concentration of AUCSN-38G/AUC SN-38 in patients with site mutation is about 2 times as high as that of other genotypes. Based on this study, we started a prospective, national multicenter clinical study in April 2012 based on the effects of the UGT1A1 genotype on the toxicity and effect of irinotecan dosage on FOLFIRI regimen for metastatic colorectal cancer. Prospective clinical studies. Methods a multicenter, prospective clinical study was carried out in 20 hospitals nationwide. Patients with metastatic colorectal cancer confirmed by histologically confirmed UGT1A1*28 and *6 genotypes were detected before treatment. According to the UGT1A1*28 and *6 genotypes, the patients were divided into wild type (*1/ *1), single site mutation type (*1/*28, *1/*6), and double loci. The mutant type (*28/*28, *6/*6, *6/*28). The wild type and single locus mutation used the standard dose FOLFIRI scheme (A group), the double loci mutant patients were randomly divided into two groups, one used the FOLFIRI scheme of the adjusted dose (CPT-11 reduction 50%) (B group), and the other group using the standard dose FOLFIRI scheme (C group). The treatment lasted to the disease progression or appearance. Untolerable toxicity. Evaluate the adverse effects according to the NCI-CTC3.0 version. Evaluate the efficacy of the solid tumor efficacy evaluation standard 1.1 (RECIST 1.1) and follow up the time of disease progression (PFS) and total survival (OS). Analyze the differences in toxicity and efficacy between the three groups and evaluate the feasibility of CPT-11 dose adjustment based on the 3UGT1A1 based type. The results were from 4 2012. From month to November 2015, a total of 670 patients with advanced colorectal cancer were selected and included in the final group of 579 patients, including 268 wild type (46.3%), single site mutant 259 (44.8%), and double loci mutant 52 (9%). Finally, 542 patients completed random and received at least one cycle of FOLFIRI regimen. In group A, 497, group B 22, and group C 23, There was no statistical difference between the three groups of clinical features (P "g0.05).A, B, C three groups of 3~4 degree neutropenia increased gradually (16.9%~21.7%, P=0.773). The incidence of 4 degree neutrophils in the C group was significantly higher than the other two groups (4.0%vs 4.5%vs 17.4%, P=0.029). Three groups of patients with thrombocytopenia The rates of 2.4%, 4.5% and 0% (P=0.483) and 3~4 degree hemoglobin reduction were 1.8%, 0% and 4.3% respectively (P=0.583). The incidence of 2~4 degree delayed diarrhea in three groups was gradually increased, but there was no statistically significant difference (P=0.805). The incidence of 3~4 degree delayed diarrhea was also not statistically significant (P=0.479). The 2~4 degree serum of three groups was not significant (P=0.805). The rate of vegetal elevation was 3%, 9%, 4.3%, respectively (P=0.165). The incidence of 2~4 degree fatigue was gradually increased in three groups (three groups were 29.6%vs31.8%vs 34.8%, P=0.850), and the incidence of 3~4 fatigue was 11.5%, 13.6%, 21.7%, and P=0.294. three between 2~ 4 degrees nausea, 18.2%, 18.2%, 34.8%, P=0.434.A, B, respectively. The efficiency (RR) of group C was 25.2% (125/497), 22.7% (5/22) and 9.1% (2/23). Although the efficiency of C group was the lowest, there was no statistically significant difference (P=0.197). The median PFS in group three was 6.13 months, 6.83 months and 5.53 months respectively, P=0.975.OS was 19.90 months, 14 and 19.93 months, and there were no statistically significant differences between the P=0.685. three groups. The pharmacokinetic analysis of 48 patients was carried out in 48 cases, including 34 cases in group A, 10 in group B and 4 in group C. AUCSN-38G/AUCSN-38 was used as the evaluation index of inactivation metabolism in the body, and AUCSN-38G/AUCSN-38 in group A was 3 times of B group (3.01vs 1.01, P=0.027), while B group was similar to C group. The risk of 4 degree neutrophils can be significantly increased by the standard FOLFIRI scheme in 6 and *28 double loci mutagenesis patients, while the use of CPT-11 halving dose can significantly reduce the risk and do not affect the efficacy and prognosis. Pharmacokinetic analysis suggests that the SN-38 inactivation ratio in CPT-11 in patients with double loci mutation is reduced after reduction. It is still significantly lower than wild type and single locus mutation patients, suggesting that dose adjustment still needs further study.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.34

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