Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization.

PURPOSE: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study. METHODS: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism. RESULTS: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity. CONCLUSION: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

In vitro demonstration of synergy/additivity between (188)rhenium and sorafenib on hepatoma lines: preliminary results.

BACKGROUND: Hepatocellular carcinoma is generally diagnosed at advanced stages, for which only palliative treatments are possible by intra-arterial route or by targeted therapies. Among these treatments, metabolic radiotherapy using (90)-yttrium or (188)Re and sorafenib are two options adopted in monotherapy. MATERIALS AND METHODS: We address the question of a possible synergy arising from the combination of these two treatments. Two primary malignant hepatoma cell lines, N1S1 (murine HCC) and HepG2 (human hepatoblastoma) were treated in media containing increasing concentrations of sorafenib with/without (188)Re to assess the cellular toxicities of each treatment alone and in combination. The combination index method was used to look for synergy or additivity. RESULTS: A synergistic advantage of a treatment combining (188)Re and sorafenib is shown in vitro on hepatoma cell lines. CONCLUSION: This combined approach is promising and now needs to be confirmed by more complex in vitro models integrating the tumoral stroma, as well as by in vivo studies.

(188)Re-SSS/Lipiodol: Development of a Potential Treatment for HCC from Bench to Bedside.

Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with ß-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugène Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 (E(ßmax) = 2.1 MeV) for the treatment of HCC. The major "milestones" of this development, from the first syntheses to the recent first injection in man, are described.

Optimization of hepatocarcinoma uptake with radiolabeled lipiodol: development of new lipiodol formulations with increased viscosity.

The aim of this study was to develop new Lipiodol formulations with increased viscosities to augment Lipiodol embolic effect and optimize efficiency of radiolabeled Lipiodol in hepatocarcinoma treatments. New Lipiodol formulations consist of Lipiodol mixtures with different stearic acid concentrations (0.8%, 1.3%, and 1.8%). These formulations were fully characterized in vitro (viscosity, rheologic profiles) and labeled with 99mTc. Their viscosities at 20°C are 54, 60, and 67cP respectively, versus 45cP for Lipiodol ultra-fluide. Second, their biodistribution profiles were studied in vivo, at 24 and 72 hours, in hepatoma-bearing rats, and compared to control group (99mTc-Lipiodol). Biodistribution at 24 hours show a Gaussian tumor uptake profile with a maximum obtained with 1.3% stearic acid, and a tumor uptake superior to control group (+67%) (p<0.05). At 72 hours, optimal tumor uptake is reached with the 0.8% formulation, with 89% increase compared with control group (p<0.05). Moreover, we show a tendency to the decrease of pulmonary uptake for the new formulations at 24 hours and 72 hours. These results suggest a correlation between viscosity and Lipiodol tumor uptake. The new 0.8% stearic acid/Lipiodol formulation appears to be the optimized formulation for Lipiodol treatments of hepatocarcinoma, since it leads to a significant increase of tumor uptake at 72 hours and possibly to a decrease of undesirable pulmonary effects.

Reduction of ß-radiation exposure during preparation of 188Re-labelled Lipiodol for hepatocellular carcinoma treatment.

Rhenium-188 (188Re) is of widespread interest for treating various diseases because of its attractive physical and chemical properties. The routine preparation of therapeutic doses of 188Re-labelled tracers can result in significant radiation exposure to the operator. We studied the impact of automating the preparation of 188Re-Lipiodol on the radiochemist's exposure, as well as the importance of the model of syringe shielding. To monitor radiation exposure continuously readable electronic personal dosimeters were used. Thermoluminescence dosimeters were fixed to the probable most exposed fingers of the radiochemist during preparation of the radiotracer and during the syringing. Dose rates were measured using a Babyline. Automation of the synthesis reduced personal dose equivalents from 2.60±4.35 to 1.61±1.20 µSv/GBq [Hp(10)] and from 38.37±55.28 to 21.84±16.14 µSv/GBq [Hp(0.07)]. Dose to the extremities was also reduced (-80% for the right hand; -58% for the left one). The Lemer-Pax PSWG syringe shield led to a slightly lower dose to the hands compared with the Medisystem (1.1±0.27 vs. 1.34±0.6 mSv/GBq for the right finger). Automation of the synthesis leads to a significant decrease in radiation exposure to the operator. The Lemer-Pax PSWG syringe shield provides better hand protection than the smaller Medisystem Mediclic.

Automation of labelling of Lipiodol with high-activity generator-produced 188Re.

This work describes optimisation of the kit formulation for labelling of Lipiodol with high-activity generator-produced rhenium-188. Radiochemical purity (RCP) was 92.52±2.3% and extraction yield was 98.56±1.2%. The synthesis has been automated with a TADDEO module (Comecer) giving a mean final yield of 52.68±9.6%, and reducing radiation burden to the radiochemist by 80%. Radiolabelled Lipiodol ((188)Re-SSS/Lipiodol) is stable for at least 7 days (RCP=91.07±0.9%).

Increased Lipiodol uptake in hepatocellular carcinoma possibly due to increased membrane fluidity by dexamethasone and tamoxifen.

INTRODUCTION: Lipiodol is used as a vector for chemoembolization or internal radiotherapy in unresectable hepatocellular carcinomas (HCCs). The aim of this study is to improve the tumoral uptake of Lipiodol by modulating membrane fluidizing agents to optimize the effectiveness of Lipiodol vectorized therapy. METHODS: The effect of dexamethasone and tamoxifen on membrane fluidity was studied in vitro by electron paramagnetic resonance applied to rat hepatocarcinoma cell line N1S1. The tumoral uptake of Lipiodol was studied in vivo on rats with HCC, which had been previously treated by dexamethasone and/or tamoxifen, after intra-arterial administration of (99m)Tc-SSS-Lipiodol. RESULTS: The two molecules studied here exhibit a fluidizing effect in vitro which appears dependent on time and dose, with a maximum fluidity obtained after 1 hr at concentrations of 20 µM for dexamethasone and 200 nM for tamoxifen. In vivo, while the use of dexamethasone or tamoxifen alone tends to lead to increased tumoral uptake of Lipiodol, this effect does not reach levels of significance. On the other hand, there is a significant increase in the tumoral uptake of (99m)Tc-SSS-Lipiodol in rats pretreated by both dexamethasone and tamoxifen, with a tumoral uptake (expressed in % of injected activity per g of tumor) of 13.57 ± 3.65% after treatment, as against 9.45 ± 4.44% without treatment (P<.05). CONCLUSIONS: Dexamethasone and tamoxifen fluidify the N1S1 cells membrane, leading to an increase in the tumoral uptake of Lipiodol. These drugs could be combined with chemo-Lipiodol-embolization or radiolabeled Lipiodol, with a view to improving the effectiveness of HCCs therapy.