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Cancer and Metastasis Reviews

, Volume 34, Issue 3, pp 497–509 | Cite as

Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma

  • Daniel H. Palmer
  • Phillip J. Johnson
Clinical

Abstract

Advanced hepatocellular carcinoma (aHCC) is a complex disease beset by underlying liver dysfunction and high molecular heterogeneity. Sorafenib, introduced in 2007, is considered the standard systemic therapy for aHCC, yet only a minority of patients show objective evidence of a response radiologically, and median overall survival is still under 1 year. Other targeted drugs for the treatment of aHCC have failed to reach their primary endpoints of improved/non-inferior overall survival in comparison with sorafenib in recent phase 3 trials. Toxicity was a significant problem, raising the question as to whether outcomes in aHCC trials are being hindered by high levels of adverse events (AEs), particularly in populations with underlying cirrhosis. This is true of six recently failed phase 3 studies involving sunitinib, erlotinib, linifanib, brivanib (two trials), and everolimus, as well as ongoing phase 2 and 3 trials of other drugs that work through similar molecular pathways. This article reviews these drugs’ toxicities, with a focus on AEs as a reason for their failure in phase 3 trials of patients with aHCC. We also review completed and ongoing phase 3 studies of combination therapies with sorafenib, as well as toxicities of many of the targeted agents in aHCC, including geographic/ethnic differences, measures of toxicity, and strategies to improve management.

Keywords

HCC Toxicity Sorafenib Nintedanib Sunitinib Brivanib 

Notes

Acknowledgments

Medical writing assistance was provided by Steven Tresker of Cactus Communications and funded by Boehringer Ingelheim. The authors retained full control of the manuscript content.

Conflict of interest

D.P. has acted in an advisory role and received educational grants and/or travel expenses from Boehringer Ingelheim, Bayer, Novartis, Abbott, and Pfizer.

Financial support

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Steven Tresker (Cactus Communications, Mumbai, India) during the preparation of this article. The authors did not receive payment for authorship of this article.

Authors’ contributions

Both authors substantially contributed to the conception and design of the review and critically revised the manuscript for important intellectual content. The authors retained control of manuscript content.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Molecular and Clinical Cancer Medicine, Institute of Translational MedicineUniversity of Liverpool and Clatterbridge Cancer CentreLiverpoolUK

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