[Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy]. / Scelte terapeutiche e trattamento con sorafenib nell'epatocarcinoma: analisi finale dello studio GIDEON in Italia.

INTRODUCTION: Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. METHODS: Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. RESULTS: In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. DISCUSSION: The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.

Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment.

BACKGROUND & AIMS: The study aimed to evaluate the tissue expression of molecules involved in intracellular signalling pathways as predictors of response to sorafenib in advanced hepatocellular carcinoma (HCC). METHODS: We considered 77 patients enrolled into three prospective trials of sorafenib treatment for whom pretreatment tumour tissue was available. The tissue expression of ß-catenin, glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK), phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) and vascular endothelial growth factor receptor-2 (VEGFR-2) was analysed by immunostaining. Stains were scored semiquantitatively and compared with a reference group of 56 untreated HCCs. RESULTS: Overall, the expression of antigens was comparable between treated and untreated patients. Shorter progression-free survival (PFS) and overall survival (OS) were associated with increased pERK staining (≥ 2+ scores) (PFS: 75th percentile 4.4 vs 8.4 months; P = 0.01; OS: 75th percentile 7.0 vs 15.0 months; P = 0.005) and VEGFR-2 staining (≥ 2+ scores) (PFS: 75th percentile 3.8 vs 7.0 months; P = 0.039; OS: 75th percentile 6.3 vs 15.0 months; P = 0.004). At multivariate analysis, both pERK and VEGFR-2 staining maintained an independent effect on OS (HR 2.09; 95% CI, 1.13-3.86, P = 0.019 and HR 2.28; 95% CI, 1.13-4.61, P = 0.021 respectively). No effect was observed for the other tested biomarkers. CONCLUSIONS: Elevated tissue expression of pERK and VEGFR-2 was predictive of poor outcome in advanced HCC treated with sorafenib.

Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.

PURPOSE: Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. PATIENTS AND METHODS: Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). RESULTS: Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). CONCLUSION: OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Hepatic intra-arterial cetuximab in combination with 5-fluorouracil and cisplatin as salvage treatment for sorafenib-refractory hepatocellular carcinoma.

BACKGROUND: Sorafenib is the only therapy approved for advanced hepatocellular carcinoma no longer eligible for transcatheter arterial chemoembolization. Hepatic intra-arterial chemotherapy has been shown to be an effective and safe therapy for advanced hepatocellular carcinoma. Cetuximab has been administered intravenously to patients with advanced hepatocellular carcinoma, showing encouraging results in terms of its safety and toxicity profile. AIM: Our purpose was to evaluate the safety and feasibility of hepatic arterial chemotherapy with cetuximab, cisplatin and 5-fluoruracil for patients with advanced hepatocellular carcinoma, not responsive or not eligible for sorafenib therapy. PATIENTS AND METHODS: From January 2010 to January 2011, 12 patients received a 2-day course of chemotherapy consisting of repeated daily hepatic arterial administration of 20 mg of cisplatin as 2-h infusion, 5-fluorouracil at 500 mg/m(2) as 5-h infusion and cetuximab 500 mg/m(2) as 12-h infusion. Cycles were repeated every 14 days. RESULTS: After a mean of four months of therapy, computed tomography revealed five partial responses, five cases of stable disease and two of progressive disease. The toxicity profile was favourable, with no G4 gastrointestinal, hematologic or skin side-effects, or severe deterioration of liver function. CONCLUSION: Hepatic intra-arterial chemotherapy with cetuximab is a safe and feasible treatment for advanced hepatocellular carcinoma, with promising results in patients with initial poor prognosis.