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  • Review Article
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Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 18, pages 293–313 (2021)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality and has an increasing incidence worldwide. Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of 50–60% of HCCs. Radiofrequency is the mainstay for local ablation at early stages and transarterial chemoembolization (TACE) remains the standard treatment for intermediate-stage HCC. Other local ablative techniques (microwave ablation, cryoablation and irreversible electroporation) or locoregional therapies (for example, radioembolization and sterotactic body radiation therapy) have been explored, but have not yet modified the standard therapies established decades ago. This understanding is currently changing, and several drugs have been approved for the management of advanced HCC. Molecular therapies dominate the adjuvant trials after curative therapies and combination strategies with TACE for intermediate stages. The rationale for these combinations is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitors and tyrosine kinase inhibitors boost immunity and prime tumours for checkpoint inhibition. In this Review, we analyse data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examine the expected effects of combinations with systemic treatments. We also discuss trial design and benchmarks to be used as a reference for future investigations in the dawn of a promising new era for HCC treatment.

Key points

  • Locoregional treatments for hepatocellular carcinoma (HCC) are aimed at eliminating or reducing tumoural viability, delaying progression and ultimately extending overall survival; options include local ablative techniques and intra-arterial techniques.

  • Radiofrequency ablation is considered the standard treatment option among local ablative techniques for very early stage tumours (<2 cm) and for tumours at early stages not suitable for surgical therapies.

  • Transarterial chemoembolization is established as the standard of care for intermediate-stage lesions (multinodular liver-only disease in asymptomatic patients with compensated liver function) leading to median survivals of 25–30 months.

  • The role of radioembolization and stereotactic body radiotherapy is still to be defined, and further trials are required to delineate a patient subset deriving benefit from these treatments.

  • No systemic therapy tyrosine kinase inhibitor has been able to improve survival when tested in combination with locoregional treatment but there is rationale for combination therapies with immunotherapy in HCC.

  • Single-agent and combination therapies are being investigated in randomized controlled trials both in an adjuvant setting and combined with intra-arterial therapies, and results are expected to change HCC management within the next 5 years.

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Fig. 1: Percutaneous local ablative techniques for the treatment of HCC.
Fig. 2: Devices for intra-arterial therapy.
Fig. 3: Outcomes of randomized controlled trials assessing TACE.
Fig. 4: Rationale for combining locoregional therapies with immune therapies.
Fig. 5: Rationale for combining TKIs with immune therapies.
Fig. 6: Rationale for combining VEGF inhibitors with immune therapies.

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Acknowledgements

J.M.L is supported by European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref. 667273-2), EIT Health (CRISH2, Ref. 18053), Accelerator Award (CRUCK, AEEC, AIRC) (HUNTER, Ref. C9380/A26813), National Cancer Institute (P30-CA196521), U.S. Department of Defense (CA150272P3), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2016-76390) and the Generalitat de Catalunya/AGAUR (SGR-1358). P.K.H. is supported by the fellowship grant of the German Research Foundation (DFG HA 8754/1-1). T.F.G. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. T.M. is supported by the NIHR UCLH Biomedical Research Centre.

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Authors and Affiliations

  1. Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Josep M. Llovet & Philipp K. Haber

  2. Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain

    Josep M. Llovet

  3. Institució Catalana d’Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    Josep M. Llovet

  4. Radiology Department Gustave Roussy Cancer Center, Vilejuif, France

    Thierry De Baere

  5. University Paris-Saclay, Saint-Aubin, France

    Thierry De Baere

  6. Division of Gastroenterology and Hepatology, Surgery and Interventional Radiology in Northwestern University, Chicago, IL, USA

    Laura Kulik

  7. Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Tim F. Greten

  8. Deptartment of Oncology, University College London Cancer Institute, London, UK

    Tim Meyer

  9. Deptartment of Oncology, Royal Free Hospital, London, UK

    Tim Meyer

  10. Department of Radiology, University of Pisa School of Medicine, Pisa, Italy

    Riccardo Lencioni

  11. Miami Cancer Institute, Miami, FL, USA

    Riccardo Lencioni

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Competing interests

J.M.L. receives research support from Bayer HealthCare Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb, Eisai Inc. and Ipsen. He has also received consulting fees from AstraZeneca, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Can-Fite, Celsion Corporation, Eisai Inc., Eli Lilly, Glycotest, Ipsen, Merck, Nucleix, Roche and Sirtex. T.D.B. has received research support from Boston-Scientific Galil, and Terumo, and advisory board fees from AstraZeneca, Boston-Scientific, Esai, Guerbet and Terumo. L.K. receives consulting fees from Bayer, Eisai, Exelixis, Gilead and Merck, and research funding from Glycotest and TARGET-HCC. T.M. has received advisory board fees from AstraZeneca, BTG, Eisai, Ipsen, Roche and Tarveda. The remaining co-authors declare no competing interests.

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Llovet, J.M., De Baere, T., Kulik, L. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 18, 293–313 (2021). https://doi.org/10.1038/s41575-020-00395-0

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