Clinical Investigation Of ¹³¹I-chTNT In Differentiated Thyroid Carcinoma Patients With Lung Metastasis

Objective:In this study, we applied a new generation radioactive drug ¹³¹I-chTNT, to investigate the pharmaceutical dynamic features,in vivo stability charac- teristics, metabolizing products, local tissue , whole body distribution, estimated absorbed doses in tumor regions and adjacent essen- tial organs in ¹³¹I-unresponsive thyroid carcinoma patients with lung metastasis. Based on this,we evaluated the therapeutic effects of ¹³¹I-chTNT onto¹³¹I-un- responsive thyroid carcinoma patients, and confirmed the safety of application in conventional therapy and internal radiotherapy.Methods:We selected 10 ¹³¹I-unresponsive thyroid carcinoma patients with lung metastasis. The mean body weight was 59±11.5 kg. After intravenously injection of ¹³¹I-chTNT in 5 ml volume at a 5 MBq/kg dose, 1 ml of peripheral blood sample was obtained at different time points including 5 minutes, 0.5 hours, 4 hours, 24 hours, 48 hours, 60 hours, 72 hours, 144 hours and 168 hours, respectively. The 24-hour urine samples were also collected within the second week after injection. To elucidate pharmaceutical dynamic features, original data were transferred to injection dose percentage by MIRD recommended protocols, and fitted to time-radioactivity curve via single- and dual-chamber model. For detecting ¹³¹I-chTNT in vivo stability characteristics and metab- olizing products, urine samples from 10 patients post-injection 24 hours, 48 hours, 72 hours and 168 hours. At each time-point, within 0.5 hours after collection, 400 ul of urine sample and 1 ml of peripheral blood sample were centrifuged for 15 minutes within 0.5 hours before filtered through 0.22 um membrane and applied for HPLC analysis. For evaluating ¹³¹I-chTNT tissue distribution, tissue puncture was performed within 24 hours after ¹³¹I-chTNT injection, and spread for radioactive auto-imaging. We used continual imaging estimation to determine region of interest, for estimating nuclide uptake ratios in different organs at different time points. Further, we calculated essential organ absorbed doses by Olinda software package to determine internal radiation doses. To evaluate ¹³¹I-chTNT therapeutic effects on solid tumors, we chose 16 cases of ¹³¹I-unresponsive thyroid carcinoma patients with lung metastasis (average body weight 49±7.5 kg), administered single intravenous injection of ¹³¹I-chTNT at 29.6 MBq/kg (5 ml in volume), and checked solid tumor associated indexes following WHO criteria twelve weeks afterward. In addition, we recorded patient life signs before injection, 30 minutes, 6 hours and 24 hours post-injection, detected peripheral blood indexes of pre-treatment, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks and 10 weeks, as well as ALT, AST, BUN concentrations before treatment and 12 weeks after treatment. Peripheral blood chromosome aberration rates were detected by collecting 1 ml of blood sample one day before treatment, 1 week, 3 months and 6 months after treatment, which was applied for safety evaluation.Results:The ¹³¹I-chTNT serum concentration-time curve fitted the dual-chamber model, with a T1/2 as 65.28±14.83 hours, the areas under curve as AUC0-t 8.93±1.32 MBq·h/ml and AUC0-∞10.58±2.19 MBq·h/ml. After intravenous administration of ¹³¹I-chTNT, the urine excretion-time curve fitted single chamber model and the radionuclide urine elimination half time was 99±9.6 hours. Within the second week after injection, (31±9)% of initial dose was eliminated by urine pathway.HPLC analysis was applied to determine serum ¹³¹I-chTNT ratios, among which serum ¹³¹I-chTNT was over 95% after 24 hours, 48 hours, and 72 hours. Even after 168 hours, serum ¹³¹I-chTNT was still over (88±7)%. In urine samples of 24 hours, 48 hours, 72 hours and 168 hours, radioactive components were 100% derived from free ¹³¹I.Histological staining demonstrated that cell nucleus were stained in blue color while cell plasma, muscles, connective tissues, RBC were stained in red color. Calcium and microbes were stained in blue or dark blue. Radio auto-imaging showed that silver particles were mainly equally located beneath nuclei membrane, with few silver particles presenting in plasma.As for internal radioactivity distribution, after intravenous injection, ¹³¹I-chTNT concentrated mostly in lung and liver, but the least in brain. The tumor regions were less clearly scanned within 0.5 hours after injection, but gradually demonstrated on day 3 to day 7. The maximal radioactivity was achieved 24 hours after injection, while maximal T/N ratio (1.28-3.83) appeared on day 3 to day 7. As for 50-year average absorbed doses in major organs, bone marrow was 0.44-0.73 Gy, ovary 0.50-0.77 Gy, testis 0.38-0.58 Gy, kidney 1.58-3.81 Gy, liver 1.08-2.59 Gy and lung 1.61-2.93 Gy, with a total average absorbed dose of 40.23-79.47 Gy. According to average absorbed doses in tumor regions, 7-day dose accounted for about (65±4)% of the 50-year average, while 14-day dose was about (89±2)% of the 50-year average.Twelve weeks after ¹³¹I-chTNT injection, 3 cases among 16 ¹³¹I-unres- ponsive thyroid carcinoma patients with lung metastasis achieved complete release, 7 cases partially released, 2 cases no change and 4 cases suffered from progression. Before treatment, 14 cases showed normal hear rate of 60-96 beats per minute, and no remarkable changes were viewed after 30 minutes, 6 hours and 24 hours. One patient was diagnosed as sinus arrhythmia, and one patient CRBBB, 2 weeks after treatment, ECG examination showed no obvious changes. Before treatment, 30 minutes, 6 hours and 24 hours post-treatment, all the 16 patients maintained normal blood pressure, breathe rate and body temperature (36.8-37.2 oC), except one patient had a body temperature of 37.8 oC before treatment, but maintained after treatment. Before and after treatment, no patient showed adverse symptoms like chilly, shivering and so forth. After treatment, one case showed slightly gastro-intestinal upsets, decreased food appetites and one case showed rash one week post-treatment which disappeared after 2 weeks.All the 16 patients showed normal RBC, platelet, white cell and granulocyte counts. Two weeks after treatment, 2 patients experienced temporal decrease in white cell counts, to 3.9×109/L,3.5×109/L, which recovered after 4 weeks. Two weeks after treatment, one patient demonstrated declined platelets to 81×109/L, and 53×109/L till 4 weeks. Another 2 patients showed deceased platelets to 68×109/L and 75×109/L in 4th week after treatment, and recovered gradually to normal levels. Peripheral blood detections of pre-treatment, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks and 10 weeks post-treatment showed no significant changes in RBC, white cell and platelet counts.All the 16 patients showed normal liver and kidney functions, demonstrating no significant variations. Six patients had increased aberration rates, dual-centromere counts and ratios 7 days after treatment, which recovered to normal level after 3 months, and achieve pre-treatment levels 6 months after treatment.Conclusion:Fully clarified ¹³¹I-chTNT associated pharmaceutical dynamic features, in vivo stability characteristics, metabolizing products, as well as local tissue and whole body distribution, and estimate absorbed doses in tumor regions and adjacent essential organs in ¹³¹I-unresponsive thyroid carcinoma patients with lung metastasis, would aid corresponding application in clinical fields. Our primary results indicated remarkable short-term therapeutic effects, without overall or local region adverse effects. For future clinical application of ¹³¹I-chTNT, a larger amount of samples, as well as long-term observations and investigations are warranted. We believe that ¹³¹I-chTNT therapeutical strategy would be a novel promising conventional trial for ¹³¹I-unresponsive thyroid carcinoma patients with lung metastasis, or other post-treatment local necrosis.