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The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma
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The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma

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

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 11560

Special Issue Editors

Dr. Zachary J. Brown

E-Mail Website
Guest Editor
Division of Surgical Oncology, NYU Langone Health, NYU Grossman Long Island School of Medicine, New York, NY, USA
Interests: hepatocellular carcinoma; gastrointestinal malignancies; cancer metastasis
Special Issues, Collections and Topics in MDPI journals
Dr. John D. Allendorf

E-Mail Website
Guest Editor
Professor of Surgery, Chief-Division of Surgical Oncology, Vice Chair-Department of Surgery, NYU Grossman Long Island School of Medicine, New York, NY 10016, USA
Interests: liver cancer; liver metastasis

Special Issue Information

Dear Colleagues,

Over the last few years, the treatment of hepatocellular carcinoma has evolved with the introduction of new systemic therapies as well as recent updates to the Barcelona Clinic Liver Cancer staging system.

We are pleased to invite you to contribute to this Special Issue of Cancers titled: “The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma”.

This Special Issue aims to review the changing treatment program for hepatocellular carcinoma as well as future directions in the management of patients with HCC.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: advances in medical therapy, including immune-based therapies in the treatment of HCC, mechanisms of resistance to systemic therapies, and advances in surgical and locoregional therapies in the treatment of HCC.

We look forward to receiving your contributions.

Dr. Zachary J. Brown
Dr. John D. Allendorf
Guest Editors

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 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.

Keywords

  • hepatocellular carcinoma
  • liver resection
  • liver transplant
  • transarterial chemoembolization
  • immune therapies
  • liver disease

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Published Papers (9 papers)

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Research

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17 pages, 4581 KiB  
Article
Detection of Hepatocellular Carcinoma in an Orthotopic Patient-Derived Xenograft with an Epithelial Cell Adhesion Molecule-Specific Peptide
by Xiaoli Wu, Shuo Feng, Tse-Shao Chang, Ruoliu Zhang, Sangeeta Jaiswal, Eun-Young K. Choi, Yuting Duan, Hui Jiang and Thomas D. Wang
Cancers 2024, 16(16), 2818; https://doi.org/10.3390/cancers16162818 - 10 Aug 2024
Viewed by 961
Abstract
Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We [...] Read more.
Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min−1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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12 pages, 700 KiB  
Article
Protective Effect of Minimally Invasive Approach on Postoperative Peak Transaminase Following Liver Resection: A Single-Center Propensity Score-Based Analysis
by Francesco Ardito, Sara Ingallinella, Quirino Lai, Francesco Razionale, Davide De Sio, Caterina Mele, Simone Vani, Maria Vellone and Felice Giuliante
Cancers 2024, 16(14), 2605; https://doi.org/10.3390/cancers16142605 - 21 Jul 2024
Viewed by 662
Abstract
Background: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open [...] Read more.
Background: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open hepatectomy by assessing the differences of postoperative ALT levels. Methods: Patients who underwent MILS between 2009 and 2019 at our unit were included and compared with open liver resections. Median ALT levels was measured on postoperative day (POD) 1, 3 and 5. Postoperative peak transaminase (PPT) of ALT was determined on POD 1. The stabilized inverse probability treatment weighing (SIPTW) process was used to balance the two groups. A multivariable logistic regression analysis was used to analyze factors associated with high PPT. Results: After SIPTW, 292 MILS were compared with 159 open resections. Median ALT levels on POD 1, 3 and 5 were significantly higher in the open group than in the MILS group (301 vs. 187, p = 0.002; 180 vs. 121, p < 0.0001; 104 vs. 60, p < 0.0001; respectively). At the multivariable logistic regression analysis, MILS showed a protective effect for high PPT. Conclusions: MILS was associated with significantly lower postoperative ALT levels compared with open liver resections. MILS showed a protective effect for high PPT. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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16 pages, 2639 KiB  
Article
Anatomical Quantitative Volumetric Evaluation of Liver Segments in Hepatocellular Carcinoma Patients Treated with Selective Internal Radiation Therapy: Key Parameters Influencing Untreated Liver Hypertrophy
by Raphaël Girardet, Jean-François Knebel, Clarisse Dromain, Naik Vietti Violi, Georgia Tsoumakidou, Nicolas Villard, Alban Denys, Nermin Halkic, Nicolas Demartines, Kosuke Kobayashi, Antonia Digklia, Niklaus Schaefer, John O. Prior, Sarah Boughdad and Rafael Duran
Cancers 2024, 16(3), 586; https://doi.org/10.3390/cancers16030586 - 30 Jan 2024
Viewed by 1358
Abstract
Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT [...] Read more.
Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT using an anatomical volumetric approach in hepatocellular carcinoma (HCC) patients with different levels of treatment selectivity and evaluate the parameters affecting those changes. This retrospective, single-institution, IRB-approved study included 88 HCC patients. Whole liver, liver segments, tumor burden, and spleen volumes were quantified on MRI at baseline and 3/6/12 months post-SIRT using a segmentation-based 3D software relying on liver vascular anatomy. Treatment characteristics, longitudinal clinical/laboratory, and imaging data were analyzed. The Student’s t-test and Wilcoxon test evaluated volumetric parameters evolution. Spearman correlation was used to assess the association between variables. Uni/multivariate analyses investigated factors influencing untreated liver volume (uLV) increase. Results: Most patients were cirrhotic (92%) men (86%) with Child–Pugh A (84%). Absolute and relative uLV kept increasing at 3/6/12 months post-SIRT vs. baseline (all, p ≤ 0.005) and was maximal during the first 6 months. Absolute uLV increase was greater in Child–Pugh A5/A6 vs. ≥B7 at 3 months (A5, p = 0.004; A6, p = 0.007) and 6 months (A5, p = 0.072; A6, p = 0.031) vs. baseline. When the Child–Pugh class worsened at 3 or 6 months post-SIRT, uLV did not change significantly, whereas it increased at 3/6/12 months vs. baseline (all p ≤ 0.015) when liver function remained stable. The Child–Pugh score was inversely correlated with absolute and relative uLV increase at 3 months (rho = −0.21, p = 0.047; rho = −0.229, p = 0.048). In multivariate analysis, uLV increase was influenced at 3 months by younger age (p = 0.013), administered 90Y activity (p = 0.003), and baseline spleen volume (p = 0.023). At 6 months, uLV increase was impacted by younger age (p = 0.006), whereas treatment with glass microspheres (vs. resin) demonstrated a clear trend towards better hypertrophy (f = 3.833, p = 0.058). The amount (percentage) of treated liver strongly impacted the relative uLV increase at 3/6/12 months (all f ≥ 8.407, p ≤ 0.01). Conclusion: Liver function (preserved baseline and stable post-SIRT) favored uLV hypertrophy. Younger patients, smaller baseline spleen volume, higher administered 90Y activity, and a larger amount of treated liver were associated with a higher degree of untreated liver hypertrophy. These factors should be considered in surgical candidates undergoing neoadjuvant SIRT. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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Review

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19 pages, 1202 KiB  
Review
Role of Imaging in Screening for Hepatocellular Carcinoma
by Irfan A. Kazi, Vinay Jahagirdar, Bareen W. Kabir, Almaan K. Syed, Asad W. Kabir and Abhilash Perisetti
Cancers 2024, 16(19), 3400; https://doi.org/10.3390/cancers16193400 - 5 Oct 2024
Viewed by 1178
Abstract
Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. [...] Read more.
Primary liver cancer is among the most common cancers globally. It is the sixth-most common malignancy encountered and the third-most common cause of cancer-related death. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for about 90% of primary liver cancers. The majority of HCCs occur in patients with underlying cirrhosis, which results from chronic liver diseases such as fatty liver, hepatitis B and hepatitis C infections, and chronic alcohol use, which are the leading causes. The obesity pandemic has led to an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which leads to nonalcoholic steatohepatitis and could progress to cirrhosis. As HCC is among the most common cancers and occurs in the setting of chronic liver disease in most patients, screening the population at risk could help in early diagnosis and management, leading to improved survival. Screening for HCC is performed using biochemical marker testing such as α-fetoprotein (AFP) and cross-sectional imaging. It is critical to emphasize that HCC could potentially occur in patients without cirrhosis (non-cirrhotic HCC), which can account for almost 20% of all HCCs. The lack of cirrhosis can cause a delay in surveillance, which could potentially lead to diagnosis at a later stage, worsening the prognosis for such patients. In this article, we discuss the diagnosis of cirrhosis in at-risk populations with details on the different modalities available for screening HCC in patients with cirrhosis, emphasizing the role of abdominal ultrasounds, the primary imaging modality in HCC screening. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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20 pages, 2337 KiB  
Review
The Molecular Mechanisms of Portal Vein Thrombosis in Hepatocellular Carcinoma
by Linda Galasso, Lucia Cerrito, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco
Cancers 2024, 16(19), 3247; https://doi.org/10.3390/cancers16193247 - 24 Sep 2024
Viewed by 809
Abstract
Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of [...] Read more.
Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of about 25–50% in HCC, determining poor prognosis and a remarkable reduction in therapeutic perspectives in these patients, leading to severe complications such as ascites, metastasis, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The aim of this review is to evaluate the molecular mechanisms that are at the basis of PVT development, trying to evaluate possible strategies in the early detection of patients at high risk of PVT. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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21 pages, 338 KiB  
Review
Evolution of Systemic Treatment for Hepatocellular Carcinoma: Changing Treatment Strategies and Concepts
by Michihisa Moriguchi, Seita Kataoka and Yoshito Itoh
Cancers 2024, 16(13), 2387; https://doi.org/10.3390/cancers16132387 - 28 Jun 2024
Viewed by 1599
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has [...] Read more.
Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
23 pages, 2587 KiB  
Review
Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress
by Linda Galasso, Lucia Cerrito, Valeria Maccauro, Fabrizio Termite, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco
Cancers 2024, 16(10), 1837; https://doi.org/10.3390/cancers16101837 - 11 May 2024
Cited by 2 | Viewed by 1280
Abstract
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma [...] Read more.
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor’s defensive fort. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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14 pages, 1097 KiB  
Review
Dynamic Contrast-Enhanced Ultrasound in the Prediction of Advanced Hepatocellular Carcinoma Response to Systemic and Locoregional Therapies
by Lucia Cerrito, Maria Elena Ainora, Giuseppe Cuccia, Linda Galasso, Irene Mignini, Giorgio Esposto, Matteo Garcovich, Laura Riccardi, Antonio Gasbarrini and Maria Assunta Zocco
Cancers 2024, 16(3), 551; https://doi.org/10.3390/cancers16030551 - 27 Jan 2024
Viewed by 1612
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the sixth most common malignant tumor in the world, with an incidence of 2–8% per year in patients with hepatic cirrhosis or chronic hepatitis. Despite surveillance schedules, it is sometimes diagnosed at [...] Read more.
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the sixth most common malignant tumor in the world, with an incidence of 2–8% per year in patients with hepatic cirrhosis or chronic hepatitis. Despite surveillance schedules, it is sometimes diagnosed at an advanced stage, requiring complex therapeutic efforts with both locoregional and systemic treatments. Traditional radiological tools (computed tomography and magnetic resonance) are used for the post-treatment follow-up of HCC. The first follow-up imaging is performed at 4 weeks after resection or locoregional treatments, or after 3 months from the beginning of systemic therapies, and subsequently every 3 months for the first 2 years. For this reason, these radiological methods do not grant the possibility of an early distinction between good and poor therapeutic response. Contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced ultrasound (DCE-US) have gained the interest of several researchers for their potential role in the early assessment of response to locoregional treatments (chemoembolization) or antiangiogenic therapies in patients with advanced HCC. In fact, DCE-US, through a quantitative analysis performed by specific software, allows the construction of time–intensity curves, providing an evaluation of the parameters related to neoplastic tissue perfusion and its potential changes following therapies. It has the invaluable advantage of being easily repeatable, minimally invasive, and able to grant important evaluations regarding patients’ survival, essential for well-timed therapeutic changes in case of unsatisfying response, and eventual further treatment planning. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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Other

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13 pages, 3610 KiB  
Systematic Review
Prevalence of and Impact on the Outcome of Myosteatosis in Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis
by Aikaterini Kamiliou, Vasileios Lekakis, George Xynos and Evangelos Cholongitas
Cancers 2024, 16(5), 952; https://doi.org/10.3390/cancers16050952 - 27 Feb 2024
Cited by 1 | Viewed by 1375
Abstract
Background: Limited data exist on the prevalence of myosteatosis (i.e., excess accumulation of fat in skeletal muscles) in hepatocellular carcinoma (HCC) patients, and no systematic review or meta-analysis has been conducted in this context. Methods: We searched for articles published from inception until [...] Read more.
Background: Limited data exist on the prevalence of myosteatosis (i.e., excess accumulation of fat in skeletal muscles) in hepatocellular carcinoma (HCC) patients, and no systematic review or meta-analysis has been conducted in this context. Methods: We searched for articles published from inception until November 2023 to assess the prevalence of myosteatosis in patients with HCC. Results: Ten studies with 3316 patients focusing on myosteatosis and HCC were included. The overall prevalence of myosteatosis in HCC patients was 50% [95% Confidence Interval (CI): 35–65%]. Using the body mass index-based criteria (two studies), the prevalence was 34%, while gender-based criteria (eight studies) yielded 54% (p = 0.31). In Asian studies (n = 8), the prevalence was 45%, compared to 69% in non-Asian countries (two studies) (p = 0.02). For viral-associated HCC (eight studies), the prevalence was 49%, rising to 65% in non-alcoholic fatty liver disease-associated cases (three studies) and 86% in alcoholic liver disease-associated cases (three studies) (p < 0.01). The prevalence of myosteatosis was higher in Child–Pugh class C (3 studies, 91%) than in A (7 studies, 73%) or B (6 studies, 50%) (p = 0.02), but with no difference between Barcelona Clinic Liver Cancer stage A (3 studies, 66%), B (4 studies, 44%) and C (3 studies, 62%) (p = 0.80). Patients with myosteatosis had a significantly higher mortality (six studies) (Relative Risk: 1.35 (95%CI: 1.13–1.62, p < 0.01). Conclusion: The prevalence of myosteatosis is high in HCC patients and is associated with more severe liver disease and higher mortality rates. Full article
(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)
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