Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

Yung-Yeh Su; Yi-Sheng Liu; Chin-Fu Hsiao; Chiun Hsu; Li-Tzong Chen

doi:10.2147/JHC.S220978

Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

J Hepatocell Carcinoma. 2022 Jun 2:9:517-536. doi: 10.2147/JHC.S220978. eCollection 2022.

Authors

Yung-Yeh Su^#^{1

2

3}, Yi-Sheng Liu^#⁴, Chin-Fu Hsiao⁵, Chiun Hsu^{6

7

8}, Li-Tzong Chen^{1

2

9

10}

Affiliations

¹ National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
² Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Department of Medical Imaging, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan.
⁵ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁶ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.
⁸ National Taiwan University Cancer Center, Taipei, Taiwan.
⁹ Department of Internal Medicine, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁰ Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

^# Contributed equally.

Abstract

Intermediate-stage hepatocellular carcinoma (HCC) consists of heterogeneous groups of patients in terms of tumor burden and organ function reserves. Although liver-directed therapy (LDT), including trans-catheter arterial chemoembolization, radiofrequency ablation or even surgical resection, is the recommended frontline treatment modality, intrahepatic and distant failures are common. The recent advances in systemic treatment, notably the introduction of immune checkpoint inhibitor (ICI)-based therapy, have significantly improved the objective tumor response rate, quality of response and overall survival in patients with recurrent and advanced HCC. Whether the combination of systemic treatment and LDT can further improve the outcome of patients with intermediate-stage HCC is currently being extensively evaluated. In this article, the recent clinical trials incorporating different ICI-based combinations with different LDT for intermediate-stage HCC were reviewed focusing on trial design issues, including patient selection, endpoint definition, and biomarker development. The strength and caveats of different combination strategies and novel biomarker development were discussed.

Keywords: biomarker; immunotherapy; liver-directed therapy.

Publication types

Review

Grants and funding

This study is funded by Kaohsiung Medical University (grant number: KMU-TC109A04-0) and Ministry of Health and Welfare, Taiwan (grant number: MOHW111-TDU-B-221-014007).