Treatment Strategy for Intermediate-Stage Hepatocellular Carcinoma: Transarterial Chemoembolization, Systemic Therapy, and Conversion Therapy

Simple Summary Systemic therapy for advanced-stage hepatocellular carcinoma (HCC) is undergoing major changes owing to the advancements made in molecular-targeted therapies and immune checkpoint inhibitors (ICIs). Although transarterial chemoembolization has been used as the standard treatment for intermediate-stage HCC, it has recently included molecular-targeted drugs and ICIs. As intermediate-stage HCC encompasses a wide variety of HCCs, the appropriate regimen to be used and the order of drug administration, including the use of anti-angiogenic inhibitors, remain controversial. This review discusses treatment strategies for intermediate-stage HCC considering the background of progress in the treatment of advanced-stage HCC. Abstract Transarterial chemoembolization (TACE) has been standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, all intermediate-stage HCC patients did not benefit from TACE treatment because intermediate-stage HCC encompasses a wide variety of HCCs. Owing to remarkable progress in systemic therapy, including molecular-targeted therapy for advanced-stage HCC, the standard treatment of HCC has recently shifted to systemic therapy. However, it remains controversial as to which treatment should be initially performed for intermediate-stage HCC. In addition, although curative treatment can be considered when the tumor shrinks, the timing of conversion therapy remains uncertain. This review summarizes the advances of HCC treatment and discusses treatment strategies for intermediate-stage HCC.

[1]  M. Kudo,et al.  IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study , 2022, Liver Cancer.

[2]  M. Kudo Implications of the TACTICS Trial: Establishing the New Concept of Combination/Sequential Systemic Therapy and Transarterial Chemoembolization to Achieve Synergistic Effects , 2022, Liver Cancer.

[3]  Yu Cheng,et al.  Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH) , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  A. Zhu,et al.  Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. , 2022, The Lancet. Oncology.

[5]  M. Kudo,et al.  Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. , 2022, NEJM evidence.

[6]  M. Kudo,et al.  Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma , 2022, Liver Cancer.

[7]  Y. Hiasa,et al.  Association of early bevacizumab interruption with efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: A landmark analysis , 2022, Hepatology research : the official journal of the Japan Society of Hepatology.

[8]  M. Kudo,et al.  Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. , 2021, The Lancet. Oncology.

[9]  M. Kudo,et al.  Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC‐B stage patients classified as beyond up to seven criteria – Multicenter analysis , 2021, Hepatology research : the official journal of the Japan Society of Hepatology.

[10]  J. Bruix,et al.  BCLC strategy for prognosis prediction and treatment recommendation Barcelona Clinic Liver Cancer (BCLC) staging system. The 2022 update. , 2021, Journal of hepatology.

[11]  M. Kudo A Novel Treatment Strategy for Patients with Intermediate-Stage HCC Who Are Not Suitable for TACE: Upfront Systemic Therapy Followed by Curative Conversion , 2021, Liver Cancer.

[12]  T. Murakami,et al.  Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update , 2021, Liver Cancer.

[13]  J. Llovet,et al.  Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  A. Jemal,et al.  Cancer Statistics, 2021 , 2021, CA: a cancer journal for clinicians.

[15]  J. Zucman‐Rossi,et al.  Hepatocellular carcinoma , 1998, Nature Reviews Disease Primers.

[16]  J. Shindoh,et al.  Lenvatinib-Transarterial Chemoembolization Sequential Therapy as an Effective Treatment at Progression during Lenvatinib Therapy for Advanced Hepatocellular Carcinoma , 2020, Liver Cancer.

[17]  M. Kudo,et al.  Exploratory Analysis of Lenvatinib Therapy in Patients with Unresectable Hepatocellular Carcinoma Who Have Failed Prior PD−1/PD-L1 Checkpoint Blockade , 2020, Cancers.

[18]  S. Billan,et al.  Treatment after progression in the era of immunotherapy. , 2020, The Lancet. Oncology.

[19]  J. Marrero,et al.  Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference , 2020, Hepatology.

[20]  Yulei N. Wang,et al.  Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. , 2020, The New England journal of medicine.

[21]  M. Kudo,et al.  A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements , 2020, Liver Cancer.

[22]  M. Kudo,et al.  Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial , 2019, Gut.

[23]  M. Kudo,et al.  Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  M. Kudo A New Treatment Option for Intermediate-Stage Hepatocellular Carcinoma with High Tumor Burden: Initial Lenvatinib Therapy with Subsequent Selective TACE , 2019, Liver Cancer.

[25]  M. Kudo,et al.  Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child–Pugh A Liver Function: A Proof-Of-Concept Study , 2019, Cancers.

[26]  M. Kudo,et al.  Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2019, The Lancet. Oncology.

[27]  M. Abecassis,et al.  Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases , 2018, Hepatology.

[28]  Gisela Schwab,et al.  Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma , 2018, The New England journal of medicine.

[29]  N. Enomoto,et al.  Up‐to‐seven criteria as a useful predictor for tumor downstaging to within Milan criteria and Child–Pugh grade deterioration after initial conventional transarterial chemoembolization , 2018, Hepatology research : the official journal of the Japan Society of Hepatology.

[30]  M. Kudo,et al.  Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial , 2018, The Lancet.

[31]  M. Kudo,et al.  Time to Transcatheter Arterial Chemoembolization Refractoriness in Patients with Hepatocellular Carcinoma in Kinki Criteria Stages B1 and B2 , 2017, Digestive Diseases.

[32]  F. Piscaglia,et al.  Transarterial chemoembolization vs bland embolization in hepatocellular carcinoma: A meta-analysis of randomized trials , 2017, United European gastroenterology journal.

[33]  Masatoshi Kudo,et al.  Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial , 2017, The Lancet.

[34]  M. Kudo,et al.  Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma , 2016, Digestive Diseases.

[35]  R. Lencioni,et al.  Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data , 2016, Hepatology.

[36]  R. Golfieri,et al.  Lipiodol transarterial chemoembolization for hepatocellular carcinoma: Where are we now? , 2016, Hepatology.

[37]  M. Kudo,et al.  Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma , 2015, Liver Cancer.

[38]  M. Kudo,et al.  Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria) , 2015, Digestive Diseases.

[39]  Y. Imai,et al.  JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan , 2014, Liver Cancer.

[40]  Y. Inaba,et al.  Prognosis of patients with intermediate-stage hepatocellular carcinomas based on the Child-Pugh score: subclassifying the intermediate stage (Barcelona Clinic Liver Cancer stage B) , 2014, Japanese Journal of Radiology.

[41]  J. Bruix,et al.  Postprogression survival of patients with advanced hepatocellular carcinoma: Rationale for second‐line trial design , 2013, Hepatology.

[42]  V. Mazzaferro,et al.  Heterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment Decisions , 2012, Seminars in Liver Disease.

[43]  Yoon-Koo Kang,et al.  Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. , 2009, The Lancet. Oncology.

[44]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[45]  R. Jain Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[46]  Pietro Andreone,et al.  Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. , 2002, Radiology.

[47]  Ramon Planas,et al.  Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial , 2002, The Lancet.

[48]  John Wong,et al.  Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma , 2002, Hepatology.

[49]  M. Dumont,et al.  European Association for the Study of the Liver , 1971 .