Abstract
No systemic therapy had been proven effective in patients with advanced hepatocellular carcinoma (HCC) until 2007, when a large randomized trial with sorafenib demonstrated a clinically relevant prolongation of survival. Currently, sorafenib represents standard treatment for patients with advanced HCC and well-preserved liver function, whilst the evidence about its effectiveness in patients with more severe liver impairment is less robust. A randomized trial to demonstrate the efficacy of sorafenib in Child-Pugh B patients with advanced HCC is currently ongoing. In the meantime, several trials are testing the role of sorafenib in early HCC (as adjuvant treatment after potentially curative loco-regional therapies) and in intermediate stage (exploring different modalities of integration of sorafenib with trans-arterial chemo-embolization). The results of all these trials will better define the potentiality and the boundaries of use of sorafenib in HCC patients.
Highlights
Sorafenib (Nexavar®, Bayer/Onyx Pharmaceuticals, Figure 1) is an orally active inhibitor of multiple receptor tyrosine kinases involved in pathways relevant for tumor growth and angiogenesis, including Raf 1, B-Raf, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor β [1]
Despite the interesting rationale, study results are not sufficient to demonstrate any advantage supporting sorafenib continuation beyond progression, and evidence-based approach suggests that best supportive care should remain the treatment for patients assigned to control arm in randomized trials of second-line treatments
Treatment of Child-Pugh B hepatocellular carcinoma (HCC) patients remains an unmet need, due to the absence of alternative treatments, and no therapeutic chance is offered to these patients
Summary
Sorafenib (Nexavar®, Bayer/Onyx Pharmaceuticals, Figure 1) is an orally active inhibitor of multiple receptor tyrosine kinases involved in pathways relevant for tumor growth and angiogenesis, including Raf 1, B-Raf, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor β [1]. The SHARP study [6] was a randomized phase 3 trial comparing sorafenib (at the dose of 400 mg twice daily) versus placebo in patients with advanced HCC. In the trial, which included a population of patients with relatively preserved liver function (Child-Pugh class A), the use of sorafenib was associated, at the second planned interim analysis, with a statistically significant and clinically relevant benefit in terms of survival over placebo (median 10.7 months versus 7.9 months; hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.55–0.87; p < 0.001). A similar randomized phase 3 comparison of sorafenib versus placebo was conducted in Asian patients with Child-Pugh class A [7], showing a similar benefit in terms of survival in 271 patients with advanced HCC (HR 0.68, 95% CI 0.50−0.93, p = 0.014)
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