A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements

Masatoshi Kudo¹, Kwang-Hyub Han², Sheng-Long Ye³, Jian Zhou⁴, Yi-Hsiang Huang^{5

6}, Shi-Ming Lin^{7

8}, Chung-Kwe Wang⁹, Masafumi Ikeda¹⁰, Stephen Lam Chan¹¹, Su Pin Choo¹², Shiro Miyayama¹³, Ann Lii Cheng^{14

15

16}

Affiliations

¹ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
² Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
⁷ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁸ College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
⁹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei City Hospital, Ren-Ai Branch and Kang Ning Hospital, Taipei, Taiwan.
¹⁰ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa-shi, Japan.
¹¹ Department of Clinical Oncology, State Key Laboratory of Translation Oncology, The Chinese University of Hong Kong, Hong Kong, China.
¹² Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
¹³ Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan.
¹⁴ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
¹⁵ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan.

PMID: 32647629
PMCID: PMC7325125
DOI: 10.1159/000507370

A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements

Masatoshi Kudo et al. Liver Cancer. 2020 Jun.

. 2020 Jun;9(3):245-260.

doi: 10.1159/000507370. Epub 2020 May 13.

Authors

Affiliations

¹ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
² Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
⁷ Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁸ College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
⁹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei City Hospital, Ren-Ai Branch and Kang Ning Hospital, Taipei, Taiwan.
¹⁰ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa-shi, Japan.
¹¹ Department of Clinical Oncology, State Key Laboratory of Translation Oncology, The Chinese University of Hong Kong, Hong Kong, China.
¹² Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
¹³ Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan.
¹⁴ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
¹⁵ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
¹⁶ Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan.

PMID: 32647629
PMCID: PMC7325125
DOI: 10.1159/000507370

Abstract

The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.

Keywords: Asia-Pacific Primary Liver Cancer Expert; Hepatocellular carcinoma; Intermediate stage; Systemic therapy; Transarterial chemoembolization.

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Conflict of interest statement

M.K. received lecture fees from Bayer, Eisai, MSD, and Bristol-Myers Squibb, research grants from Chugai, Otsuka, Takeda, Taiho, Daiichi Sankyo, Eisai, AbbVie, EA Pharma, Gilead Sciences, Astellas Pharma, and Bristol-Myers Squibb, and advisory consulting fees from MSD, Eisai, Bayer, Bristol-Myers Squibb, Roche, and Ono Pharmaceutical. K.-H.H. received lecture fees from Eisai, Gilead Sciences and AstraZeneca and research grants from Bristol-Myers Squibb, Eisai and Ono Pharmaceutical. S.-L.Y., Z.J., Y.-H.H., and S.-M.L. has no conflicts of interest to declare. C.-K.W. had no conflict of interest. M.I. received honoraria from Eisai, Bayer, and Lilly and received research funds from Lilly, Bayer, Takeda, Eisai, Bristol Myers Squibb, AstraZeneca, Novartis, Chugai, and Merck biopharma. S.L.C. received advisory consulting fees from Eisai, MSD, Ipsen, and AstraZeneca, and research fund from Eisai, Bayer, and MSD. S.P.C. received honoraria and consulting fees from Eisai, Bayer, BMS, Roche, Celgene and AstraZeneca. Also received speaker fees from BMS, Eisai and Lilly. S.M. received honoraria (speaker fees) from Eisai, Guerbet, Bayer, MSD, Bristol-Myers, Daiichi Sankyo, Asahi Intecc, Terumo, Philips, and Piolax. A.L.C. received consultant from Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., Bayer Yakuhin, ISPEN, and Eli Lilly.

Figures

**Fig. 1**
Definition of intermediate-stage HCC used in this manuscript. In this APPLE consensus meeting, intermediate-stage HCC was defined as: (i) a single tumor with a maximum size of ≥5 cm in BCLC A; and (ii) BCLC B stage HCC. BCLC, Barcelona Clinic Liver Cancer.

**Fig. 2**
Heterogeneity of intermediate-stage HCC and grade of response to TACE in each subgroup. cTACE, conventional transarterial chemoembolization.

**Fig. 3**
Changing the treatment strategy for patients with TACE-unsuitable intermediate-stage HCC. Different from conventional sequence from TACE to systemic therapy, systemic therapy (lenvatinib) before selective TACE may be the better treatment strategy especially in patients with intermediate stage HCC with high tumor burden. TACE, transarterial chemoembolization.

**Fig. 4**
A new paradigm for treatment strategy in HCC. For patients who are unsuitable to TACE, systemic therapy using agents with a high response rate followed by selective TACE would be a better treatment strategy to prolong patients' survival. TACE, transarterial chemoembolization.

See this image and copyright information in PMC

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A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements

Affiliations

A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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