Second-line treatment options in hepatocellular carcinoma

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Donatella Marino MD, Clizia Zichi MD, Marco Audisio MD, Elisa Sperti MD, Massimo Di Maio MD

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For many years, sorafenib has been the only approved systemic treatment for advanced hepatocellular carcinoma (HCC). For over a decade, randomized controlled trials exploring the efficacy of new drugs both in first- and second-line treatment have failed to prove any survival benefit. However, in the past few years, several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In addition, early phase I and II trials have shown promising results of immunotherapy alone or in combination with tyrosine-kinase inhibitors or monoclonal antibodies in the same setting of patients. In this review, we will discuss the evidence on second-line options for HCC, focusing on the latest results that are currently refining the treatment scenario.

Keywords: cabozantinib, hepatocellular carcinoma, immunotherapy, ramucirumab, regorafenib, second line, treatment.

Citation: Marino D, Zichi C, Audisio M, Sperti E, Di Maio M. Second-line treatment options in hepatocellular carcinoma. Drugs in Context 2019; 8: 212577. DOI: 10.7573/dic.212577

Contributions: Donatella Marino performed the literature research and writing. Massimo Di Maio conceived the topic of the review and provided support in writing. All other authors reviewed all drafts of this manuscript and approved the final version. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosure and potential conflicts of interest: Donatella Marino, Clizia Zichi, Marco Audisio, and Elisa Sperti report no conflict of interest. Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Lilly, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, and Janssen. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at

Acknowledgements: None.

Funding declaration: There was no funding associated with the preparation of this article.

Copyright: Copyright © 2019 Marino D, Zichi C, Audisio M, Sperti E, Di Maio M. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Correct attribution: Copyright © 2019 Marino D, Zichi C, Audisio M, Sperti E, Di Maio M. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0.

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Correspondence: Massimo Di Maio, Department of Oncology, University of Turin, Turin, Italy; Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, Turin 10128, Italy.

Provenance: invited; externally peer reviewed.

Submitted: 19 December 2018; Peer review comments to author: 29 January 2019; Revised manuscript received: 4 March 2019; Accepted: 5 March 2019; Publication date: 10 April 2019.

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