title: Advanced unresectable hepatocellular carcinoma: new biologics as fresh ammunition or clues to disease understanding?
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is a prevalent malignancy associated with a guarded prognosis. At present, sorafenib is the only approved systemic therapy for patients with advanced disease. The effect of sorafenib on overall survival is modest and limited in time by the occurrence of drug resistance.
  
  
  RESULTS
  Together with the increasing knowledge of molecular pathways involved in HCC, targeted molecules have been developed and tested in first and second line following sorafenib. These include antiangiogenic drugs, as well as biologicals inhibiting cell proliferation and survival. Recent phase III trials investigated sunitinib, linifanib, brivanib and erlotinib, but none of them were found superior to sorafenib. New findings in mechanisms of drug resistance create opportunities in the treatment of sorafenib-refractory disease, with cMET inhibition as the most promising approach. This article reviews the pathways involved in HCC and their targets as well as potential strategies for drug development in the future.
  
  
  CONCLUSIONS
  Advanced HCC has been the subject of intensive clinical research following the success of sorafenib. Despite many failures, some agents show promising results in phase II trials. Targeting new pathways, using multidrug regimens and tailoring treatment guided by predictive markers should allow new successes.
authors.affiliation: Department of Hepatology, University Hospitals Leuven and Department of Clinical and Experimental Medicine, KU Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dekervel
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
mesh_terms: D001688:Biological Products / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D001688:Biological Products; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib