Journal of Liver Cancer

Review Articles

Systemic therapy for combined hepatocellular-cholangiocarcinoma: a comprehensive review of chemotherapy, immunotherapy, and targeted therapy: Jung Yong Hong, Dong Hyun Sinn, Sang Yun Ha; J Liver Cancer. 2026;26(1):36-44. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.02

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Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy exhibiting both hepatocytic and cholangiocytic differentiation. Since the 2019 World Health Organization (WHO) reclassification, growing molecular and clinical evidence has reshaped our understanding of this entity. However, patients with cHCC-CCA have been systematically excluded from landmark clinical trials in both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), leaving clinicians without prospective evidence to guide treatment selection. This review comprehensively evaluates the current evidence on systemic therapy for advanced cHCC-CCA, encompassing cytotoxic chemotherapy, immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and molecularly targeted agents. Retrospective data indicate that gemcitabine plus platinum-based chemotherapy achieves the most consistent efficacy among conventional regimens, with median overall survival of 10-16 months. ICIs demonstrate objective response rates of 20-33% with durable responses in a subset of patients, supported by the finding that approximately 57% of cHCC-CCA tumors harbor an immune-high phenotype. Nearly 25% of tumors carry potentially actionable genomic alterations, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and human epidermal growth factor receptor 2 (HER2) amplification. The molecular heterogeneity of cHCC-CCA, with tumors classifiable as HCC-like or CCA-like in approximately 75% of cases, provides a rational framework for personalized treatment selection. We propose an emerging molecular classification-based treatment algorithm and identify critical gaps requiring dedicated prospective investigation. For clinical settings where comprehensive genomic profiling is not feasible, we discuss a pragmatic surrogate-based approach using imaging characteristics and serum tumor markers to guide initial treatment selection. We also address post-progression treatment considerations, including phenotype-based regimen switching and the role of re-biopsy

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Curative Effect Evaluation of Targeted Therapy and Chemotherapy for Non-Resectable Combined Hepatocellular-Cholangiocarcinoma: A Systematic Review and Meta-Analysis
永豪林
Advances in Clinical Medicine.2026; 16(05): 920. CrossRef

Systemic treatment strategies for combined hepatocellular-cholangiocarcinoma: current evidence and future direction: Jeesun Yoon; J Liver Cancer. 2026;26(1):45-54. Published online February 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.02.24

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Abstract PDF

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy characterized by biphenotypic differentiation and marked biologic heterogeneity. Owing to its low incidence, diagnostic complexity, and lineage plasticity, standardized systemic treatment strategies remain undefined. Molecular and pathologic studies suggest a progenitor cell origin, with tumors exhibiting genomic, transcriptomic, and immunologic features overlapping with both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This heterogeneity contributes to variable therapeutic responsiveness and underscores the need for biologically informed treatment approaches. Current systemic treatment evidence is derived predominantly from retrospective analyses. Platinum-based cytotoxic chemotherapy has demonstrated modest but consistent clinical activity and remains the most commonly adopted palliative backbone. More recently, immunotherapy has shown encouraging anti-tumor activity, including combination strategies incorporating anti-angiogenic agents. Biomarker signals provide mechanistic rationale for immune-angiogenic therapeutic integration. Emerging platforms, including programmed cell death-1 (PD-1)/vascular endothelial growth factor (VEGF) bispecific antibodies, further expand the systemic treatment landscape. In parallel, multimodal strategies integrating locoregional interventions with systemic therapy are gaining traction, particularly for patients with liver-dominant disease. Despite these advances, prospective disease-specific trials remain lacking, and optimal therapeutic sequencing and patient selection strategies are yet to be defined. Future progress will depend on biomarker-driven trial design, incorporation of molecular lineage stratification, and rational combination approaches. A deeper understanding of the pathological and molecular architecture of cHCC-CC will be essential to establish optimized, disease-specific systemic treatment paradigms for this rare but clinically challenging malignancy.

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A Comprehensive Understanding of DCTPP1 as an Emerging Therapeutic Target in Liver Cancer
Hye In Ka, Se Ha Jang, Hyung Seok Kim, Hyun Sun Jung, Jung Woo Eun
Current Issues in Molecular Biology.2026; 48(8): 770. CrossRef

Case Report

Durable complete response after discontinuation of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma with portal vein tumor thrombosis: the first report: Pramod Kumar, Pradeep Krishna, Rohit Maidur, Naveen Chandrashekhar, Suresh Raghavaiah; J Liver Cancer. 2025;25(1):134-137. Published online November 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.09.26

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230 Downloads
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Abstract PDF

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a dismal prognosis. Atezolizumab plus bevacizumab (atezo-bev) is the recommended palliative treatment, and approximately 10% of the patients may experience a complete response (CR), according to the mRECIST criteria. The treatment duration is until disease progression or unacceptable side effects occur. Long-term continuation can cause potential toxicities and a substantial financial burden, making early treatment discontinuation a viable option. This report describes durable CR after discontinuing atezo-bev treatment in three patients with HCC and PVTT.

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Immunotherapy in Hepatocellular Carcinoma with Portal Vein Tumour Thrombosis: From Poor Prognosis to Curative-Intent Strategies
Luca Marzi, Rodolfo Sacco, Luisa Siciliani, Saveria Lory Crocè, Mauro Giuffrè, Cristina Stasi, Chiara Turri, Monica Zoeschg, Andrea Mega
Cancers.2026; 18(4): 627. CrossRef

Review Articles

Multidisciplinary approaches to downstaging hepatocellular carcinoma: present and future: Sang-Youn Hwang, Hyunwook Choi, Wan Jeon, Ryoung-Go Kim; J Liver Cancer. 2024;24(2):171-177. Published online September 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.08.30

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6 Web of Science
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Abstract PDF

Downstaging of hepatocellular carcinoma (HCC) is typically defined as the reduction in size or number of viable tumors through locoregional therapy (LRT), aiming to meet the established criteria for liver transplantation (LT). According to the Barcelona Clinic Liver Cancer (BCLC) staging system, a subgroup of patients with BCLC-B may benefit most from downstaging therapies. The United Network Organ Sharing downstaging protocol identifies potential candidates for downstaging by setting out ‘inclusion criteria’ and defining ‘successful downstaging.’ Additionally, the protocol considers factors related to tumor biology, such as an alphafetoprotein level <500 ng/mL after LRT. Reports indicate that successful downstaging rates following LRT are about 50%, with post- LT recurrence rates comparable to those of patients within the Milan criteria. A comprehensive multicenter US study on 10-year outcomes post-LT after downstaging showed 10-year post-LT survival and recurrence rates of 52.1% and 20.6%, respectively, for patients whose disease was downstaged; this compares to 61.5% and 13.3% for those consistently within the Milan criteria. Recently, the development of effective systemic treatments for HCC, such as immuno-oncologic agents, has provided additional opportunities for downstaging. Numerous clinical trials are exploring a multidisciplinary approach (MDA) combining LRT and systemic therapy. Although concrete evidence of the superiority of MDA for HCC downstaging is lacking, some retrospective studies and phase I and II trials have shown promising results regarding the efficacy and safety of MDA for this purpose. In this review, we will also discuss the future of MDA protocols in downstaging for improved clinical outcomes.

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Erin M. Duggan, Nishtha Singh, Joanna K. Weeks, Adam Talenfeld, Benjamin May, Resmi Charalel, Ian Dinmore, Sarah Stucky, Tea Binder, Alexander J. Berman, Yana Glemaud, Arush Anand, Anthony Choi, Rebecca Craig-Schapiro, Dustin Carpenter, Benjamin Samstein,
Digestive Disease Interventions.2026;[Epub] CrossRef
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Landon L. Chan, Stephen L. Chan
Journal of Clinical Oncology.2026; 44(11): 949. CrossRef
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Jaejun Lee, Hyun Yang, Keungmo Yang, Ji Won Han, Pil Soo Sung, Jeong Won Jang, Si Hyun Bae
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Expanding the path to cure - a narrative review on optimizing multimodality sequencing in HCC
Howard J. Lim, Arndt Vogel, Emma M. Dunne, Mayur Brahmania, Vincent C. Tam, Robert J. Abraham, Jennifer J. Knox, Jason K. Wong, Prosanto Chaudhury, Ravi Ramjeesingh, Peter T.W. Kim, Ilidio Martins, Leandro C. Leite, David Valenti, Gonzalo Sapisochin, Davi
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A concise review of updated global guidelines for the management of hepatocellular carcinoma: 2017-2024
Hyunjae Shin, Su Jong Yu
Journal of Liver Cancer.2025; 25(1): 19. CrossRef
The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment
Stephen Lam Chan, Hui-Chuan Sun, Yang Xu, Hongmei Zeng, Hashem B El-Serag, Jeong Min Lee, Myron E Schwartz, Richard S Finn, Jinsil Seong, Xin Wei Wang, Valérie Paradis, Ghassan K Abou-Alfa, Lorenza Rimassa, Jia-Horng Kao, Bo-Heng Zhang, Josep M Llovet, Jo
The Lancet.2025; 406(10504): 731. CrossRef
Liver Transplantation for Hepatocellular Carcinoma: A Comprehensive Review
Seok-Hwan Kim
Convergence Hepatology.2025; 1(1): 24. CrossRef
Radioembolization of primary liver tumors for patients with pre-existing ascites: beyond Child-Pugh score
Fayez J. Jabboure, Joshua A. Marlow, Wyatt D. Reed, Naganathan B. Mani, Nassir Rostambeigi
Abdominal Radiology.2025; 51(7): 3418. 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

53,045 Views
720 Downloads
16 Web of Science
17 Citations

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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Frontiers in Oncology.2026;[Epub] CrossRef
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Hyunjae Shin, Su Jong Yu
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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
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Racha Hosni, Niklas Klümper, Christine Sanders, Sana Hosni, Vittorio Branchi, Alexander Semaan, Abdullah Alajati, Natalie Pelusi, Susanna S. Ng, Damian J. Ralser, Saif-Eldin Abedellatif, Hanno Matthaei, Jörg Kalff, Jasmitha Boovadira Poonacha, Veronika Lu
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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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Zijie He, Yizhen Chen, Genglin Li, Jintao Wang, Yuxin Wang, Pengjie Tu, Yangyun Huang, Lilan Zhao, Xiaojie Pan, Hengrui Liu, Wenshu Chen
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Original Articles

Downstaging with atezolizumab-bevacizumab: a case series: Anand V. Kulkarni, Parthasarathy Kumaraswamy, Balachandran Menon, Anuradha Sekaran, Anuhya Rambhatla, Sowmya Iyengar, Manasa Alla, Shantan Venishetty, Sumana Kolar Ramachandra, Giri V. Premkumar, Mithun Sharma, P. Nagaraja Rao, Duvvur Nageshwar Reddy, Amit G. Singal; J Liver Cancer. 2024;24(2):224-233. Published online May 27, 2024; DOI: https://doi.org/10.17998/jlc.2024.05.12

9,967 Views
321 Downloads
13 Web of Science
15 Citations

Abstract PDF Supplementary Material

Backgrounds/Aims
Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezo-bev remains unknown.
Methods
In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging.
Results
Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age, 58.5 years; women, 17%; Barcelona Clinic Liver Cancer stage system B/C, 5/7) had received 3-12 cycles of atezo- bev, and four of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 days (range, 54-114) following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 months (range, 4-30), none of the alive patients developed HCC recurrence or graft rejection.
Conclusions
Surgical therapy, including LT, is possible after atezo-bev therapy in well-selected patients after downstaging.

Citations

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Variceal Bleeding Due to Single-tremelimumab Regular-interval Durvalumab: Immunotherapy Induced or Cirrhosis Driven?
Vamshi K. Ankam, Srujana Priya, Arif M. Khan, Manu Tandon, Mithun Sharma, Padaki N. Rao, Duvvur N. Reddy, Anand V. Kulkarni
Journal of Clinical and Experimental Hepatology.2026; 16(1): 103175. CrossRef
Effectiveness and safety of Atezolizumab and Bevacizumab as conversion therapy for unresectable or advanced HCC in real-world clinical practice in Russia: Multicenter retrospective observational study
I. A. Dzhanyan, O. D. Olisov, E. Yu. Antonova, M. S. Novruzbekov, I. V. Savchenko, E. A. Moroz, K. K. Laktionov, K. A. Romanova, D. I. Yudin, M. N. Khagazheeva, V. V. Breder
Meditsinskiy sovet = Medical Council.2026; (21): 36. CrossRef
The rise of transplant oncology in primary liver cancer and metastatic disease
Charles-Henri Wassmer, Maximiliano Gelli, Tiffany Cho Lam Wong, Zhihao Li, Anudari Zorigtbaatar, Rebecca Marino, Laia Aceituno Sierra, René Adam, Albert Chi Yan Chan, Julie Heimbach, Pål Dag Line, Vincenzo Mazzaferro, Gonzalo Sapisochin, Parissa Tabrizian
Hepatology.2026;[Epub] CrossRef
Evidence rising, integration lagging: the bottleneck of circulating free and tumor DNA application in liver transplantation for hepatocellular carcinoma
Sami Shoucair, Ahmed Sayed Ahmed, Valberto Sanha, Geofia Crasta, Wei Kelly Wu, Dylan Isaacson, Woo Jin Choi, Ramsey Ugarte, Mariam Ismail, Suneel Kamath, Shilpa Junna, Jamak Modaresi-Esfeh, Alejandro Pita, Koji Hashimoto, Mazhar Khalil, Jaekeun Kim, David
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Kuan-Chang Lai, San-Chi Chen
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Juraj Prejac, Domina Kekez, Hana Lučev, Borna Ćutić, Viktor Domislović, Vibor Šeša, Gordan Adžić, Marin Golčić
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Sumana Kolar Ramachandra, G. Venkata Rao
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The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment
Stephen Lam Chan, Hui-Chuan Sun, Yang Xu, Hongmei Zeng, Hashem B El-Serag, Jeong Min Lee, Myron E Schwartz, Richard S Finn, Jinsil Seong, Xin Wei Wang, Valérie Paradis, Ghassan K Abou-Alfa, Lorenza Rimassa, Jia-Horng Kao, Bo-Heng Zhang, Josep M Llovet, Jo
The Lancet.2025; 406(10504): 731. CrossRef
Review Article: Liver Transplantation for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors
Anand V. Kulkarni, Amit G. Singal, K. Rajender Reddy
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Ji Hoon Kim, Ji Won Han, Hee Sun Cho, Jeong Won Jang, Kwon Yong Tak, Pil Soo Sung
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Jaejun Lee, Jae-Sung Yoo, Ji Hoon Kim, Dong Yeup Lee, Keungmo Yang, Bohyun Kim, Joon-Il Choi, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Ji Won Han, Pil Soo Sung
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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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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.

Citations

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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

12,486 Views
298 Downloads
24 Web of Science
23 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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Combination of interventional oncology local therapies and immunotherapy for the treatment of hepatocellular carcinoma: Dong-Hyun Kim; J Liver Cancer. 2022;22(2):93-102. Published online April 22, 2022; DOI: https://doi.org/10.17998/jlc.2022.03.28

17,046 Views
272 Downloads
24 Citations

Abstract PDF

Interventional oncology (IO) local therapies of hepatocellular carcinoma (HCC) can activate anti-cancer immunity and it is potentially leading to an anti-cancer immunity throughout the body. For the development of an effective HCC treatment regime, great emphasis has been dedicated to different IO local therapy mediated immune modulation and possible combinations with immune checkpoint inhibitor immunotherapy. In this review paper, we summarize the status of combination of IO local therapy and immunotherapy, as well as the prospective role of therapeutic carriers and locally administered immunotherapy in advanced HCC.

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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

11,538 Views
122 Downloads
9 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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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

9,897 Views
141 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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Case Report

Nivolumab for Advanced Hepatocellular Carcinoma with Multiple Lung Metastases after Sorafenib Failure: Jaewoong Kim, Jin Won Chang, Jun Yong Park; J Liver Cancer. 2020;20(1):72-77. Published online March 31, 2020; DOI: https://doi.org/10.17998/jlc.20.1.72

8,718 Views
159 Downloads
4 Citations

Abstract PDF

Over the past decade, standard first-line systemic treatment of advanced hepatocellular carcinoma (HCC) has been based on sorafenib, a multi-kinase inhibitor. Regorafenib, another tyrosine kinase inhibitor, is the only second-line therapy that has been globally approved after progression under sorafenib treatment. Recently, immunotherapeutic agents have emerged as promising treatment options in many different malignancies, including advanced HCC. Nivolumab is the first immunotherapy approved by the Food and Drug Administration for use in HCC patients with advanced-stage second-line after sorafenib failure. In this report, a case of advanced HCC with multiple lung metastases in which a complete response and maintained progression-free status was achieved with nivolumab, following the failure of transarterial chemoembolization and sorafenib is presented. We hope this report may help expand the clinical application of second-line treatment.

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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

12,458 Views
210 Downloads
8 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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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

9,833 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.

Citations

Citations to this article as recorded by

Exploring the potential of Toxoplasma gondii in drug development and as a delivery system
Chanjin Yoon, Yu Seong Ham, Woo Jin Gil, Chul-Su Yang
Experimental & Molecular Medicine.2024; 56(2): 289. 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
Journal of Liver Cancer.2024; 24(1): 81. CrossRef
Revamping the innate or innate-like immune cell-based therapy for hepatocellular carcinoma: new mechanistic insights and advanced opportunities
Disha D. Shah, Bhavarth P. Dave, Parv A. Patel, Mehul R. Chorawala, Vishvas N. Patel, Palak A. Shah, Manish P. Patel
Medical Oncology.2023;[Epub] CrossRef
Differences between exhausted CD8+ T cells in hepatocellular carcinoma patients with and without uremia
Chen Xiaohong, Zou Jianzhou, Shen Bo, Lv Wenlv, Cao Xuesen, Xiang Fangfang
Canadian Journal of Physiology and Pharmacology.2021; 99(4): 395. CrossRef
Nivolumab for Advanced Hepatocellular Carcinoma with Multiple Lung Metastases after Sorafenib Failure
Jaewoong Kim, Jin Won Chang, Jun Yong Park
Journal of Liver Cancer.2020; 20(1): 72. CrossRef

Case Report

A Case of Management for Advanced Hepatocellular Carcinoma with Extrahepatic Metastasis by Autologous Natural Killer Cells Combined with Immune Checkpoint Inhibitor: Woo, Ara , Kim, Eun Ju , Shin, Sun Young , Jeon, Hong Jae , Park, Hana , Chon, Young Eun , Lee, Yun Bin , Hwang, Seong Gyu , Rim, Kyu Sung , Lee, Joo Ho; J Liver Cancer. 2018;18(1):67-74. Published online March 31, 2018; DOI: https://doi.org/10.17998/jlc.18.1.67

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Abstract PDF: Hepatocellular carcinoma (HCC) has extremely poor prognosis. Immunotherapy has emerged as a new treatment for a number of cancers. Adoptive immunotherapy is one of the important cancer immunotherapy, which relies on the various lymphocytes including cytotoxic T lymphocytes, natural killer (NK) and cytokine induced killer cells. Also, there has been advance in techniques of NK cell activation to more effectively kill the cancer cells. Of note, recently the blocking antibodies targeting programmed cell death protein 1 (PD-1) have shown promising results in diverse cancers including HCC. We report our recent experience of a patient accompanying advanced HCC with extrahepatic metastases. Disease progression had occurred after sorafenib administration, while the patient showed local tumor control and tumor marker decrease by NK cell immunotherapy combined with PD-1 inhibitor therapy. Though, there was no definite survival advantage due to impaired liver function, which might be caused by treatment related toxicities as well as cancer progression.

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