Treatment Hepatocellular Carcinoma With ¹³¹I-Labeled-Metuximab (Licartin) Combination With Transcatheter Arterial Chemoembolization (TACE): A Clinical Study

Part 1Pharmacokinetics of Treatment Hepatocellular Carcinoma with ¹³¹I-Labeled-Metuximab Combination with TACEObjectiveTo study pharmacokinetics of ¹³¹I-labeled-metuximab(Licartin) combinaton with transcatheter arterial chemoembolization(TACE) for treatment of hepatocellular carcinoma(HCC).Materials and methodsLicartin(27.75MBq/kg) and the mixture of anticancer drug and Lipiodol with interval 20 minutes later were administered to 29 patients with HCC via a transfemoral catheter.After the Licartin was administrated,the pharmacokinetic and biodistribution data were collected by means of venous blood samples,urine collections,and 4 or 5γ-scintigraphies(SPECT) over 7days.The pharmacokinetic parameters were determined from integration of the blood radioactivity-time curves using the SPSS 12.0 software.The tumor-no-tumor ratio(T/NT) was calculated by ROI(Regions of interest).ResultsA mean administered activity was 1.865GBq(1.47-2.23GBq) in 42 treatment sessions.The blood radioactivity-time curves integrated by SPSS 12.0 software followed the dynamics two-compartment model,t_1/2a1.96±1.65h,t_1/2α19.07±5.91h, t_1/2β57.09±10.92h,C_max2.113(10⁹min^-1·L^-1),AUC1.302±0.3735(10¹¹h·min^-1·L^-1).The urine radioactivity was 52.2%of administration dosage during 144h after administration.SPECT scans of the whole body showed the significant accumulation of the radioconjugate in liver tumor and faint uptake in other organs until 14 days (n=15).From 2.88 to 1.64 were observed in tumor-to-liver ratio at 3h to 168h(n=7). Compared with those in the treatment with Lcartin alone,the t test showed a significant difference of biological half time and C_max in Lcartin combination with TACE(p＜0.001),while no significant difference of AUC between them(p=0.252).Conclusions1 Licartin combination with TACE for treatment of HCC is helpful to significantly accrete the radioconjugate in liver tumor,achieve the targeting of tumor with high dose rate and protect normal organs from radiotoxictiy.2 Pharmacokinetics of Licartin combination with TACE for treatment of HCC followed the dynamic two-compartment mode.Bioavailability and metabolism of Licartin in human body has not changed.Part 2Dosimetry of Treatment Hepatoeellular Carcinoma with ¹³¹I-Labeled-Metuximab Combination with TACEObjectiveTo assess the radiation absorbed dose to organs of ¹³¹I-Labeled-Metuximab (Licartin) and transarterial chemoembolization(TACE) in the treatment of heptaocellular carcinoma(HCC).Materials and methodsLicartin(27.75MBq/kg) and the mixture of anticancer drug and Lipiodol with interval 20 minutes later were administered to 29 patients with HCC via a transfemoral catheter.The pharmacokinetic and dosimetric data were collected by means of venous blood samples,urine collections,and 4 or 5γ-scintigraphies (SPECT) over 7days.The total amount of activity in percent of injected activity(%ID) of main organ and the total body were calculated by ROI(Regions of interest).The cumulated activity was determined from integration of the time-%ID curves using the SPSS 12.0 software.Absorbed doses to organ and red marrow were estimated according to the MIRD(Medical Internal Radiation Dose) formalism and blood-based marrow estimation with a red marrow-to-blood activity concentration ratio.The tumor-no tumor ratio was calculated as well.ResultsA mean administered activity was 1.865GBq(1.47-2.23GBq).SPECT scans showed the significant accumulation of the radioconjugate in liver tumor and faint uptake in other organs until 14 days.Organ absorbed Dose(n=12):The total absorbed dose to the liver,spleen,thyroid,lungs,kidney and total-body was 3.19±1.0Gy, 3.65±2.4Gy,3.61±2.4Gy,0.97±0.23Gy,0.96±0.35Gy and 0.57±1.6Gy(mean±SD), with 0.55±0.09 Gy to the red marrow(n=7),respectively.From 2.88 to 1.64 were observed in tumor-to-liver ratio at 3h to 168h.Conclusions1 Licartin combination with TACE for treatment of HCC prolonged the resident time of radionuclide within targeting tumor and achieved the higher tumor-no tumor ratios and promised the maximum internal absorbed dose delivered to tumor.2 Internal absorbed dose estimated by the organ mass fixed and blood undirected way,absorbed dose to the major organ and red marrow were far more than the limit radiation dose,promised the tolerant and safety of patient.Part 3Treatment Hepatocellular Carcinoma with Licartin Combination with TACE: A clinical studyObjectiveTo evaluate safety,toxicity and response of of ¹³¹I-Labeled-Metuximab(Licartin) combination with transcatheter arterial chemoembolization(TACE) in the treatment of heptaocellular carcinoma(HCC).Materials and methodsPatients with unresected HCC,diagnosed by means of CT or MRI,α-fetoprotein (AFP) level or biopsy,testing trial of Metuximab was negative,received Lugol's liquid for up to 10 days until discharge.Licartin(total activity of 27.72 MBq measured by kg) and the mixture of anticancer drug and Lipiodol with interval 20 minutes later were administered via a hepatic arterary.The pharmacokinetic and dosimetric data were collected by means of venous blood samples,urine samples and SPECT over 7 days.Absorbed doses to the various organs were calculated according to the MIRD formalism,using the SPSS 12.0 software.The toxicity was assessed until 4 week after administration by means of the Common Toxicity Criteria scale. The response was evaluated on CT or MRI and by monitoring of AFP.Patients without evidence of sever adverse event were eligible for repetitive treatment sessions with 4 week interval.ResultsTwenty-nine patients with HCC(26 men and 3 women),median age was 52 years(range,31-70 years),underwent 42 treatment sessions between October,2007 and September,2008.According to Child-Pugh classification system,there were 26 patients with Child-Pugh A and 3 patients with Child-Pugh B.There were no significant differences of T/NT on SPECT after treatment 5 day between two group seperated by tumor size(p=0.275).According to NCI-CTC scales,3 grade adverse events included fatigue,fever,vomiting,tumor pain,increase in billirubine and ALT, decrease in WBC and PLT and HB,whereas 4 grade was decrease PLT.Compared with those in the base line before treatment,Wilcoxon test showed a significantly improved WBC,PLT,HB,TBIL,ALT level and Child-Pugh grades in 1 week after treatment or 4 week later(p=0.004,0.027,0.033,0.033,0.036).Except for HB,TBIL, ALT and Child-Pugh grades,there were no significant differences of WBC and PLT level between 1 week after treatment and 4 week later(p=0.211,0.18).Compared with the base line before treatment,paired-smpals t test showed no significant difference of AFP level 4 weeks later(p=0.114).Response assessment showed 3 cases of partial response,disease stabilization in 23cases,and progressive disease in 3 cases.With Kaplan-Meier method,the 6 month and 1 year overall survival rates were 72.41%and 58.62%,respectively.The mean TTP was 5.49±0.58 months,and the mean OS was 11.57±1.01 months.Log-rank test showed a significant difference in the 1 year survival rates betweenâ…¢stage andâ…£stage patients(p=0.0254),1 year rates in theâ…¢stage patients was 81.82%,while those in theâ…£stage paitents was 44.44%.Conclusions1 Lcartin combination with TACE for treatment of HCC afforded more selective tumor targeting and enhancement of the therapeutic radiation dose delivered and the effect ionizing radiation by chemotherapy to be radiosensitizers and synergistic properties added,achieved more survival benefit for paitnet from the treatment HCC with internal radiation therapy.2 HCC with multiply tumors nodules sized＜3 cm may be the best choice for treatment with Lcartin combination with TACE.3 Lcartin combination with TACE for treatment of HCC is tolerated relatively well by patients with Child-Pugh A scale and tumor embolization in the branch of portal vein.4 An acceptable toxicity and safety to patients treated with Lcartin combination with TACE on the current dose of Licartin at 27.75MBq/kg.