Journal of Liver Cancer

Review Articles

Strategic drug sequencing in hepatocellular carcinoma in the era of chemo-diversity: maximizing the therapeutic benefit of lenvatinib: Hideki Iwamoto, Shigeo Shimose, Hironori Koga, Takumi Kawaguchi; J Liver Cancer. 2026;26(1):83-92. Published online December 27, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.12

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Abstract PDF: The emergence of systemic therapies has ushered in an era of chemo-diversity for hepatocellular carcinoma, in which drug sequencing is pivotal for maximizing outcomes. Among available agents, lenvatinib is notable for its potent anti-angiogenic and immunomodulatory properties. This review proposes a structured building-block strategy for optimizing sequential drug therapy, conceptualizing each treatment line as a block that contributes cumulatively to survival, and grounding the discussion in clinical insights from lenvatinib administration. We comprehensively evaluated clinical trials, preclinical investigations, and real-world data to identify actionable approaches that enhance tolerability and prolong progression-free survival, with a particular focus on mitigating adverse events, optimizing dosing schedules, and integrating with transarterial therapies. Five refinements emerge as central to maximizing therapeutic benefit: early detection and classification of adverse events, use of supportive agents such as L-carnitine and branched-chain amino acids, structured telephone follow-up, optimization of dosing schedules, including weekend-off regimens, and strategic combination with transarterial therapy. In addition, rationale-based sequencing and clinically relevant switching criteria that extend beyond RECIST are summarized. Collectively, these measures increase the height of each therapeutic block, thereby contributing to cumulative survival within the building-block strategy. In the current era of chemo-diversity, lenvatinib remains a cornerstone agent when accompanied by these clinical refinements. The review provides a practical and conceptual framework for enhancing efficacy through structured sequencing, proactive adverse-event mitigation, and synergistic locoregional strategies, with broad applicability to real-world clinical practice.

The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma: Matthew Man Pok Lee, Landon Long Chan, Stephen Lam Chan; J Liver Cancer. 2023;23(2):262-271. Published online August 17, 2023; DOI: https://doi.org/10.17998/jlc.2023.07.17

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20 Citations

Hepatocellular carcinoma (HCC) frequently presents as advanced stage with poor prognosis and high mortality. Systemic treatment is the treatment of choice for advanced disease. In 2007, the first multi-kinase inhibitor (MKI) sorafenib was approved and shown to modestly prolong overall survival (OS). The progress of systemic therapy has been slow afterwards until 2018 when lenvatinib, another MKI, was shown to be non-inferior to sorafenib on median OS as the first-line therapy for HCC. Since then, remarkable progress has been achieved on the treatment of advanced HCC, including the development of second-line targeted treatment, including regorafenib, cabozantinib and ramucirumab from 2017 to 2019. A growing focus has been placed on immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4. These ICIs have proven their potency in treating HCC as both initial and subsequent line of therapy. At present, both regimens of atezolizumab combined with bevacizumab, as well as the combination of tremelimumab and durvalumab, are recommended as the first-line treatments based on positive phase III clinical trials. With the advancement of ICIs, it is anticipated that the role of MKIs in the treatment of HCC will evolve. In this article, lenvatinib, one of the most commonly used MKIs in HCC, is chosen to be reviewed.

Citations

Citations to this article as recorded by

The role of rare ginsenosides in the prevention and treatment of liver diseases
Yingming Zhang, Yanfei Liu, Yuchong Wei, Ze Ren, Ying-Hua Jin, Guiying Li
Journal of Ethnopharmacology.2026; 355: 120666. CrossRef
Hepatic stellate cells shape the ECM-disorganized and immunosuppressive microenvironment via CCL11/CCR3 axis in lenvatinib-treated hepatocellular carcinoma
Na Qiang, Cheng Lan, An Lin, Hiroaki Kanzaki, Masanori Inoue, Naoya Kanogawa, Takayuki Kondo, Sadahisa Ogasawara, Masato Nakamura, Shingo Nakamoto, Dawei Cui, Hang Lv, Qiuran Xu, Guiping Chen, Junjie Ao
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A Narrative Review of the Therapeutic Effectiveness of Lenvatinib in Comparison With Immunotherapy for the Treatment of Non-Viral Advanced Hepatocellular Carcinoma
Pankaj Sonone , Sumit Goyal, Nilesh Lokeshwar, Shruti Dharmadhikari, Gaurav Puppalwar, Chintan Khandhedia, Amey Mane, Suyog Mehta
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Lenvatinib combined with immune checkpoint inhibitors for unresectable, recurrent, or metastatic hepatocellular carcinoma: a real-world study
Huifang Kong, Yan Chen, Hong Li, Di Wang, Xiujuan Chang, Zhen Zeng, Wei Zhang
The Oncologist.2026;[Epub] CrossRef
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Diyar Akhmet, Akihiko Soyama, Ayaka Kinoshita, Hajime Matsushima, Hajime Imamura, Takashi Hamada, Ayaka Satoh, Kazushige Migita, Shun Nakamura, Baglan Askeyev, Masanori Fukushima, Tomohiko Adachi, Shinji Okano, Hisamitsu Miyaaki, Susumu Eguchi
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Ai-Yu Nie, Zhong-Hui Xiao, Jia-Li Deng, Na Li, Li-Yuan Hao, Sheng-Hao Li, Xiao-Yu Hu
World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef
The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: a phase II trial
Da Xu, Hongwei Wang, Quan Bao, Kemin Jin, Ming Liu, Wei Liu, Xiaoluan Yan, Lijun Wang, Yanqiao Zhang, Guangyu Wang, Yue Ma, Zhigang Ma, Chunhui Zhang, Jiebing Tang, Sha Wang, Jiaohui Pang, Ting Xu, Kun Wang, Baocai Xing
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Ansofaxine Hydrochloride inhibits hepatocellular carcinoma growth and enhances targeted therapy through the EGFR/MAPK pathway
Yongfei He, Qiang Tao, Shutian Mo, Meifeng Chen, Jicai Wang, Hang Zhai, Shengjie Hong, Qiang Gao, Guangquan Zhang, Chuangye Han, Xianjie Shi
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Reduced-Dose or Discontinuation of Bevacizumab Might Be Considered after Variceal Bleeding in Patients with Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab: Case Reports
Kyeong-Min Yeom, Young-Gi Song, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
Medicina.2024; 60(1): 157. CrossRef
The Position of Multikinase Inhibitors in the Era of Immune-Checkpoint Inhibitors for Hepatocellular Carcinoma
Beom Kyung Kim
Gut and Liver.2024; 18(1): 3. CrossRef
Fatal intratumoral hemorrhage in a patient with hepatocellular carcinoma following successful treatment with atezolizumab/bevacizumab: A case report
Kyeong-Hoon Park, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
World Journal of Clinical Cases.2024; 12(22): 5177. CrossRef
Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives
Jianzhong Liu, Shuai Xia, Baoyi Zhang, Dina Mostafa Mohammed, Xiangliang Yang, Yanhong Zhu, Xinnong Jiang
Discover Oncology.2024;[Epub] CrossRef
Consistent efficacy of hepatic artery infusion chemotherapy irrespective of PD‑L1 positivity in unresectable hepatocellular carcinoma
Ji Kim, Young Kim, Hee-Chul Nam, Chang-Wook Kim, Jae-Sung Yoo, Ji Han, Jeong Jang, Jong Choi, Seung Yoon, Ho Jong Chun, Jung Oh, Suho Kim, Sung Lee, Pil Sung
Oncology Letters.2024;[Epub] CrossRef
The Role of the MiR-181 Family in Hepatocellular Carcinoma
Jinbiao Chen, Ken Liu, Mathew A. Vadas, Jennifer R. Gamble, Geoffrey W. McCaughan
Cells.2024; 13(15): 1289. CrossRef
Role of transarterial chemoembolization for hepatocellular carcinoma with extrahepatic metastases in the era of advancing systemic therapy
Byeong Geun Song, Myung Ji Goh, Wonseok Kang, Dong Hyun Sinn, Geum-Youn Gwak, Yong-Han Paik, Joon Hyeok Lee, Moon Seok Choi
Journal of Liver Cancer.2024; 24(2): 243. CrossRef
Dual effects of targeting neuropilin-1 in lenvatinib-resistant hepatocellular carcinoma: inhibition of tumor growth and angiogenesis
Junjie Ao, Na Qiang, Hiroaki Kanzaki, Masato Nakamura, Risa Kakiuchi, Jiaqi Zhang, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Naoya Kanogawa, Ryo Nakagawa, Takayuki Kondo, Sadahisa Ogasawara, Shingo Nakamoto, Ryosuke Muroyama, Jun Kato, Naoya Kato
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A Potential Pneumothorax Induced by Immune Checkpoint Inhibitors: A Case Report and Literature Review
Yoon-E Shin, Hyuk Kim, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
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Challenges and advances of immune checkpoint therapy
Lingyu Li, Yingli Sun
Clinical and Translational Discovery.2024;[Epub] CrossRef
Current perspectives on the pharmacological treatment of advanced hepatocellular carcinoma: a narrative review
Hye-Jin Yoo, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
The Ewha Medical Journal.2024;[Epub] CrossRef
Vascular Endothelial Growth Factor (VEGF) Family and the Immune System: Activators or Inhibitors?
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Case Report

A case report of a patient presented with skin ulcer after treatment of lenvatinib: Serin Cha, Dong Woo Kim, Jung Wan Choe, Tae Hyung Kim, Seung Young Kim, Jong Jin Hyun, Sung Woo Jung, Ja Seol Koo, Young Kul Jung, Hyung Joon Yim; J Liver Cancer. 2021;21(2):194-198. Published online September 30, 2021; DOI: https://doi.org/10.17998/jlc.2021.09.20

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6 Citations

Abstract PDF

A 60-year-old man diagnosed with unresectable hepatocellular carcinoma (HCC) presented to the hospital with pain in the perineal region. He had been taking lenvatinib every day for 2 months after he was diagnosed with HCC with metastases to the lymph node, small bowel mesentery, and retroperitoneal space. Enhanced abdominal computed tomography revealed mild elevation in intensity in the perineal subcutaneous tissue with subcutaneous emphysema. The patient was diagnosed with Common Terminology Criteria for Adverse Events grade 3, skin ulceration of stage IV with full-thickness skin loss and tissue necrosis in the muscular layer. The patient was taken off the medication with prescription of antibiotics, and after 3 weeks, the skin has fully recovered. This is the first report of an HCC patient who presented with a skin ulceration of stage IV after lenvatinib treatment. We recommend stopping the medication immediately and changing to alternative treatments with appropriate supportive care.

Citations

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Drug-induced skin ulcer: real-world pharmacovigilance analysis based on the FDA adverse event reporting system
Qiubai Jin, Jiufei Fang, Feihong Ren, Jiaqi Li, Shuanglin Zhou, Ping Song
Expert Opinion on Drug Safety.2025; : 1. CrossRef
Lenvatinib-Associated Vaginal Necrosis and Rectovaginal Fistula After Brachytherapy
Keiichiro Baba, Taisuke Sumiya, Takashi Saito, Motohiro Murakami, Hideyuki Sakurai
Cureus.2025;[Epub] CrossRef
Hospital-Based Observational Study of Mucocutaneous Adverse Reactions of Tyrosine Kinase Inhibitors
Sona C. Gowda, Tonita Mariola Noronha, Vijith Shetty
Indian Journal of Medical and Paediatric Oncology.2025;[Epub] CrossRef
Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review)
Ganghui Ye
American Journal of Cancer Research.2024; 14(9): 4113. CrossRef
Multiple lenvatinib‐associated skin ulcers: A case report and literature review
Soo Hyun Jeon, Woo Jin Lee, Chong Hyun Won, Sung Eun Chang, Mi Woo Lee, Joon Min Jung
Australasian Journal of Dermatology.2023;[Epub] CrossRef
Tyrosine Kinase Inhibitors Induced Scrotal Ulcerations
Abhipsa Samal, Nibedita Dixit, Bikash R. Kar, Liza Mohapatra
Indian Journal of Dermatology.2023; 68(2): 235. CrossRef

Original Article

Infiltration of T Cells and Programmed Cell Death Ligand 1-expressing Macrophages as a Potential Predictor of Lenvatinib Response in Hepatocellular Carcinoma: Pil Soo Sung, Sung Woo Cho, Jaejun Lee, Hyun Yang, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon; J Liver Cancer. 2020;20(2):128-134. Published online September 30, 2020; DOI: https://doi.org/10.17998/jlc.20.2.128

6,792 Views
113 Downloads
8 Citations

Abstract PDF

Background/Aims
Lenvatinib was recently proven to be non-inferior to sorafenib in treating unresectable hepatocellular carcinoma (HCC) in a phase-3 randomized controlled trial. In this study, we investigated whether the response to lenvatinib was affected by tumor immunogenicity.
Methods
Between May 2019 and April 2020, nine patients with intermediate-to-advanced HCC, who were treated with lenvatinib after liver biopsy, were enrolled. Immunohistochemical staining and multi-color flow cytometry were performed on specimens obtained from liver biopsy.
Results
Among the nine patients enrolled, four showed objective responses (complete responses+partial responses). Immunohistochemical staining for CD3, CD68, and programmed cell death ligand 1 (PD-L1) demonstrated that patients with objective responses showed marked infiltration of T cells and PD-L1-expressing macrophages in intra-tumoral and peri-tumoral tissues compared to those without objective responses. A significant difference in the numbers of infiltrated T cells, both in the intra-tumoral (P<0.01) and peri-tumoral regions (P<0.05), were identified between responders and non-responders. Regarding the number of infiltrated macrophages, no significant difference was found between the responders and non-responders, although the number of PD-L1-expressing tumor-associated macrophages was significantly higher in responders than that in non-responders (P<0.05).
Conclusions
Tumor immunogenicity, as indicated by T cell and PD-L1-positive macrophage infiltration, affects lenvatinib response in unresectable HCC.

Citations

Citations to this article as recorded by

Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review)
Ganghui Ye
American Journal of Cancer Research.2024; 14(9): 4113. CrossRef
Recent Advances in Immune-based Therapy for Hepatocellular Carcinoma
Kyung Won Park, Tae Hoon Park, Eun Ji Jang, Pil Soo Sung
Journal of Digestive Cancer Research.2024; 12(2): 115. CrossRef
Higher Number of Tumor-Infiltrating PD-L1+ Cells Is Related to Better Response to Multikinase Inhibitors in Hepatocellular Carcinoma
Ji Won Han, Ji Hoon Kim, Dong Hyun Kim, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jaegyoon Ahn, Hyun Yang, Pil Soo Sung
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Intrahepatic inflammatory IgA+PD-L1high monocytes in hepatocellular carcinoma development and immunotherapy
Pil Soo Sung, Dong Jun Park, Pu Reun Roh, Kyoung Do Mun, Sung Woo Cho, Gil Won Lee, Eun Sun Jung, Sung Hak Lee, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Jonghwan Choi, Jaegyoon Ahn, Seung Kew Yoon
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Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma
Pil Soo Sung
Clinical and Molecular Hepatology.2022; 28(3): 333. CrossRef
Blood-based biomarkers for immune-based therapy in advanced HCC: Promising but a long way to go
Pil Soo Sung, Isaac Kise Lee, Pu Reun Roh, Min Woo Kang, Jaegyoon Ahn, Seung Kew Yoon
Frontiers in Oncology.2022;[Epub] CrossRef
Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection
Pil Soo Sung, Eui-Cheol Shin
Journal of Clinical Medicine.2021; 10(2): 221. CrossRef
Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma
Dong-Jun Park, Pil-Soo Sung, Gil-Won Lee, Sung-Woo Cho, Sung-Min Kim, Byung-Yoon Kang, Won-Hee Hur, Hyun Yang, Soon-Kyu Lee, Sung-Hak Lee, Eun-Sun Jung, Chang-Ho Seo, Joseph Ahn, Ho-Joong Choi, Young-Kyoung You, Jeong-Won Jang, Si-Hyun Bae, Jong-Young Cho
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