Study On The Correlation Of 5-FU Plasma Concentration And Associated Genes With Efficacy And Adverse Events In Chemotherapy Of Advanced Gastric Cancer

Objective:Our study was retrospectively observed and analyzed the correlation between the plasma concentration of 5-FU and efficacy,adverse events in 38 cases AGC(advanced gastric cancer),who treated with FOLFOX.We also analyzed the correlation between 5-FU clinical drug-related genes and plasma concentration,adverse events in 25 cases among them.Methods:38 cases were treated with FOLFOX(oxaliplatin,leucovorin and 5-fluorouracil)q3w.Peripheral blood was collected to measure the concentration after 5-FU was continuously pumped into 12h.25 cases among them were collected peripheral blood to detect 5-FU related genes before the first treatment.The chemotherapy regimen changed or patients can not tolerate this regimen or patients wish to terminate the participation of the study,plasma concentration detection was stopped.According to the dist:ribution of 5-FU plasma concentration and quartile of AUC,we divided into 3 groups:≤45ng/ml,46～151ng/ml,>151ng/ml,analyze the the correlation between 5-FU plasma concentration and clinical data,efficacy,adverse events,PFS and OS,and the correlation between 5-FU related-gene and 5-FU concentration,adverse events.K-S test verify normal distribution,chi-square test or Fisher’s exact test analyze correlation between each group.Kalplan-Meier test and Log-rank test analyze the survival analysis.Cox regression analysis was used to analyze the correlation between 5-FU plasma concentration and TNM staging,efficacy,adverse events,PFS and OS.P<0.05 was considered statistically significant.Results:The 5-FU average plasma concentration is 116.08ng/ml in 38 cases AGC,median plasma concentration is 92±106.5ng/ml,standard deviation is 113.362ng/ml.The correlation between 5-FU plasma concentration group and gender,age,TNM stage,myelosuppression,gastrointestinal reaction and hand-foot syndrome was no significant difference.There was no significant difference between 5-FU plasma concentration and efficacy(chi-square=1.583,P=0.896).The correlation between 5-FU concentration and the incidence rate of skin and mucous reaction was statistically significant(chi-square=16.831,P=0.001).Ⅰ-Ⅱ level skin and mucous reaction rate will be increased in 5-FU concentration ≤45ng/ml group.Ⅲ～Ⅳ level skin and mucous reaction rate will be increased in 5-FU concentration>151ng/ml group.There was no significant difference between 5-FU concentration and 21GSTP1,62ABCB1,68MTHFR,93MTHFR gene mutation.The correlation between 68MTHFR gene mutation and the adverse events was statistically significant(chi-square=27.227,P<0.001),68MTHFR(667C>T)gene polymorphism with CC homozygous wild type increase the incidence rate of skin and mucous reaction and hand-foot syndrome:TT homozygous mutation increase the incidence rate of myelosuppression and gastrointestinal reaction.The incidence rate of adverse event with CT heterozygous mutation was between CC and TT,but the incidence rate of myelosuppression and gastrointestinal reaction with CT genotype of AGC patients still have a certain risk of toxicity.3 groups median progression-free survival time of 5-FU plasma concentration:4±11.25 months,7±2 months,and 6.5±1.25 months.The median overall survival:8±11.25 months,8±3 months,7±3 months.There was no significant difference between 5-FU plasma concentration and PFS,OS.(chi-square=0.984,P=0.611,chi-square=0.693,P=0.707).The results suggest that 5-FU dosage based on BSA can not improve survival in AGC.The results of Cox regression analysis showed that 5-FU plasma concentration,TNM stage,adverse reaction and curative effect were not independent prognostic factors in AGC(chi-square=15.246,P=0.055).Conclusion:Based on the 5-FU dosage of BSA,the 5-FU plasma concentration was not statistically significant with FPS,OS,may not be the best mode of administration.It is a more effective method to detect plasma concentration based on PK for 5-FU.On the other hand,The efficacy and side effects of 5-FU were related to the gene polymorphism and expression level of metabolic enzymes.In order to predict the treatment effect and avoid the toxic effects that caused by drug concentration and gene mutation.We should analyze the genotype information and detect the 5-FU plasma concentration of AGC patients,and then achieve the drug delivery model which adjust the 5-FU dosage based on PK.