Journal of Liver Cancer

Review Articles

Toward a future role for liver biopsy in HCC: literature evidence and survey-based perspectives from Korean experts: Hae Lim Lee, Su Jong Yu, Sung Hak Lee, Min Woo Lee, Han Ah Lee, Yuri Cho, Jeong-Ju Yoo, Ha Il Kim, Jae Geun Lee, Hye Won Lee, Jihyun An, Sun Young Yim, Pil Soo Sung, Jonggi Choi, Jae Hyun Yoon, Eun Ju Cho, Jinhong Jung, Dongho Hyun, Ijin Joo, Yu Rim Lee, YoungRok Choi, Bo Hyun Kim, Sung Hyun Kim, Soon Sun Kim, Jeong-Han Kim, Haeryoung Kim, Pyoung-Jae Park, Hyun Phil Shin, Ki Tae Yoon, Sang Min Yoon, Minjong Lee, Jai Young Cho, Jin-Young Choi, Do Young Kim, June Sung Lee, Mi-Sook Kim, Kyung Sik Kim; Received May 4, 2026 Accepted August 22, 2026 Published online September 3, 2026; DOI: https://doi.org/10.17998/jlc.2026.08.27 [Accepted]

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Abstract PDF: The role of liver biopsy in hepatocellular carcinoma (HCC) is being re-evaluated in the era of precision oncology and biomarker-driven systemic therapy. Although histopathological examination remains the diagnostic gold standard, HCC is unique among solid tumors in that accurate non-invasive imaging criteria allow diagnosis without routine biopsy in selected clinical settings. However, increasing biological heterogeneity, expanding therapeutic options, and the growing need for molecular stratification have renewed interest in tissue-based evaluation. Recent international guidelines have gradually broadened the indications for liver biopsy, particularly in selected diagnostic scenarios, prior to systemic therapy, and for molecular profiling. Beyond diagnostic confirmation, liver biopsy provides important information for histological subtyping, prognostic stratification, and biomarker discovery. Advances in immunohistochemistry, next-generation sequencing, and artificial intelligence–assisted pathology have further enhanced the clinical value of tumor tissue. In parallel, contemporary cohort studies indicate that liver biopsy is associated with low complication rates when modern techniques and standardized peri-procedural management are applied. Despite these advances, the integration of liver biopsy into routine clinical practice remains limited. To contextualize this gap, the Korean Liver Cancer Association conducted a nationwide survey of HCC specialists. The survey showed that liver biopsy is infrequently performed in current practice due to perceived procedural risks and limited immediate impact on therapeutic decision-making. Taken together, accumulating evidence supports a reappraisal of the clinical role of liver biopsy in HCC. Optimizing procedural safety, standardizing indications, and integrating tissue-based molecular insights into therapeutic decision-making may help bridge the gap between emerging evidence and real-world practice.

Strategic driving of the cancer-immunity cycle in HCC: roles of immune, molecular-targeted, and locoregional therapies: Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi; Received April 16, 2026 Accepted August 22, 2026 Published online September 3, 2026; DOI: https://doi.org/10.17998/jlc.2026.08.26 [Accepted]

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Abstract PDF: Hepatocellular carcinoma (HCC) treatment has entered the immunotherapy era, characterized by multiple systemic and locoregional therapeutic options. Understanding how each modality modulates the tumor immune microenvironment (TIME) is essential to optimize treatment strategies. The cancer-immunity cycle provides a conceptual basis for antitumor immunity, consisting of a priming phase involving antigen release and T-cell activation, and an effector phase characterized by cytotoxic T-cell-mediated tumor elimination. Immune checkpoint inhibitor (ICI)-based combinations play a central role in HCC treatment. Anti-PD-L1 plus anti-VEGF therapy primarily activates the effector phase by reducing regulatory T cells and macrophages and enhancing cytotoxic T-cell infiltration. In contrast, CTLA-4 blockade-based regimens primarily promote the priming phase by activating CD4⁺ T cells and dendritic cells. Molecular-targeted agents also modulate the TIME. VEGF inhibition commonly reduces immunosuppressive cell populations, lenvatinib enhances cytotoxic T-cell activation through fibroblast growth factor inhibition, and cabozantinib promotes dendritic cell-mediated immune activation via AXL inhibition. Locoregional therapies, including transarterial therapies, stereotactic body radiotherapy, and transarterial radioembolization with Yttrium 90, induce tumor injury, release tumor-associated antigens, and activate inflammatory signaling. In this review, we propose the concept of “strategic driving of the cancer-immunity cycle,” in which treatment selection and sequencing are guided by their ability to activate distinct phases of the cycle. This concept may provide a rational strategy to maximize antitumor efficacy in HCC.

Special Contribution

Stereotactic body radiation therapy for hepatocellular carcinoma: 2026 expert consensus-based practical recommendation of the Korean Liver Cancer Association: Jinhong Jung, Han Ah Lee, Do Young Kim, Hyun-Cheol Kang, Sun Hyun Bae, Ji Hye Min, Gyu Sang Yoo, Jeong Il Yu, Seo Hee Choi, Hae Lim Lee, Subin Heo, Chai Hong Rim, Sang Min Yoon, June Sung Lee; Received July 9, 2026 Accepted August 22, 2026 Published online September 2, 2026; DOI: https://doi.org/10.17998/jlc.2026.08.22 [Accepted]

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Abstract PDF: Stereotactic body radiation therapy (SBRT) is a noninvasive, high-precision radiation technique that delivers a high dose to the tumor in a limited number of fractions, typically five or fewer, and is increasingly used as a curative-intent option for hepatocellular carcinoma (HCC), particularly when surgical resection, liver transplantation, or local ablative therapies are not feasible. Although domestic and international guidelines have incorporated SBRT into the treatment algorithm for HCC, the lack of comprehensive evidence and expert opinion regarding patient selection, pretreatment evaluation, treatment planning and delivery, complication management, and post-treatment follow-up has resulted in substantial variation in clinical practice. Accordingly, an expert consensus-based practical recommendations for SBRT were developed by a group of radiation oncologists, hepatologists, and radiologists from the Research Committee of the Korean Liver Cancer Association, based on expert surveys, a comprehensive review of evidence-based literature, and a modified Delphi process. Encompassing the entire clinical workflow of liver SBRT, these recommendations are intended to provide practical guidance for the safe and effective implementation of SBRT in patients with HCC.

Review Articles

NRF2-Mediated immune evasion and ferroptosis resistance in hepatocellular carcinoma: implications for immune checkpoint inhibitor response: Setya Jenio Malangi, Dian Siswanto, Mansur Ibrahim, Noviana Dwi Lestari, Muhaimin Rifa'i; Received May 27, 2026 Accepted June 28, 2026 Published online June 30, 2026; DOI: https://doi.org/10.17998/jlc.2026.06.28 [Accepted]

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Abstract PDF: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, and immune checkpoint inhibitors have become central to systemic treatment for advanced disease. However, durable responses are limited to a subset of patients, indicating the need to clarify tumor-intrinsic mechanisms that shape immune resistance. Nuclear factor erythroid 2–related factor 2 (NRF2), encoded by Nuclear Factor Erythroid 2-Related Factor 2 Like 2 (NFE2L2), is a stress-responsive transcription factor that regulates antioxidant defense, detoxification, metabolism, and redox adaptation. Although transient NRF2 activation protects hepatocytes from oxidative injury, persistent activation in HCC may promote tumor survival, immune escape, and resistance to therapy. Emerging evidence links NRF2 activity to two biologically connected processes: suppression of ferroptosis and remodeling of the tumor immune microenvironment. Through downstream targets involved in glutathione synthesis, cystine transport, iron handling, and lipid peroxide detoxification, NRF2 can reduce ferroptotic vulnerability. In parallel, NRF2-associated inflammatory and immune-regulatory pathways, including the Cyclooxygenase-2 - Prostaglandin E2 (COX2–PGE2) axis, may contribute to immune-cold phenotypes and impaired response to immune checkpoint blockade. This review summarizes current evidence on NRF2/KEAP1 signaling in HCC, with emphasis on its role in immune escape, ferroptosis suppression, and its potential implications as a biomarker and therapeutic target for understanding and potentially improving immune checkpoint inhibitor responsiveness. We also discuss the potential of NRF2-related biomarkers and therapeutic strategies, while emphasizing the challenges of selectively targeting NRF2 in patients with underlying liver dysfunction.

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; J Liver Cancer. 2026;26(1):55-64. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.04

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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 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 RT, 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.

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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Abstract PDF

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
Efficacy and safety of camrelizumab combined with apatinib as second‐line and beyond treatment for advanced combined hepatocellular‐cholangiocarcinoma
Haiyun Geng, Fang Dai, Kuimin Mei, Mengran Cao, Haiqing Hua, Xinlei Gong
Clinical and Translational Discovery.2026;[Epub] 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

1,863 Views
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1 Citation

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

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.

Special Contribution

Expert survey on systemic therapy indications for hepatocellular carcinoma in Korea: bridging clinical practice and reimbursement criteria: Hyun Yang, Soon Sun Kim, Seong Hee Kang, Jieun Kwon, Do Young Kim, Eunju Kim, Hyun Phil Shin, Jeong Il Yu, Jeong-Ju Yoo, Eileen L. Yoon, Sangheun Lee, Young Eun Chon, Janghan Jung, Jaekyung Cheon, Woosun Choi, Seul Ki Han, Ji Eun Han, Moon Haeng Hur, Hyun Woong Lee, Hyung Joon Kim; J Liver Cancer. 2025;25(2):160-168. Published online July 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.07.02

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Abstract PDF: This survey aimed to collect expert opinions from multidisciplinary specialists involved in the management of hepatocellular carcinoma (HCC) in Korea regarding real-world criteria for systemic therapy indications. In response to discrepancies between national reimbursement policies and clinical decision-making, members of the Korean Liver Cancer Association and Korean Association for the Study of the Liver participated in a web-based survey from February 4 to 14, 2025. A total of 89 respondents, primarily experienced clinicians, provided their views on major clinical scenarios including infiltrative HCC, bilobar multifocal disease, huge tumors, vascular invasion, extrahepatic metastasis, and transarterial chemoembolization (TACE) refractoriness. There was high agreement for including infiltrative HCC (69.7%), suspected portal vein invasion (70.8%), and TACE refractoriness (82.0%) as systemic therapy indications. TACE refractoriness, in particular, aligns with current guideline definitions. Additionally, over half of respondents (51.7%) supported extrahepatic metastasis under similar conditions. Notably, multidisciplinary discussion was emphasized across scenarios, but many respondents also favored allowing primary physician discretion in select cases. This report provides consolidated expert input to inform future updates to reimbursement policies and promote alignment with real-world clinical practice. These findings may help bridge the gap between national coverage criteria and clinical decision in systemic therapy for HCC.

Review Articles

Evolving roles of systemic therapy in hepatocellular carcinoma: neoadjuvant and adjuvant strategies: Ho Soo Chun, Minjong Lee, Tae Hun Kim; J Liver Cancer. 2025;25(2):178-186. Published online June 16, 2025; DOI: https://doi.org/10.17998/jlc.2025.06.13

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1 Web of Science
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Abstract PDF

Surgical resection for early-stage hepatocellular carcinoma (HCC) provides the potential for long-term survival but recurrence rates within 5 years were up to 70%. Thus, neoadjuvant or adjuvant strategies can be important to improve outcomes. Previous efforts with sorafenib in the adjuvant setting failed to show significant benefits in recurrence-free survival (RFS) or overall survival. However, developments in systemic therapies such as immune checkpoint inhibitors or tyrosine kinase inhibitors have revitalized this field. Although the IMBrave050 trial failed to demonstrate a significant improvement in RFS with one year of adjuvant treatment using atezolizumab combined with bevacizumab in high-risk patients treated with resection or ablation, several other ongoing trials are investigating this promising approach. Neoadjuvant or adjuvant approach using systemic therapies is also gaining attention, supported by phase 1 or 2 clinical trials indicating high objective response rates. In addition, systemic therapies are being increasingly studied as down-staging strategies for resection or liver transplantation. The growing complexity of HCC treatment such as the integration of neoadjuvant and adjuvant strategies underscores the importance of a multidisciplinary approach to optimize therapeutic decision-making in this evolving areas.

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Adjuvant cytokine-induced killer cell immunotherapy in hepatocellular carcinoma: real-world data and 9-year extended follow-up of a randomized controlled trial
Hyunjae Shin, Youngsu Park, Byeong Geun Song, Won-Mook Choi, Hyung Joon Han, Youngwoo Lee, Tae-Jin Song, Jong-Eun Yeon, Young-Suk Lim, Moon Haeng Hur, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Yoon Jun Kim, Joon Hyeok Lee, Jung-Hwan Yoon, Jeong-Hoon Lee
Cancer Immunology, Immunotherapy.2026;[Epub] CrossRef
Regorafenib as Second-Line Versus Later-Line Therapy in Advanced Hepatocellular Carcinoma: A Multicenter Real-World Study with Exploratory Analysis of Prior Immune Checkpoint Inhibitor Exposure
Kwon Yong Tak, Hee Sun Cho, Jaejun Lee, Kyeungmo Yang, Ahlim Lee, Ji Won Han, Soon Kyu Lee, Hyun Yang, Heechul Nam, Hee Yeon Kim, Seungwon Lee, Seok-Hwan Kim, Do Seon Song, Myeong Jun Song, Jung Hyun Kwon, UIm Chang, Soon Woo Nam, Chang Wook Kim, Jeong Wo
Targeted Oncology.2026;[Epub] CrossRef

Epidemiology and genomic features of biliary tract cancer and its unique features in Korea: Seonjeong Woo, Youngun Kim, Sohyun Hwang, Hong Jae Chon; J Liver Cancer. 2025;25(1):41-51. Published online March 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.27

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223 Downloads
6 Web of Science
7 Citations

Abstract PDF Supplementary Material

Biliary tract cancer (BTC) is a rare but highly aggressive malignancy that includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, and gallbladder cancer (GBC). While BTC has a low global incidence, its regional variations are notable. Among nations, Korea has the second-highest incidence of BTC globally, with the highest mortality rate worldwide, underscoring the need for a deeper understanding of this cancer. Liver fluke infection and hepatitis B virus infection are key risk factors unique to Korea, contributing to regional differences in BTC incidence. Additionally, genomic alterations in Korean patients with BTC differ from those in other populations, including lower frequencies of IDH1 mutations and FGFR2 fusions in ICC and a higher prevalence of ERBB2 amplification in GBC. Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

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Hea Lim Choi, Danbee Kang, In Woon Han, Hong Kwan Kim, Hyeong Seok Kim, Sang Hyun Shin, Jin Seok Heo, Dong Wook Shin, Hongbeom Kim
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Jorge Adeva, Alfredo Carrato, Teresa Macarulla
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A concise review of updated global guidelines for the management of hepatocellular carcinoma: 2017-2024: Hyunjae Shin, Su Jong Yu; J Liver Cancer. 2025;25(1):19-30. Published online February 10, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.03

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Abstract PDF

Many guidelines for hepatocellular carcinoma (HCC) have been published and are regularly updated worldwide. HCC management involves a broad range of treatment options and requires multidisciplinary care, resulting in significant heterogeneity in management practices across international communities. To support standardized care for HCC, we systematically appraised 13 globally recognized guidelines and expert consensus statements, including five from Asia, four from Europe, and four from the United States. These guidelines share similarities but reveal notable discrepancies in surveillance strategies, treatment allocation, and other recommendations. Geographic differences in tumor biology (e.g., prevalence of viral hepatitis, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease) and disparities in available medical resources (e.g., organ availability, healthcare infrastructure, and treatment accessibility) complicate the creation of universally applicable guidelines. Previously, significant gaps existed between Asian and Western guidelines, particularly regarding treatment strategies. However, these differences have diminished over the years. Presently, variations are often more attributable to publication dates than to regional differences. Nonetheless, Asia-Pacific experts continue to diverge from the Barcelona Clinic Liver Cancer system, particularly with respect to surgical resection and locoregional therapies, which are viewed as overly conservative in Western guidelines. Advancements in systemic therapies have prompted ongoing updates to these guidelines. Given that each set of guidelines reflects distinct regional characteristics, strengths, and limitations, fostering collaboration and mutual complementarity is essential for addressing discrepancies and advancing global HCC care.

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Molecular and immune landscape of hepatocellular carcinoma for therapeutic development: Hiroyuki Suzuki, Sumit Mishra, Subhojit Paul, Yujin Hoshida; J Liver Cancer. 2025;25(1):9-18. Published online December 6, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.02

13,373 Views
610 Downloads
10 Web of Science
11 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents and immune checkpoint inhibitors and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein, glypican-3, and epithelial cell adhesion molecule have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

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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

6,572 Views
230 Downloads
1 Web of Science
1 Citation

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
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Review Article

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

12,106 Views
394 Downloads
6 Web of Science
8 Citations

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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