Correlation Analysis Between Paclitaxel Pharmacokinetics Parameter T_c>0.05and Chemotherapeutic Effect And Safety In Esophageal Cancer

Background and objective:The risk factors for esophageal cancer include genetic,chronic inflammation of esophagus,foods containing nitrosamines,smoking,drinking etc.Now the incidence of esophageal cancer shows downward trend by year,but still have caused great threat to our health.Thus,more effective treatment for esophageal cancer need to be developed.Surgery,radiotherapy and chemotherapy are considered the main accepted treatment for this disease.Seventy percent of patients are in advanced stage when they were diagnosed.The median survival time is 4-8 months.Chemotherapy is still the main stay of treatment for patients with advanced esophageal cancer.At present,fluorouracil(5-Fu),paclitaxel(PTX)and platinum are frequently administered in the treatment of advanced esophageal cancer(AEC).The National Comprehensive cancer network(NCCN)guideline recommends these three drugs combined for AEC.Taxol plasma concentration is easy to be detected during chemotherapy and previous study found that the exposure time of critical plasma concentration of PTX no less than 0.05umol/L(Tc>0.05)is an effective pharmacokinetic parameters that could predict clinical toxicity and efficacy.The aim of this study is to confirm the correlation between PTX pharmacokinetic parameters Tc>0.05 with short-term response for patients with AEC who accepted PTX-based chemotherapy,and to explore the correlation between Tc>0.05 with side effects of chemotherapy and degree of side effects in patients with 2 levels of Tc>0.05(Tc>0.05<28h and Tc>0.05?28h).Materials and MethodsPatients were enrolled into this study with histologically or cytologically confirmed AEC.All patients enrolled were diagnosed in Jiangsu Cancer Hospital who received PTX+nedaplatin(NDP)or PTX+NDP+5-Fu.Two-three ml peripheral blood was taken 18-30h after the intravenous infusion of PTX to detect the concentration of PTX and enter into the kit-related calculation template to calculate Tc>0.05.Demographic characteristics,clinicopathologic characteristics and laboratory indexes were recorded according to medical records.Based on CT(computed tomography)and MRI(magnetic resonance imaging)detection,short-term response was estimated according to Response Evaluation Criteria in Solid Tumors(RECIST),and designated as complete response(CR),partial response(PR),stable disease(SD)and progressive disease(PD).Side effects were graded according to the National Cancer Institute Common Adverse Reaction Terminology Criteria v4.0(NCI-CTCAE v4.0).In addition,the value of Tc>0.05 5 is divided into 2 levels,and to estimate differences in side effects between these 2 levels.STATA 18.0 software and GraphPad Prism7.0 were used for statistical analysis.Student's t test was used to compare PTX plasma concentration and Tc>0.05 with clinicopathologic characteristics and investigate the association between Tc>0.05 with short-time response.Chi-square analysis or Fisher's exact test was used to compare the degree of adverse reactions between 2 levels of Tc>0.05.Scatter diagram of the association between Tc>0.05 and short-term response was made by GraphPad Prism7.0.P<0.05 was considered statistically signifcant.Results(1)We recruited 51 patients who were treated with PTX-based chemotherapy in JiangSu Cancer Hospital from June 2014 to February 2017(including 43 males and 8 females;17 cases in stage ?B,34 in stage ?:70?KPS<80 in 17,KPS?80 in 34).The range of concentration of PTX in all 51 patients were from 13 to 94umol/L,the median was 47umol l L,and averaged 52.55±2.99umol/L.Tc>0.05 were in the range of 11-55 h,the median was 23 h,and the mean was 24.65 ± 1.04 h.No significant differences between the concentration of PTX and Tc>0.05 with clinicopathological characteristics(e.g.age,gender and TNM classification).(2)There is statistically significant difference between Tc>0.05 and short-term response(P<0.05).The mean values of Tc>0.05 were 29.18 ± 1.87h and 24.05 ± 1.30h in patients with PR and SD,respectively.The mean value of Tc>0.05 was 26.47 ± 1.19h in patients with PR+SD and 20.27±1.66h in PD.The scatter diagram showed that Tc>0.05 in patients with PR was higher than that in SD,and Tc>0.05 in SD was higher than that in PD.Meanwhile,Tc>0.05 in patients with PR+SD was higher than that in PD.(3)Frequently seen side effects were neutropenia,thrombocytopenia,gastrointestinal side reaction,impaired liver function and neurotoxicity,the incidence rates were 60.8%,58.8%,43.1%,27.5%,13.7%,respectively.No significant differences between Tc>0.05 and severity of gastrointestinal side reactions was found.Significant differences were detected between Tc>0.05 with grade ?-? and ?-? thrombocytopenia and grade ?-? and ?-? neutropenia.Tc>0.05 in patients with grade ?-?thrombocytopenia and neutropenia was higher than that of grade ?-?thrombocytopenia and neutropenia.No significant differences between gastrointestinal side reactions with 2 levels of Tc>0.05(Tc>0.05<28h and Tc>0.05>28h).However,there were statistically significant differences between 2 levels of Tc>0.05(Tc>0.05<28h and Tc>0.05 ?28h)and the degree of neutropenia and thrombocytopenia(P=0.002 and P=0.041).Conclusions(1)Tc>0.05 suggested to be correlated with short-term response for PTX based chemotherapy in treating patients with AEC.And higher Tc>0.05 is correlated with better response.(2)In our study,it was found that frequently seen side effects were leukopenia,thrombocytopenia,gastrointestinal side reactions and all these side effects could reach grade ?-?.Tc>0.05 was found to be significantly increased in patients with grade?-? thrombocytopenia and neutropenia.(3)There is significant difference between severity of myelosuppression and 2 levels of Tc>0.05 (Tc>0.05<28h and Tc>0.05?28h).These suggested that AEC patients who accepted PTX-based chemotherapy and had Tc>0.05? 28 should be considered for prophylaxis treatment for severe myelosuppression.