Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2016; 8(2): 173-185
Published online Feb 15, 2016. doi: 10.4251/wjgo.v8.i2.173
Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis?
Kiruthikah Thillai, Paul Ross, Debashis Sarker
Kiruthikah Thillai, Paul Ross, Debashis Sarker, Department of Medical Oncology, Guy’s and St Thomas NHS Trust, London SE1 9RT, United Kingdom
Kiruthikah Thillai, Debashis Sarker, Division of Cancer Studies, King’s College London, Guy’s Hospital, London SE1 9RT, United Kingdom
Paul Ross, Debashis Sarker, Institute of Liver Studies, King’s College Hospital NHS Trust, London SE5 9RS, United Kingdom
Author contributions: All authors equally contributed to this paper with conception and design of the manuscript, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Supported by Department of Health via the National Institute for Health Research Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Debashis Sarker, Division of Cancer Studies, King’s College London, Guy’s Hospital Campus, Great Maze Pond, London Bridge, London SE1 9RT, United Kingdom. debashis.sarker@kcl.ac.uk
Telephone: +44-20-71884260 Fax: +44-20-71880919
Received: August 8, 2015
Peer-review started: August 11, 2015
First decision: September 22, 2015
Revised: November 16, 2015
Accepted: December 9, 2015
Article in press: December 11, 2015
Published online: February 15, 2016
Processing time: 179 Days and 2.8 Hours
Abstract

Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.

Keywords: Hepatocellular carcinoma; Molecular targets; Genomics; Sorafenib; Tyrosine kinase inhibitors

Core tip: This review discusses the current drug therapy landscape for advanced hepatocellular carcinoma, in particular the reasons for failure of several clinical trials of molecularly targeted therapy and future directions of research to address these problems.