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Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence
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Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (10 January 2024) | Viewed by 9131

Special Issue Editor

Dr. Takefumi Kimura

E-Mail Website
Guest Editor
Faculty of Medicine, Shinshu University, Matsumoto, Japan
Interests: hepatitis; liver cirrhosis; hepatitis B; liver diseases; hepatocellular carcinoma; cirrhosis; liver transplantation; liver failure; histology; gastroenterology

Special Issue Information

Dear Colleagues, 

Hepatocellular carcinoma (HCC) treatment options have expanded significantly with the advent of multi-kinase inhibitors and immune checkpoint inhibitors. In addition to drug therapy, there have been remarkable advances in liver transplantation, minimally invasive surgery, the technology involved in ablation therapy, the choice of embolization materials and anticancer drugs for embolization therapy, and radiation therapy. Modern HCC treatment requires not only curative treatment of early-stage lesions, but also the construction of new treatment systems that lead to a cure for advanced HCC and appropriate treatment of recurrent HCC. In addition, NASH and alcoholic liver cancers are expected to increase as viral hepatitis is controlled. The management of side effects in these non-viral HCCs may differ due to differences in drug sensitivity, accompanied with diabetes mellitus and hypertension. In this Special Issue, we call for papers from a wide range of medical, surgical, and radiological perspectives on treatment strategies for advanced disease, approaches to recurrent disease, and management of side effects associated with treatment in the new era of HCC practice.

Dr. Takefumi Kimura
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 151 KiB  
Editorial
Advancements in the Treatment Landscape of Hepatocellular Carcinoma
by Takefumi Kimura
Cancers 2024, 16(5), 1054; https://doi.org/10.3390/cancers16051054 - 5 Mar 2024
Viewed by 627
Abstract
The landscape of hepatocellular carcinoma (HCC) treatment has expanded significantly with the advent of multi-kinase inhibitors and immune checkpoint inhibitors [...] Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)

Research

Jump to: Editorial, Review, Other

13 pages, 606 KiB  
Article
Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab
by Matthias Jeschke, Johannes M. Ludwig, Catherine Leyh, Kim M. Pabst, Manuel Weber, Jens M. Theysohn, Christian M. Lange, Ken Herrmann, Hartmut H. -J. Schmidt and Leonie S. Jochheim
Cancers 2023, 15(17), 4274; https://doi.org/10.3390/cancers15174274 - 26 Aug 2023
Viewed by 1284
Abstract
Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment [...] Read more.
Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)
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14 pages, 5139 KiB  
Article
Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma
by Youngsic Jeon, Taejung Kim, Hyukjoon Kwon, Jeong-Kook Kim, Young-Tae Park, Jungyeob Ham and Young-Joo Kim
Cancers 2023, 15(15), 3987; https://doi.org/10.3390/cancers15153987 - 5 Aug 2023
Cited by 3 | Viewed by 2056
Abstract
Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research [...] Read more.
Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research on combination therapy using cabozantinib to improve efficacy and safety when treating patients. Here, we investigated the effect of a combination treatment of cabozantinib and CBD on HCC cells. CBD treatment enhanced the sensitivity of HCC cells to cabozantinib-mediated anti-cancer activity by increasing cytotoxicity and apoptosis. Phospho-kinase array analysis demonstrated that the apoptotic effect of the combination treatment was mainly related to p53 phosphorylation regulated by endoplasmic reticulum (ER) stress when compared to other kinases. The inhibition of p53 expression and ER stress suppressed the apoptotic effect of the combination treatment, revealing no changes in the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, or cleaved caspase-9. Notably, the effect of the combination treatment was not associated with cannabinoid receptor 1 (CNR1) and the CNR2 signaling pathways. Our findings suggest that the combination therapy of cabozantinib and CBD provides therapeutic efficacy against HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)
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15 pages, 3990 KiB  
Article
Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors
by Qianqian Zheng, Masaya Kawaguchi, Hayato Mikami, Pan Diao, Xuguang Zhang, Zhe Zhang, Takero Nakajima, Takanobu Iwadare, Takefumi Kimura, Jun Nakayama and Naoki Tanaka
Cancers 2023, 15(14), 3744; https://doi.org/10.3390/cancers15143744 - 24 Jul 2023
Viewed by 1533
Abstract
Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH [...] Read more.
Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progression to NASH, liver cirrhosis, and HCC. However, most of the NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet, named OYC-NASH2 diet, for 60 weeks. Treatment of OYC-NASH2 diet for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 48-week treatment. Liver nodules emerged at 12 weeks of the treatment, > 2 mm diameter liver tumors developed in all mice at 24 weeks of the treatment and HCC appeared after 36-week treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemicals for NASH-HCC-targeted therapies. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)
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Review

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28 pages, 457 KiB  
Review
Potential Predictive Biomarkers of Systemic Drug Therapy for Hepatocellular Carcinoma: Anticipated Usefulness in Clinical Practice
by Kenta Motomura, Akifumi Kuwano, Kosuke Tanaka, Yuta Koga, Akihide Masumoto and Masayoshi Yada
Cancers 2023, 15(17), 4345; https://doi.org/10.3390/cancers15174345 - 30 Aug 2023
Cited by 2 | Viewed by 1192
Abstract
In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to [...] Read more.
In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)

Other

20 pages, 6796 KiB  
Systematic Review
Prevalence and Effect of Low Skeletal Muscle Mass among Hepatocellular Carcinoma Patients Undergoing Systemic Therapy: A Systematic Review and Meta-Analysis
by Meng-Hsuan Kuo, Chih-Wei Tseng, Ching-Sheng Hsu, Yen-Chun Chen, I-Ting Kao, Chen-Yi Wu and Shih-Chieh Shao
Cancers 2023, 15(9), 2426; https://doi.org/10.3390/cancers15092426 - 23 Apr 2023
Cited by 3 | Viewed by 1912
Abstract
Low skeletal muscle mass (LSMM) is associated with poor outcomes in hepatocellular carcinoma (HCC) patients. With the emergence of new systemic therapeutics, understanding the effect of LSMM on HCC treatment outcomes is critically important. This systematic review and meta-analysis investigates the prevalence and [...] Read more.
Low skeletal muscle mass (LSMM) is associated with poor outcomes in hepatocellular carcinoma (HCC) patients. With the emergence of new systemic therapeutics, understanding the effect of LSMM on HCC treatment outcomes is critically important. This systematic review and meta-analysis investigates the prevalence and effect of LSMM among HCC patients undergoing systemic therapy as reported in studies identified in searches of the PubMed and Embase databases published through 5 April 2023. The included studies (n = 20; 2377 HCC patients undergoing systemic therapy) reported the prevalence of LSMM assessed by computer tomography (CT) and compared the survival outcomes [overall survival (OS) or progression-free survival (PFS)] between HCC patients with and without LSMM. The pooled prevalence of LSMM was 43.4% (95% CI, 37.0–50.0%). A random-effects meta-analysis showed that HCC patients receiving systemic therapy with comorbid LSMM had a lower OS (HR, 1.70; 95% CI, 1.46–1.97) and PFS (HR, 1.32; 95% CI, 1.16–1.51) than did those without. Subgroup analysis according to systemic therapy type (sorafenib, lenvatinib, or immunotherapy) yielded similar results. In conclusion, LSMM is prevalent among HCC patients undergoing systemic therapy and is associated with poorer survival. Early intervention or prevention strategies to improve muscle mass may be necessary for this patient population. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence)
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