Expert consensus on clinical trials for use of systemic therapy in patients with hepatocellular carcinoma undergoing surgical and locoregional therapies

Background Advances in systemic therapy for advanced hepatocellular carcinoma (HCC) have fuelled a growing interest in evaluating these therapies in earlier stages of disease. However, trial design remains challenging due to the marked clinical and biological heterogeneity of early-stage and intermediate-stage HCC. Objective A multidisciplinary group of cancer experts was convened by the HCC-Live Consortium to discuss inclusion criteria, risk stratification, treatment arms and appropriate endpoints of trials evaluating perioperative and combination therapies in patients with HCC. Design Consensus statements were defined as those obtaining >70% approval by panellists. Results The panel achieved consensus regarding nine consensus statements for neoadjuvant or perioperative systemic therapy and nine statements for combination locoregional plus systemic therapy. Statements emphasised recruiting carefully selected patient populations, employing treatment strategies and duration that balance efficacy with safety and using clinically relevant endpoints. Trials evaluating neoadjuvant/perioperative approaches should include patients at the highest risk of recurrence, with a recommended primary outcome of 2-year event-free survival using restricted mean survival time. Trials evaluating combination therapies should include a homogeneous patient population and use an appropriate comparator arm that aligns with clinical practice. Specifically, systemic therapy was the recommended comparator arm for patients with larger tumour burden and locally advanced disease. The recommended primary outcome for combination trials was progression-free survival and overall survival, with an alpha-recycling strategy. Secondary endpoints are essential to inform clinical applicability. Conclusion Optimal design of HCC trials is important to rigorously evaluate the role of systemic therapy in patients undergoing surgical resection or in combination with locoregional therapy.

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Journal
Gut
Published
2026-09-24
DOI
https://doi.org/10.1136/gutjnl-2026-339505
Primary Topic
Hepatocellular Carcinoma Treatment and Prognosis
Type
article
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article

Expert consensus on clinical trials for use of systemic therapy in patients with hepatocellular carcinoma undergoing surgical and locoregional therapies

David James Pinato, Julie K. Heimbach, Nina Niu Sanford, Amit G. Singal et al.
Gut
Hepatocellular Carcinoma Treatment and Prognosis
article

Expert consensus on clinical trials for use of systemic therapy in patients with hepatocellular carcinoma undergoing surgical and locoregional therapies

David James Pinato, Julie K. Heimbach, Nina Niu Sanford, Amit G. Singal, Robin Kate Kelley, Adam Yopp, Parissa Tabrizian, Robert J. Lewandowski, Neehar D. Parikh, Anthony El- Khoueiry, Ruitao Lin, Josep Maria Llovet, Neil J. Mehta, Arndt Vogel, Siddharth A. Padia, Edward Kim, Richard Finn, Karim Halazun, Riad Salem, Mark Yarchoan, Hop S Tran Cao, Augusto Villanueva, Vatche G Agopian, Anjana Pillai, Garcia-Reyes Kirema, Gonzalo Sapisochin, Adam M Burgoyne
article en

Abstract

Background Advances in systemic therapy for advanced hepatocellular carcinoma (HCC) have fuelled a growing interest in evaluating these therapies in earlier stages of disease. However, trial design remains challenging due to the marked clinical and biological heterogeneity of early-stage and intermediate-stage HCC. Objective A multidisciplinary group of cancer experts was convened by the HCC-Live Consortium to discuss inclusion criteria, risk stratification, treatment arms and appropriate endpoints of trials evaluating perioperative and combination therapies in patients with HCC. Design Consensus statements were defined as those obtaining >70% approval by panellists. Results The panel achieved consensus regarding nine consensus statements for neoadjuvant or perioperative systemic therapy and nine statements for combination locoregional plus systemic therapy. Statements emphasised recruiting carefully selected patient populations, employing treatment strategies and duration that balance efficacy with safety and using clinically relevant endpoints. Trials evaluating neoadjuvant/perioperative approaches should include patients at the highest risk of recurrence, with a recommended primary outcome of 2-year event-free survival using restricted mean survival time. Trials evaluating combination therapies should include a homogeneous patient population and use an appropriate comparator arm that aligns with clinical practice. Specifically, systemic therapy was the recommended comparator arm for patients with larger tumour burden and locally advanced disease. The recommended primary outcome for combination trials was progression-free survival and overall survival, with an alpha-recycling strategy. Secondary endpoints are essential to inform clinical applicability. Conclusion Optimal design of HCC trials is important to rigorously evaluate the role of systemic therapy in patients undergoing surgical resection or in combination with locoregional therapy.

Gut
Northwestern University (US), Institució Catalana de Recerca i Estudis Avançats (ES), Hebron University (PS), Mount Sinai Health System (US), Mount Sinai Hospital (US), University Health Network (CA), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), University of California, Los Angeles (US), University of California, San Francisco (US), University of Michigan (US), UCLA Medical Center (US), Toronto General Hospital (CA), WinnMed (US), Princess Margaret Cancer Centre (CA), University of California San Diego (US), University of Chicago (US), Southwestern Medical Center (US), USC Norris Comprehensive Cancer Center (US), Vall d'Hebron Hospital Universitari (ES), Northwestern Medicine (US), Miami Transplant Institute (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Sidney Kimmel Comprehensive Cancer Center (US), Southwestern Medical Center (US), Imperial College London (GB), The University of Texas Southwestern Medical Center (US), University of California, Berkeley (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 13%
Hepatocellular Carcinoma Treatment and Prognosis
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