Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis.

PURPOSE: Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or (90)Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. METHODS: We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. RESULTS: A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. CONCLUSION: SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials.

Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability.

Synergy between yttrium-90 (90Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with 90Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with 90Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with 90Y radioembolization for treatment of liver cancer.

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.

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.