本文選題：伊立替康 + UGT1A1��； 參考：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：研究背景與目的伊立替康(CPT-11)聯(lián)合氟尿嘧啶,亞葉酸鈣的FOLFIRI方案是目前治療轉(zhuǎn)移性結(jié)直腸癌的標(biāo)準(zhǔn)化療方案之一。嚴重的中性粒細胞減少和遲發(fā)性腹瀉限制了更廣泛的應(yīng)用。尿苷二磷酸葡糖醛酸轉(zhuǎn)移酶1A1(UGT1A1)是參與CPT-11在人體內(nèi)失活代謝的關(guān)鍵酶。在歐美高加索人種中,UGT1A1*28純合變異的患者應(yīng)用CPT-11發(fā)生嚴重不良反應(yīng)的風(fēng)險較大,需要減量,但具體減量標(biāo)準(zhǔn)目前尚無定論。在亞洲人種中UGT1A1*6與UGT1A1*28具有相似作用,我們課題組在研究中發(fā)現(xiàn),UGT1A1*28和*6雙位點突變患者體內(nèi)AUCSN-38G/AUC SN-38的藥物濃度大約為其他基因型患者的2倍�；谠撗芯�,我們于2012年4月啟動了一項前瞻性、全國多中心臨床研究,依據(jù)UGT1A1基因型調(diào)整伊立替康劑量對FOLFIRI方案治療轉(zhuǎn)移性結(jié)直腸癌的毒性和療效影響的前瞻性臨床研究。方法在全國20家醫(yī)院開展了這項多中心、前瞻性臨床研究。選取經(jīng)組織學(xué)證實的轉(zhuǎn)移性結(jié)直腸癌患者,治療前檢測UGT1A1*28和*6基因型。根據(jù)UGT1A1*28和*6基因型將患者分為野生型(*1/*1)、單個位點突變型(*1/*28,*1/*6)、雙位點突變型(*28/*28,*6/*6,*6/*28)。野生型及單個位點突變型采用標(biāo)準(zhǔn)劑量的FOLFIRI方案(A組),雙位點突變型患者進行隨機分組,一組采用調(diào)整劑量的FOLFIRI方案(CPT-11減量50%)(B組),另一組采用標(biāo)準(zhǔn)劑量的FOLFIRI方案(C組)。治療持續(xù)至疾病進展或出現(xiàn)不可耐受的毒性。根據(jù)NCI-CTC3.0版評價不良反應(yīng)。采用實體瘤療效評價標(biāo)準(zhǔn)1.1(RECIST 1.1)評價療效,并隨訪其疾病進展時間(PFS)和總生存期(OS)。分析三組間毒性和療效的差異,評價根據(jù)3UGT1A1基因型進行CPT-11劑量調(diào)整的可行性。結(jié)果自2012年4月至2015年11月,共670例晚期結(jié)直腸癌患者參與篩選,最終入組患者579例,其中野生型268例(46.3%),單個位點突變型259(44.8%),雙位點突變型52(9.0%)。最終有542例患者完成隨機并接受至少一個周期的FOLFIRI方案治療。其中A組497人,B組22人,C組23人,三組臨床特征間差異均無統(tǒng)計學(xué)意義(P"g0.05)。A、B、C三組的3~4度中性粒細胞減少的發(fā)生率呈逐漸升高趨勢(16.9%~21.7%,P=0.773)。其中C組的4度中性粒減少的發(fā)生率顯著高于其他兩組(4.0%vs 4.5%vs 17.4%,P=0.029)。三組患者的3~4度血小板減低的發(fā)生率分別為2.4%,4.5%和0%(P=0.483),3~4度血紅蛋白減低的發(fā)生率分別1.8%,0%和4.3%(P=0.583)。三組患者間2~4度遲發(fā)性腹瀉的發(fā)生率逐漸升高,但無統(tǒng)計學(xué)顯著差異(P=0.805)。其中3~4度遲發(fā)性腹瀉的發(fā)生率也無統(tǒng)計學(xué)差異(P=0.479)。三組間2~4度血清膽紅素升高率分別為3.0%、9.0%、4.3%,無統(tǒng)計學(xué)差異(P=0.165)。三組間2~4度乏力的發(fā)生率呈逐漸升高趨勢(三組分別為29.6%vs31.8%vs 34.8%,P=0.850),3~4乏力的發(fā)生率分別為11.5%、13.6%、21.7%,P=0.294。三組間2~4度惡心、嘔吐的發(fā)生率依次為25.4%、18.2%、34.8%,P=0.434。A、B、C組的有效率(RR)分別為25.2%(125/497),22.7%(5/22)和9.1%(2/23)。雖然C組的有效率最低,但無統(tǒng)計學(xué)顯著差異(P=0.197)。三組的中位PFS分別為6.13個月、6.83個月和5.53個月,P=0.975。OS分別為19.90個月、14.0個月和19.93個月,P=0.685。三組間均無統(tǒng)計學(xué)顯著差異。研究對48例患者進行了藥代動力學(xué)分析,其中A組34例,B組10例,C組4例。以AUCSN-38G/AUCSN-38作為CPT-11在體內(nèi)失活代謝的評價指標(biāo),A組的AUCSN-38G/AUCSN-38是B組的3倍(3.01vs 1.01,P=0.027),而B組和C組的AUCSN-38G/AUCSN-38相似,分別為1.01、1.75,P=0.888。結(jié)論UGT1A1*6及*28雙位點突變型患者采用標(biāo)準(zhǔn)FOLFIRI方案可導(dǎo)致4度中性粒細胞減低的風(fēng)險顯著增加,而采用CPT-11減半劑量能顯著降低這一風(fēng)險,同時并不影響療效及預(yù)后。藥代動力學(xué)分析提示,減量后對于雙位點突變型患者CPT-11體內(nèi)SN-38失活比例仍顯著低于野生型和單個位點突變型患者,提示劑量調(diào)整仍需進一步研究。
[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.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.34

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