Journal of Liver Cancer

Review Articles

The role of radiotherapy in the management of combined hepatocellular-cholangiocarcinoma: current evidence and future perspectives: Seo Hee Choi, Woong Sub Koom, Ik Jae Lee; Received February 15, 2026 Accepted March 4, 2026 Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.04 [Accepted]

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Abstract PDF: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and highly aggressive hybrid malignancy characterized by a poor prognosis and high recurrence rates due to its dual histological nature. In the absence of established standard-of-care protocols, clinical management strategies are frequently extrapolated from the guidelines for its components, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). This review evaluates the evolving role of radiotherapy (RT) as an integral part of the multidisciplinary care for cHCC-CCA. Adjuvant RT may be considered for patients exhibiting high-risk pathological features, such as positive or close resection margins, lymphovascular invasion, and perineural invasion. For unresectable disease unfeasible for surgery or transarterial therapies, definitive RT using intensified doses—analogous to iCCA protocols—is employed to improve local control. High-precision modalities, particularly particle therapies such as proton or carbon ion radiotherapy, are emphasized as preferred options for delivering ablative doses while minimizing toxicity and preserving functional liver reserve. Furthermore, preliminary clinical evidence suggests a potential synergy between RT and immune checkpoint inhibitors, with reported cases demonstrating complete responses or successful conversion to curative-intent resection. While current evidence remains limited to retrospective cohorts and case series, the strategic integration of precision RT offers a rational pathway for optimizing outcomes in cHCC-CCA, necessitating further prospective validation.

Immune-related adverse events in hepatocellular carcinoma: Organ-specific patterns and management approaches: Sul Ki Choi, Seonjeong Woo, Hong Jae Chon; Received October 31, 2025 Accepted December 21, 2025 Published online December 29, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.21 [Accepted]

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Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. The recent introduction of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape for advanced HCC. Combination regimens, such as atezolizumab plus bevacizumab, durvalumab plus tremelimumab, and nivolumab plus ipilimumab have demonstrated significant survival improvements over conventional tyrosine kinase inhibitors (TKIs) and have become the new standard of care. However, ICIs can trigger immune-related adverse events (irAEs) through overactivation of the immune system, affecting multiple organs, including the skin, gastrointestinal tract, liver, endocrine system, lungs, and heart. Patients with HCC frequently have underlying liver diseases, such as chronic hepatitis or cirrhosis, placing them at a higher risk of hepatic irAEs compared to that with other cancer types, which can markedly influence prognosis. The pathophysiology of irAEs is driven by a series of interconnected immune mechanisms, including excessive T-cell activation, disruption of immune tolerance, cytokine dysregulation, complement-mediated injury, and innate immune activation. Clinical decisions regarding the continuation, interruption, or discontinuation of ICIs, as well as the administration of corticosteroids or immunosuppressants, should be guided by the severity of toxicity. Organ-specific management strategies and multidisciplinary collaboration are essential, particularly for severe presentations. This review summarizes the incidence, mechanisms, and management strategies for ICI-related irAEs in advanced HCC and provides practical insights for clinical decision-making.

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Response: Reassessing the Use of Nivolumab Plus Ipilimumab After Atezolizumab Plus Bevacizumab in Advanced HCC
Jung Sun Kim, Thomas Yau, Hong Jae Chon
Liver International.2026;[Epub] CrossRef

New systemic treatment options for advanced cholangiocarcinoma: Valentina Zanuso, Giulia Tesini, Elena Valenzi, Lorenza Rimassa; J Liver Cancer. 2024;24(2):155-170. Published online August 8, 2024; DOI: https://doi.org/10.17998/jlc.2024.08.07

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Abstract PDF

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

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Khalil Choucair, Shadi Chamseddine, Asfar Azmi, Philip A. Philip
Frontiers in Oncology.2026;[Epub] CrossRef
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Taek Chung, Seungho Oh, Jeongsoo Won, Jiho Park, Jeong Eun Yoo, Ho Kyoung Hwang, Gi Hong Choi, Chang Moo Kang, Dai Hoon Han, Sangwoo Kim, Young Nyun Park
Journal of Hepatology.2025; 83(1): 119. CrossRef
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Hyunjae Shin, Su Jong Yu
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Modulating Wnt/β-catenin pathway activity to enhance chemosensitivity in cholangiocarcinoma
Kevin Delgado-Calvo, Luke Boulter, Oscar Briz, Aleksandra Rozyczko, Paula Olaizola, Jose J.G. Marin, Rocio I.R. Macias, Elisa Lozano
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Diagnostic value of quantitative DWI and IVIM parameters in differentiating intrahepatic cholangiocarcinoma and hepatocellular carcinoma: a systematic review and meta-analysis
Saeed Mohammadzadeh, Alisa Mohebbi, Mehrad Zare, Faeze Salahshour, Afshin Mohammadi
Abdominal Radiology.2025;[Epub] CrossRef
Advanced cholangiocarcinoma with human epidermal growth factor receptor 2 (HER2) amplification treated with Trastuzumab deruxtecan (T-DXd): A case report
Xiaohui Bao, Zhi Chen, Jin Xiong, Zhenzhou Yang, Ni Zhang
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Validation of prognostic models for predicting postsurgical outcomes in intrahepatic cholangiocarcinoma patients using a multicenter cohort
Dong Hwan Kim, Sang Hyun Choi, Sehee Kim, Woohyung Lee, Hyung-Don Kim, Hyungjin Rhee, Eun-Suk Cho, Suk-Keu Yeom, Sumi Park, Seung Soo Lee, Mi-Suk Park
International Journal of Surgery.2025; 111(10): 7032. CrossRef
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Viviana A. Ruiz-Pozo, Santiago Cadena-Ullauri, Patricia Guevara-Ramírez, Rafael Tamayo-Trujillo, Elius Paz-Cruz, Alejandro Cabrera-Andrade, Ana Karina Zambrano
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Yong-Zhi Zhuang, Li-Quan Tong, Xue-Ying Sun
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Jun Gu Kang, Taek Chung, Dong Kyu Kim, Hyungjin Rhee
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Resectability and survival outcome in real world practice of 720 cholangiocarcinoma patients: intrahepatic, perihilar and distal cholangiocarcinoma.
Poowanai Sarkhampee, Weeris Ouransatien, Nithi Lertsawatvicha, Satsawat Chansitthichock, Paiwan Wattanarath
World Journal of Surgical Oncology.2024;[Epub] CrossRef

Original Articles

Cure can be achieved by conversion to microwave ablation following atezolizumab-bevacizumab therapy in unresectable hepatocellular carcinoma: Rene John D. Febro, Engelbert Simon S. Perillo, Akemi A. Kimura, Stephen N. Wong; J Liver Cancer. 2024;24(2):234-242. Published online June 3, 2024; DOI: https://doi.org/10.17998/jlc.2024.05.23

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Abstract PDF

Backgrounds/Aims
Atezolizumab/bevacizumab is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) and may facilitate curative conversion through resection and locoregional therapies. However, there have been very few reports on curative conversion using microwave ablation (MWA). This study aimed to determine the curative conversion rate with MWA using atezolizumab-bevacizumab as the first-line treatment in patients with uHCC, and to compare the characteristics and survival of patients with and without curative conversion.
Methods
Consecutive patients with uHCC who were started on atezolizumab-bevacizumab from May 2021 to December 2023 in a single tertiary center were included. Objective response rate (ORR) and disease control rate (DCR) were based on the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) criteria.
Results
Twenty consecutive patients with uHCC (60% advanced-stage) were included, 90% exceeding the up-to-7 criteria. The ORR and DCR were 35% and 60%, 35% and 55% using RECIST and mRECIST, respectively. Five patients (25%) underwent successful curative conversion with MWA (four advanced and one intermediate stage) despite a median HCC size of 6.1 cm (range, 2.4-7.3). Two of these patients were tumor and drug-free 132-133 weeks from the 1st atezolizumab-bevacizumab dose. Patients who underwent curative conversion had significantly longer survival than those who did not (P=0.024). Other factors associated with survival were male sex, Child-Pugh class A, and an objective response.
Conclusions
Despite the relatively large tumor size, successful curative conversion with MWA was achieved with first-line atezolizumab-bevacizumab in uHCC. However, data from prospective multicenter trials are required to determine whether this strategy is universally applicable.

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Curative Treatment after Immunotherapy Leads to Excellent Outcomes in Patients with Hepatocellular Carcinoma
Gwang Hyeon Choi, Hyun-Seok Kim, Michael Luu, Alexander Kuo, Walid S. Ayoub, Hirsh Trivedi, Yun Wang, Aarshi Vipani, Pin-Jung Chen, Steven A. Miles, Emily A. Kaymen, Andrew Hendifar, Tsuyoshi Todo, Todd V. Brennan, Georgios Voidonikolas, Steven A. Wisel,
Liver Cancer.2025; : 1. CrossRef

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis: Jeayeon Park, Yun Bin Lee, Yunmi Ko, Youngsu Park, Hyunjae Shin, Moon Haeng Hur, Min Kyung Park, Dae-Won Lee, Eun Ju Cho, Kyung-Hun Lee, Jeong-Hoon Lee, Su Jong Yu, Tae-Yong Kim, Yoon Jun Kim, Tae-You Kim, Jung-Hwan Yoon; J Liver Cancer. 2024;24(1):81-91. Published online January 19, 2024; DOI: https://doi.org/10.17998/jlc.2023.12.25

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11 Citations

Abstract PDF Supplementary Material

Background/Aim
Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT).
Methods
We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1.
Results
A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74).
Conclusion
The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

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Jeayeon Park, Su Jong Yu
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Tien-Shin Chou, Chun-Feng Wu, Chih-Lang Lin, Chao-Wei Hsu
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Mengjie Jiang, Chao Chen, Yujie Hu, Gang Lin, Huafeng Li
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Review Articles

Complications of immunotherapy in advanced hepatocellular carcinoma: Young-Gi Song, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim; J Liver Cancer. 2024;24(1):9-16. Published online November 29, 2023; DOI: https://doi.org/10.17998/jlc.2023.11.21

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269 Downloads
16 Citations

Abstract PDF

Immune checkpoint inhibitors (ICIs) are highly effective in cancer treatment. However, the risks associated with the treatment must be carefully balanced against the therapeutic benefits. Immune-related adverse events (irAEs) are generally unpredictable and may persist over an extended period. In this review, we analyzed common irAEs reported in highly cited original articles and systematic reviews. The prevalent adverse reactions include fatigue, pyrexia, rash, pruritus, diarrhea, decreased appetite, nausea, abdominal pain, constipation, hepatitis, and hypothyroidism. Therefore, it is crucial to conduct evaluations not only of gastrointestinal organs but also of cardiac, neurologic, endocrine (including the frequently affected thyroid), and ophthalmic systems before commencing ICIs. This review further explores commonly reported types of irAEs, specific irAEs associated with each ICI agent, rare yet potentially fatal irAEs, and available treatment options for managing them.

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A multidisciplinary approach with immunotherapies for advanced hepatocellular carcinoma: Yu Rim Lee; J Liver Cancer. 2023;23(2):316-329. Published online September 22, 2023; DOI: https://doi.org/10.17998/jlc.2023.09.04

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Abstract PDF

Hepatocellular carcinoma (HCC) is a highly aggressive disease that is usually diagnosed at an advanced stage. Advanced HCC has limited treatment options and often has a poor prognosis. For the past decade, tyrosine kinase inhibitors have been the only treatments approved for advanced HCC that have shown overall survival (OS) benefits; however, but their clinical efficacy has been limited. Recent trials have demonstrated promising advancements in survival outcomes through immunotherapy-based treatments, such as combinations of immune checkpoint inhibitors (ICIs) with other ICIs, antiangiogenic drugs, and locoregional therapies. The atezolizumab-bevacizumab and durvalumab-tremelimumab (STRIDE) regimen has significantly improved survival rates as a first-line treatment and has become the new standard of care. Therefore, combined treatments for advanced HCC can result in better treatment outcomes owing to their synergistic effects, which requires a multidisciplinary approach. Ongoing studies are examining other therapeutic innovations that can improve disease control and OS rates. Despite improvements in the treatment of advanced HCC, further studies on the optimal treatment selection and sequences, biomarker identification, combination approaches with other therapies, and development of novel immunotherapy agents are required. This review presents the current treatment options and clinical data of the ICI-based combination immunotherapies for advanced HCC from a multidisciplinary perspective.

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Ji Yeon Lee, Jaejun Lee, Suho Kim, Jae-sung Yoo, Ji Hoon Kim, Keungmo Yang, Ji Won Han, Jeong Won Jang, Jong Yong Choi, Seung Kew Yoon, Ho Jong Chun, Jung Suk Oh, Pil Soo Sung
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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

16,148 Views
435 Downloads
17 Citations

Abstract PDF

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.

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Case Report

Concurrent transarterial radioembolization and combination atezolizumab/ bevacizumab treatment of infiltrative hepatocellular carcinoma with portal vein tumor thrombosis: a case report: Min Kyung Park, Su Jong Yu; J Liver Cancer. 2022;22(1):69-74. Published online March 21, 2022; DOI: https://doi.org/10.17998/jlc.2022.03.09

7,423 Views
137 Downloads
6 Citations

Abstract PDF

Treatment options for advanced hepatocellular carcinoma (HCC) have been rapidly evolving. Herein, we describe a patient with advanced HCC and portal vein tumor thrombosis (PVTT) who responded decisively to a multidisciplinary approach. The patient had an ill-defined infiltrative HCC (diffuse subtype), with several intrahepatic metastasis and tumor invasion of left portal vein. Concurrent use of transarterial radioembolization (TARE) and systemic therapeutics (atezolizumab + bevacizumab) ultimately proved successful. There was marked reduction in tumor volume after TARE and an additional three cycles of atezolizumab plus bevacizumab. This concurrent treatment was well tolerated, without adverse events during immunotherapy. The impressive results achieved suggest that concurrent TARE and combination atezolizumab/bevacizumab is a promising treatment approach for advanced HCC with PVTT.

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Management strategies for advanced hepatocellular carcinoma with portal vein tumor thrombosis
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Review Articles

Advances in immune checkpoint inhibitors for hepatocellular carcinoma: Ji Won Han, Su-Hyung Park; J Liver Cancer. 2021;21(2):139-145. Published online September 30, 2021; DOI: https://doi.org/10.17998/jlc.2021.09.24

9,720 Views
120 Downloads
7 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and the second leading cause of cancer-related death worldwide. Although recent advances in immune checkpoint inhibitor-based immunotherapy have initiated a new era for advanced HCC treatment, the majority of HCC patients receiving immune checkpoint blockades do not derive clinical benefit. Thus, there remains an urgent need for novel immunotherapeutic strategies with improved therapeutic efficacy. Here we review recent studies of immune checkpoint blockade in HCC, providing the necessary basis for the rational design of immunotherapy.

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Miho Akabane, Yuki Imaoka, Ghee Rye Lee, Timothy M. Pawlik
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Complete response and HBsAg clearance of advanced hepatocellular carcinoma associated with hepatitis B by DEB−TACE combined systematic therapy: a case report
Baiguo Xu, Yufeng Cui, Hao Cui, Ning Wang, Zhongsong Gao, Qing Ye
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Role of transarterial chemoembolization for hepatocellular carcinoma with extrahepatic metastases in the era of advancing systemic therapy
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Journal of Liver Cancer.2024; 24(2): 243. CrossRef
Dynamic Peripheral T-Cell Analysis Identifies On-Treatment Prognostic Biomarkers of Atezolizumab plus Bevacizumab in Hepatocellular Carcinoma
Ji Won Han, Min Woo Kang, Soon Kyu Lee, Hyun Yang, Ji Hoon Kim, Jae-Sung Yoo, Hee Sun Cho, Eun Ji Jang, Deok Hwa Seo, Jung Hyun Kwon, Soon Woo Nam, Si Hyun Bae, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Pil Soo Sung
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Systemic therapy for advanced hepatocellular carcinoma: consideration for selecting second-line treatment: Bo Hyun Kim, Joong-Won Park; J Liver Cancer. 2021;21(2):124-138. Published online September 30, 2021; DOI: https://doi.org/10.17998/jlc.2021.09.23

8,784 Views
139 Downloads
4 Citations

Abstract PDF

Several molecular-targeted agents have been tested as first- or second-line therapies for hepatocellular carcinoma (HCC) but failed to improve clinical outcomes; sorafenib has been the only approved systemic agent for treating HCC for almost 10 years. Regorafenib resulted in a significant improvement in overall survival and thus was approved for HCC patients previously treated with sorafenib. Subsequently, cabozantinib and ramucirumab demonstrated superior overall survival compared with placebos in phase III clinical trials. Immune checkpoint inhibitors such as nivolumab with or without ipilimumab and pembrolizumab are also available in some countries for patients who are unresponsive to sorafenib. Some second-line agents are available for patients who are unresponsive to sorafenib; however, little is known about the considerations for selecting appropriate secondline systemic agents. Hence, this study aimed to review the current and future perspectives of second-line systemic agents.

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Se Jun Park, Kabsoo Shin, In-Ho Kim, MyungAh Lee, Tae Ho Hong, Hyunho Kim
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Bo Hyun Kim, Su Jong Yu, Wonseok Kang, Sung Bum Cho, Soo Young Park, Seung Up Kim, Do Young Kim
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Case Report

Infiltrative hepatocellular carcinoma with multiple lung metastasis completely cured using nivolumab: a case report: Ji Eun Han, Hyo Jung Cho, Soon Sun Kim, Jae Youn Cheong; J Liver Cancer. 2021;21(2):169-176. Published online September 30, 2021; DOI: https://doi.org/10.17998/jlc.2021.08.26

9,469 Views
123 Downloads
1 Citation

Abstract PDF

The current Food and Drug Administration-approved systemic treatments for advanced hepatocellular carcinoma (HCC) include multikinase inhibitors (tyrosine kinase inhibitor [TKI]) and immune checkpoint inhibitors (ICIs). Among ICIs, nivolumab is used as secondline therapy for advanced HCC after sorafenib failure or patient intolerance. In this case, a patient with infiltrative HCC and portal vein tumor thrombosis was treated with hepatic arterial infusion chemotherapy (HAIC) and radiation therapy. New lung metastasis developed after HAICs; thus, lenvatinib treatment was initiated. However, the disease progressed. Thereafter, sorafenib treatment was initiated but he developed intolerance, with grade 3 sorafenib-related diarrhea. Subsequently, nivolumab was administered as rescue therapy. He demonstrated a partial response to nivolumab after the third treatment and viable HCCs in the lungs and liver completely disappeared after the 24th treatment. These findings suggest that nivolumab could be used as an effective rescue therapy for advanced HCC progression after TKI treatment.

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Intermediate-stage (BCLC stage B) infiltrative hepatocellular carcinoma: safety and efficacy of chemoembolization
Seong Ho Kim, Jin Hyoung Kim, Gun Ha Kim, Ji Hoon Kim, Heung-Kyu Ko, Hee Ho Chu, Ji Hoon Shin, Dong Il Gwon, Gi-Young Ko, Hyun-Ki Yoon, Shakir Aljerdah, Nayoung Kim
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Review Articles

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma: Su Jong Yu, Tim F. Greten; J Liver Cancer. 2020;20(1):1-16. Published online March 31, 2020; DOI: https://doi.org/10.17998/jlc.20.1.1

11,071 Views
209 Downloads
6 Citations

Abstract PDF

Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.

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Masaud Shah, Muhammad Hussain, Hyun Goo Woo
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Ching-Hua Hsieh, Pei-Chin Chuang, Yueh-Wei Liu
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Huihai Yang, Martina Mang Leng Lei, Longfei Xie, Yinuo Shou, Terence Kin Wah Lee
Clinical and Molecular Hepatology.2025; 31(3): 706. 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
Diagnostics.2023; 13(8): 1453. CrossRef
Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data
Uasim Harkus, Miriam Wankell, Pranavan Palamuthusingam, Craig McFarlane, Lionel Hebbard
Seminars in Cancer Biology.2022; 86: 799. CrossRef
Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma
Pil Soo Sung
Clinical and Molecular Hepatology.2022; 28(3): 333. CrossRef

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma: Yuri Cho, Jimin Han, Won Kim; J Liver Cancer. 2019;19(1):1-11. Published online March 31, 2019; DOI: https://doi.org/10.17998/jlc.19.1.1

8,679 Views
159 Downloads
5 Citations

Abstract PDF

Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumorspecific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.

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