| Objective: mFOLFOX6(5-FU combined with oxaliplatin)and FOLFIRI(5-FU combined with irinotecan)based on fluorouracil are first-line chemotherapy regimens for advanced colorectal cancer.At present,the clinical dose is usually calculated on the basis of body surface area.This method of dose calculation will lead to differences in efficacy and adverse reactions among individuals.This difference may be closely related to gene polymorphism and blood concentration of 5-FU.In view of the current situation,individualized drug delivery technology is rarely used in clinical practice,so this study intends to use individualized drug administration technique to observe the use of 5-FU combined with oxaliplatin or irinotecan in patients with advanced colorectal cancer,from the combination of drug use,gene polymorphism and therapeutic drug concentration monitoring to evaluate the clinical application value and clinical benefits of individualized drug administration in 5-FU-based combination chemotherapy,in order to improve clinical efficacy,reduce related adverse reactions,improve patients’ drug compliance and quality of life,and provide a basis for individual and accurate treatment of patients with advanced colorectal cancer.Methods: The subjects of this study were patients who were diagnosed with advanced colorectal cancer and received mFOLFOX6(5-FU combined with oxaliplatin)or FOLFIRI(5-FU combined with irinotecan)regimen in the first affiliated Hospital of Southern Anhui Medical College(Yijishan Hospital).(1)to compare the difference of efficacy and adverse reactions between mFOLFOX6 group and FOLFIRI group.(2)within mFOLFOX6 group: to study the correlation between 5-FU and oxaliplatin-related gene loci(DPYD*2A(1905+1G>A),DPYD(2846 A>T),DPYD*13(1679T>G),GSTP1(313A>G)and MTHFR(677C>T)with efficacy and adverse reaction.According to the blood concentration of 5-FU,the patients were divided into individualized group and control group.According to the blood concentration of 5-FU,the three results were divided into high concentration group(AUC>30 mg·h/L),intermediate concentration group(20 mg · h/L ≤ AUC ≤ 30 mg · h/L)and low concentration group(AUC<20 mg·h/L).The therapeutic efficacy and adverse reactions of patients in each group were analyzed.(3)in FOLFIRI group: to study the correlation between 5-FU and irinotecan gene loci(DPYD*2A(1905+1G>),DPYD(2846 A>T),DPYD*13(1679 T>G),MTHFR(677C>T)UGT1A1*6(211G>A)and UGT1A1*28(-53-52TA[6][7]))with efficacy and adverse reactions.According to the blood concentration of 5-FU,the patients were divided into individualized group and control group.According to the blood concentration of 5-FU,the three results were divided into high concentration group,intermediate concentration group and low concentration group.The therapeutic efficacy and adverse reactions of patients in each group were analyzed.Results: A total of 67 patients were included in this study,including 41 patients in mFOLFOX6 group and 26 patients in FOLFIRI group.No mutation was found in DPYD*2A(1905+1G > A),DPYD(2846A> T)and DPYD*13(1679T>G).The range of AUC was 9.60 ～ 40.90 mg·h/L.(1)there were significant differences in efficacy and adverse reactions between mFOLFOX6 group and FOLFIRI group.In terms of curative effect,the progression-free survival time and the decrease of carcinoembryonic antigen in mFOLFOX6 group were significantly better than those in FOLFIRI group.Although there was no statistical difference,the objective remission rate and treatment failure time in mFOLFOX6 group were also better than those in FOLFIRI group.In terms of adverse reactions,the incidence of neutropenia and thrombocytopenia in mFOLFOX6 group was significantly higher than that in FOLFIRI group.(2)in mFOLFOX6 group:gene polymorphism was correlated with efficacy and adverse reactions.In terms of efficacy,the decrease of carbohydrate antigen 125 of CT/TT genotype at MTHFR(677C>T)site was significantly better than that of CC genotype,and the treatment failure time of AA genotype at GSTP1(313A>G)was significantly better than that of AG/GG genotype,but the objective remission rate of AA genotype was lower than that of AG/GG genotype.In terms of adverse reactions,the incidence of neutropenia of CT/TT genotype at MTHFR(677C>T)was significantly higher than that of CC genotype.There was no statistical difference between blood drug concentration and each curative effect index,but there was a significant correlation between blood drug concentration and adverse reactions.The incidence of abnormal liver function in low concentration group and control group was significantly lower than that in intermediate concentration group(P<0.05),while the incidence of leukopenia in high concentration group and intermediate concentration group was significantly higher than that in control group(P<0.05).The incidence of neutropenia in high concentration group and intermediate concentration group was significantly higher than that in low concentration group and control group(P<0.05).The incidence of thrombocytopenia in high concentration group was significantly higher than that in low concentration group and control group(P<0.05).(3)within FOLFIRI group: gene polymorphism was correlated with efficacy and adverse reactions.In terms of efficacy,the carcinoembryonic antigen reduction of CT/TT genotype at MTHFR(677C>T)was significantly better than that of CC,and the carbohydrate antigen of AG/AA genotype was significantly better than that of GG genotype at UGT1A1*6(211G>A).In terms of adverse reactions,the incidence of hemoglobin decrease of CT/TT genotype at MTHFR(677C>T)was significantly higher than that of CC genotype(P < 0.014).The incidence of abnormal liver function of GG genotype at UGT1A1*6(211G>A)locus was significantly higher than that of AG/AA genotype,but the incidence of leukopenia of AG/AA genotype was significantly higher than that of GG genotype,and the incidence of abnormal liver function of 6/6AT genotype of UGT1A1*28(-53-52 TA [6] [7])was significantly higher than that of 6/7AT genotype.There was no statistical difference between blood drug concentration and each curative effect index,but there was a significant correlation between blood drug concentration and adverse reactions.The incidence of abnormal liver function in low concentration group was significantly lower than that in control group,intermediate concentration group and high concentration group(P<0.05).The incidence of thrombocytopenia in the low concentration group was significantly lower than that in the control group and high concentration group(<0.05).Conclusion: The curative effect of mFOLFOX6 regimen is better than that of FOLFIRI regimen,but the incidence of adverse reactions is also more serious.MTHFR(677C > T)CT/TT genotype compared with CC genotype showed better efficacy and higher incidence of adverse reactions.GSTP1(313A>G)locus in mFOLFOX6 regimen was significantly correlated with efficacy,UGT1A1*6(211G>A)in FOLFIRI regimen was significantly correlated with efficacy,and UGT1A1*6(211G>A)and UGT1A1*28(-53-52TA[6][7])loci were significantly correlated with adverse reactions.In this study,there was no significant difference in the blood concentration of 5-FU among the subgroups and the curative effect.There was a significant correlation between the blood concentration of 5-FU and adverse reactions,which was more obvious in the mFOLFOX6 group than in the FOLFIRI group.Therefore,the application of5-FU-based chemotherapy in clinical practice should be considered comprehensively,combined with individual drug delivery technology,and fully weigh the efficacy and adverse reactions,so that the clinical treatment of patients with advanced colorectal cancer will benefit best. |
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