Journal of Liver Cancer

Original Article

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.

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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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.

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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101 Downloads
2 Citations

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.

Citations

Citations to this article as recorded by

Reduced-Dose or Discontinuation of Bevacizumab Might Be Considered after Variceal Bleeding in Patients with Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab: Case Reports
Kyeong-Min Yeom, Young-Gi Song, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
Medicina.2024; 60(1): 157. CrossRef
Hepatocellular Carcinoma: Advances in Systemic Therapy
Insija Ilyas Selene, Merve Ozen, Reema A. Patel
Seminars in Interventional Radiology.2024; 41(01): 056. CrossRef

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

2,725 Views
253 Downloads
2 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.

Citations

Citations to this article as recorded by

Reduced-Dose or Discontinuation of Bevacizumab Might Be Considered after Variceal Bleeding in Patients with Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab: Case Reports
Kyeong-Min Yeom, Young-Gi Song, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
Medicina.2024; 60(1): 157. CrossRef
The Position of Multikinase Inhibitors in the Era of Immune-Checkpoint Inhibitors for Hepatocellular Carcinoma
Beom Kyung Kim
Gut and Liver.2024; 18(1): 3. CrossRef

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

3,264 Views
106 Downloads
4 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.

Citations

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Biologics, Immunotherapies, and Cytotoxic Chemotherapy for Hepatocellular Carcinoma following Current Recommendations by the BCLC: A Review of Agents
Rajangad S. Gurtatta, Sydney E. Whalen, Charles E. Ray
Seminars in Interventional Radiology.2024; 41(01): 084. CrossRef
Combining immunotherapy with transarterial radioembolization
ZeynepCeren Balaban Genc, Efe Soydemır, SevalAy Ersoy, Tunc Ones
Indian Journal of Nuclear Medicine.2023; 38(2): 145. CrossRef
The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence
Maria Cerreto, Ferdinando Cardone, Lucia Cerrito, Leonardo Stella, Francesco Santopaolo, Maria Pallozzi, Antonio Gasbarrini, Francesca Romana Ponziani
Current Oncology.2023; 30(10): 8774. CrossRef
Is multidisciplinary treatment effective for hepatocellular carcinoma with portal vein tumor thrombus?
Won Hyeok Choe
Journal of Liver Cancer.2022; 22(1): 1. CrossRef

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

3,570 Views
99 Downloads
3 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.

Citations

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Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies
Logan Muzyka, Nicolas K. Goff, Nikita Choudhary, Michael T. Koltz
International Journal of Molecular Sciences.2023; 24(13): 10456. CrossRef
Integrative analysis of lactylation-related genes and establishment of a novel prognostic signature for hepatocellular carcinoma
Diankui Cai, Xiaoqing Yuan, D. Q. Cai, Ang Li, Sijia Yang, Weibang Yang, Jinxin Duan, Wenfeng Zhuo, Jun Min, Li Peng, Jinxing Wei
Journal of Cancer Research and Clinical Oncology.2023; 149(13): 11517. CrossRef
Editorial on immune checkpoint inhibitors in the treatment of hepatocellular carcinoma
Samantha M Ruff, Timothy M Pawlik
Immunotherapy.2023; 15(16): 1323. CrossRef

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

3,973 Views
112 Downloads
2 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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Expression of Peptidyl Arginine Deiminase 2 Is Closely Associated with Recurrence in Patients with Hepatocellular Carcinoma
Sunho Uhm, Yoon Cho, Ji-Young Choe, Ji Park, Min-Jeong Kim, Won-Ho Han, Junyong Lee, Jung Lee, Dong Shin, Jae Soh, Hyun Lim, Ho Kang, Sung-Hoon Moon, Sung-Eun Kim
Diagnostics.2023; 13(4): 659. CrossRef
Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma
Bo Hyun Kim, Su Jong Yu, Wonseok Kang, Sung Bum Cho, Soo Young Park, Seung Up Kim, Do Young Kim
Journal of Gastroenterology and Hepatology.2022; 37(3): 428. CrossRef

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

3,121 Views
78 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.

Citations

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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
European Radiology.2023; 33(12): 8736. CrossRef

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

6,792 Views
191 Downloads
3 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.

Citations

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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

5,089 Views
144 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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Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis
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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
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