Dose Exploration And Pharmacokinetic Study Of Raltitrexed In HIPEC

Background and Objective:Pelvic and peritoneal malignancies such as ovarian cancer,gastric cancer,colorectal cancer,pseudomyxoma peritoneum and primary peritoneal carcinoma are prone to develop into peritoneal surface malignancies with regional progression,which is called peritoneal metastatic carcinoma.Once patients with pelvic and peritoneal malignancies progress to peritoneal cancer,it usually means advanced stage.The survival time of patients is only 6 to 8 months.At the same time,patients are accompanied by serious complications,including malignant ascites,abdominal pain,abdominal distension,loss of appetite,fatigue,etc.,which greatly reduces the quality of life of patients.Conventional intravenous chemotherapy is often less effective because of the plasma-peritoneal barrier.Abdominal heat perfusion chemotherapy is widely used in the treatment of primary or metastatic peritoneal cancer.The clinical efficacy of rhatitrexed in HIPEC for the treatment of abdominal metastasis of gastrointestinal tumors and the control of malignant ascites has been widely recognized.Although a large number of studies have proved that Raltitrexed has considerable efficacy in the treatment of peritoneal cancer,there is no standard recommended dose when Raltitrexed is applied in HIPEC at present,and no relevant studies have been reported on the safety,efficacy,relationship between dose and efficacy and pharmacokinetic characteristics of Raltitrexed in HIPEC.The primary objective of this study was to determine the maximum tolerated dose and dose-restricted toxicity of Raltitrexed in HIPEC for patients with abdominal metastasis of gastrointestinal tumors associated with malignant ascites,in order to evaluate its safety and provide reference for clinical use.Secondary objectives were to explore the relationship between dose and efficacy in HIPEC,pharmacokinetic（PK）characteristics,and to evaluate the antitumor activity of Raltitrexed in patients with peritoneal cancer,including objective response rate（ORR）,disease control rate（DCR）,progression-free survival（PFS）,and overall patient survival（OS）.Methods:In this study,a total of 12 patients were included in the dose escalation phase,and were divided into four dose levels（3.0mg/m²,3.5mg/m²,4.0mg/m² and 5.0mg/m²）by using the traditional"3+3"experimental escalation scheme.The clinical efficacy and possible side effects of patients in each dose group were closely observed after HIPEC.At the same time,serum samples of patients were collected at the specified time to determine the plasma concentration of Raltitrexed.Pharmacokinetic parameters of raltitrexel in HIPEC were calculated using pharmacokinetic analysis software,including T_max,T_1/2,C_max,AUC,V_z,etc.,and correlation analysis of parameter characteristics was conducted.Results:No dose-limiting toxicity was observed in all patients enrolled in this study during the dose escalation phase,so the maximum tolerated dose of Raltitrexed in HIPEC could not be determined.The most common treatment related adverse events（TEAE）were decreased hemoglobin（83.3%）,bloating（75%）and constipation（75%）,followed by abdominal pain,leukopenia,elevated AST and elevated ALT（66.7%）,and also included vomiting,hiccups,hair loss,diarrhea,fever and anorexia.All of them were grade 1 or grade 2 adverse reactions,and most of them recovered to normal after symptomatic treatment.The frequency and severity of adverse reactions were dose-dependent.Overall objective response rate（ORR）was 75.0%,disease control rate（DCR）was 100%,median OS was 13.0 months（95%CI:3.239-22.761）,and median PFS was 10.4 months（95%CI:3.078-8.922）.Pharmacokinetic studies showed that there was a dose-dependent relationship between the C_max,T_1/2,V_z,AUC_0→last and AUC_0→∞of Raltitrexed.The serum concentration reached a peak about 1 hour after administration,and showed a single exponential attenuation after reaching the peak.The average final half-life(T_1/2)was323.05～615.21h.The mean retention time(MRT_0→∞)reached 401.31～613.61h,the apparent volume of distribution（V_z）was 3381.88～6763.65 L/m2,and the overall clearance rate（CL）was 6.94～7.69L/h·m2.The pharmacokinetics of Raltitrexed in HIPEC were proportional to the dose.It should be further explored in future studies.Conclusion:1.Raltitrexed in HIPEC has controllable adverse reactions and good antitumor activity in patients with primary or metastatic peritoneal cancer,so 5.0mg/m2 can be used as the recommended dose of Raltitrexed in HIPEC.2.The pharmacokinetics of Raltitrexed in HIPEC were proportional to dose and showed minimal systemic exposure and good tolerability compared to intravenous administration,deserving further study in a larger cohort.