A Study On The Relationship Between Tc>0.05 And The Clinical Efficacy And Toxicity Of Paclitaxel In Patients With Gastric Cancer

Background and objective:Gastric cancer,one of the most common tumors,is the third cancer-related death in China.Most patients with dastric cancer are diagnosed in advanced stage due to lack of obvious early syndromes.These patients have to be treated with chemotherapy when they lose the chance of surgery.For patients with advanced gastric cancer,the response rate of paclitaxel monotherapy is only 17%-33%.However when paclitaxel combined with fluorouracil or platinum,the response rate could reach 50%-60%,median survival of only 11-12 months,and 5 year survival rate still less than 5%.Therefore,how to maximize the effect of chemotherapy and reduce the related toxicity therefore has attracted more and more attention.With the development of paclitaxel pharmacokinetical and detection and technology,dynamic evaluation of blood concentration of paclitaxel is feasible.Analysis on the relationship between side effects,efficacy and pharmacokinetic parameters could be associated with the adjustment of dosage of paclitaxel,which has great significance regarding personalized medicine.The purpose of this study is to investigate blood concentration and pharmacokinetic parameters of paclitaxel(Tc>0.05)to clarify the pharmacokinetics of paclitaxel in patients with advanced gastric cancer.Methods:In this study gastric cancer patients,should be confirmed by cytologically or histopathologically,Affiliated Jiangsu Cancer Hospital of Nanjing Medical University&Jiangsu Institute of Cancer Research.All patients were staged according to the 7th edition of the AJCC cancer staging manual,and should be unresectable locally advanced,or with recurrent and metastatic diease.Blood concentration of paclitaxel was detected by latex turbidimetric method.Blood concentrations were determined by MyPTX method.Calculation of Tc>0.05 is bases on the computational software of pharmacokinetics model of attached with MyPTX.The therapeutic effect was evaluated according to criteria of RECIST,and the adverse reactions were evaluated according to the Common Adverse Reaction Terminology Criteria of National Cancer Institute v4.0(NCI-CTCAE v4.0).The experimental data was statistically analysied using SPSS20.0 software and GraphpadPrism6.0 graphics.Measurement data were expressed with mean+standard deviation(x±s).Pearson correlation analysis,independent samples t test and ANOVA were used to analyze the relationship between Tc>0.05 and response,and chi squared test and ANOVA to analyze the relationship between Tc>0.05 and adverse reaction.P<0.05 stands for significant level of statistics analysis.Results:1.Relationship between Tc>0.05 and clinical pathological characteristics and absolute dose.In this study,steady state of plasma concentration(C)was measured by MyPTX in 18 to 30 hours after the infusion of paclitaxel.Clinical and pathological characteristics of all patients and the corresponding Tc<0.05 of the chi square test or one-way ANOVA showed that different gender,age,Tc>0.05,staging of patients with KPS score and TNM stage were no significant difference.Pearson analysis showed the absolute dosage of Paclitaxel and Tc>0.05 was positively correlated,P=0.0005,which indicates obvious correlation and statistical significance.And the linear regression equation is Tc<0,05=11.53+-0.07462*AD.2.The relationship between Tc>0.05 and efficacy of PaclitaxelAll enrolled patients completed at least 2 cycles of chemotherapy,then underwent physical and imaging examination within 2 weeks after 2 cycles of chemotherapy.According to RECIST,one-factor analysis of variance showed that the average difference of Tc<0.05 among three groups,partial remission group(group PR),stable disease group(SD group),progress group(group PD),was no statistically significance(P=0.549).Using two independent samples t test to determine the relationship of Tc>0.05 between disease control group(group DCR)and PD group.The results suggest that in DCR group,Tc>0.05 was significantly higher than that of the PD group,and the difference was statistically significant(P=0.022).3.Analysis of the correlation between Tc>0.05 and the adverse reaction of paclitaxelIn this study,patients were divided into two groups according to the mean value of Tc>0.05 of paclitaxel,group Tc>0.05<26h was the low exposure group,Tc>0.05≥26h group was high exposure group.Compare the elinieal characteristics between two groups,our results showed that no significant differences of Tc>0.05 in age,gender,TNM stage and KPS scores.According to NCI-CTCAE v4.0,chi square test on side effects occurrenee between two groups,results suggested that leukopenia in high exposure group was more common than that in low expose group,and the difference was statistically significant(P=0.006).One-factor analysis of variance on Tc>0.05 in 4 levels of bone marrow suppression showed that the differenee was statistically significant(P=0.0016).Pearson analysis showed the absolute neutrophil count nadir(ANCN)and Tc>0.05 was positively negative correlated,P=0.024,which indicates obvious correlation and statistical significance,and the linear regression equation is Tc>0.05=39.25-3.356*ANCN.This suggests that in clinical work,Tc>0.05 for patients with bone marrow suppression,could be a guide to apply granulocyte colony-stimulating factor(G-CSF)to prevent leukogenia.Differences between low and high exposure group with regard to severity of anemia and thrombocytopenia were not statistically significant.There were no significant differences in liver damage,gastrointestinal side effect and peripheral neurotoxicity,in terms of consideration of low and high exposure group.Therefore,paclitaxel Tc>0.05 could be used as an indicator of efficacy and side effects.Conclusions1.The difference between clinicopathologic feature and Tc>0.05 was not significantly different.The absolute dosage of Paclitaxel and Tc>0.05 was positively correlated,(P=0.0005),which indicates Tc>0.05 could guide dosage adjustment clinically.2.Tc>0.05 of DCR group was significantly higher than that of PD group,suggesting that paclitaxel Tc>0.05 could be used as an indicator to observe and improve the efficacy of paclitaxel in treating with advanced gastric cancer.3.Compared with low exposed group,patients in high exposed group could have more serious bone marrow depression.Thus paclitaxel Tc>0.05 could be used as an indicator to monitor the safety of Paclitaxel.Therefore,according to the Tc>0.05 we can adjust the dosage of PTX during the next chemotherapy cycle of,so as to realize the individualized treatment.