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Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (...
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Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition)

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 12619

Special Issue Editor

Dr. Ilyas Sahin

E-Mail Website
Guest Editor
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
Interests: liver cancer; biliary cancer; gallbladder cancer; immunotherapy; targeted therapy; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of the Special Issue titled “Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment”.

Hepatobiliary malignancies, including primary neoplasms of the liver (hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma) and those of the extrahepatic biliary system (distal cholangiocarcinoma and gallbladder carcinoma), are usually aggressive with poor prognosis and limited treatment options. The main objective for the early stage of these tumors is to cure the disease, yet recurrence is common, and most patients with hepatobiliary cancer present with unresectable or advanced disease. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced HCC. However, TKIs are gradually being replaced by the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) as first-line treatment. Due to specific challenges such as the immunosuppressive tumor microenvironment of the liver, the development of immunotherapy in hepatobiliary cancers compared to other cancers has lagged. Fortunately, there are multiple early and advanced-stage ongoing clinical trials investigating the efficacy of combination therapies which might change the landscape of HCC management for different stages in the near future. For advanced biliary tract cancers, genomic characterization has paved the way for developing targeted therapies (FGFR2, IDH1, and BRAF inhibitors) and opened the door to precision medicine. More recently, adding an immunotherapy, durvalumab (anti-PD-L1), to standard chemotherapy for biliary tract cancers has shown improvement in survival. Overall, despite evolving treatment options for hepatobiliary malignancies, there is a substantial unmet clinical need for the early detection of disease, expanding current treatment approaches, such as immunotherapy, and finding novel therapies of these debilitating tumors.

For this Special Issue of Cancers, we welcome the submission of original research and review articles that provide an overview of the most recent advances and future challenges for the diagnosis and treatment of hepatobiliary cancers.

Dr. Ilyas Sahin
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 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

  • hepatobiliary cancers
  • hepatocellular carcinoma
  • cholangiocarcinoma
  • gallbladder cancer
  • immunotherapy
  • targeted therapy
  • precision medicine

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Published Papers (7 papers)

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Research

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27 pages, 2306 KiB  
Article
Impact of Surgical Resection After Induction Gemcitabine Plus S-1-Based Chemoradiotherapy in Patients with Locally Advanced Pancreatic Ductal Adenocarcinoma: A Focus on UR-LA Cases
by Masashi Kishiwada, Shugo Mizuno, Aoi Hayasaki, Benson Kaluba, Takehiro Fujii, Daisuke Noguchi, Takahiro Ito, Yusuke Iizawa, Akihiro Tanemura, Yasuhiro Murata and Naohisa Kuriyama
Cancers 2025, 17(6), 1048; https://doi.org/10.3390/cancers17061048 - 20 Mar 2025
Viewed by 285
Abstract
Background: This study aimed to assess the safety and efficacy of gemcitabine plus S-1-based chemoradiotherapy (GS-CRT) among patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), especially among those with unresectable locally advanced (UR-LA) cases. Methods: A total of 351 consecutive PDAC patients [...] Read more.
Background: This study aimed to assess the safety and efficacy of gemcitabine plus S-1-based chemoradiotherapy (GS-CRT) among patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), especially among those with unresectable locally advanced (UR-LA) cases. Methods: A total of 351 consecutive PDAC patients were enrolled and prognostic predictors of disease-specific survival (DSS) were identified. Results: The treatment completion rate was 98.9% and Grade 3 or higher adverse events occurred in 181 cases (51.6%). Among 319 re-evaluated patients, pancreatectomy was performed in 184 (57.7%). Based on resectability, the 5-year DSS rates for the entire cohort were 39.6% (R), 43.8% (BR-PV), 21.2% (BR-A) and 13.3% (UR-LA), while the predictors of DSS were performance status (PS), hemoglobin (Hb) level, celiac artery (CA) involvement of ≥180 degrees and JPS 8th T category. In the resected cases, the predictors of DSS were preoperative PS, preoperative CA19-9 level, preoperative JPS-T factor, degree of histological response and adjuvant chemotherapy. In UR-LA resected patients, preoperative prognostic nutritional index (PNI), absence of pathological venous invasion and adjuvant chemotherapy were predictors of DSS. Conclusions: Even though Grade 3 or higher adverse events were encountered in about half of the cases, they were uneventfully managed. Therefore, GS-CRT is safe and highly tolerable with potential to improve patients‘ prognosis. Preoperative PS, CA19-9 levels and histological response are important prognostic factors, as well as adjuvant therapy. In UR-LA patients, prognostic nutritional index (PNI) and adjuvant chemotherapy were important for curative intent surgery. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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12 pages, 654 KiB  
Article
Sequential Use of Sorafenib and Regorafenib in Hepatocellular Cancer Recurrence After Liver Transplantation: Treatment Strategies and Outcomes
by Mehmet Fatih Ozbay, Hakan Harputluoglu, Mustafa Karaca, Omer Tekin, Mehmet Ali Nahit Şendur, Muhammed Ali Kaplan, Berksoy Sahin, Caglayan Geredeli, Fatih Teker, Deniz Tural, Sezer Saglam, Timuçin Çil, Ahmet Bilici, Cihan Erol, Ziya Kalkan, Ertugrul Bayram, Oguzhan Selvi, İlkay Gültürk, Sema Sezgin Göksu and Ali Murat Tatlı
Cancers 2024, 16(22), 3880; https://doi.org/10.3390/cancers16223880 - 20 Nov 2024
Cited by 1 | Viewed by 1335
Abstract
Background and Aims: During liver transplantation, hepatocellular carcinoma (HCC) recurrence remains a critical challenge for patient survival. Targeted therapies, such as sorafenib and regorafenib, have been utilized to manage relapsed HCC in this unique setting. This study aimed to assess the efficacy of [...] Read more.
Background and Aims: During liver transplantation, hepatocellular carcinoma (HCC) recurrence remains a critical challenge for patient survival. Targeted therapies, such as sorafenib and regorafenib, have been utilized to manage relapsed HCC in this unique setting. This study aimed to assess the efficacy of Sorafenib and Regorafenib in patients with HCC who experienced recurrence after liver transplantation. We focused on survival outcomes, treatment responses, and the management of side effects in this patient group. Methods: We conducted a retrospective analysis of 73 patients who experienced HCC recurrence post-liver transplantation between 2012 and 2022 across 11 oncology centers in Turkey. Patients were categorized according to Child–Pugh classification and treated with sorafenib as first-line therapy and Regorafenib in case of progression. Survival rates were analyzed using the Kaplan–Meier method, and risk factors were evaluated using Cox regression analysis. Results: Of the 73 patients included in the study, 62 were male (84.9%), and 11 were female (15.1%), with a mean age of 61.5 ± 10.9 years. All patients received sorafenib as first-line treatment. Among patients who experienced progression with sorafenib or discontinued treatment due to toxicity, 45.2% (n = 33) continued treatment with regorafenib. The median progression-free survival (PFS1) time with sorafenib was 5.6 months, and the one-year survival rate was 24.3%. The median progression-free survival (PFS2) time with regorafenib, which was administered as second-line treatment, was also calculated as 5.9 months. Overall survival (OS) duration was determined as 35.9 months. The most common side effects associated with both drugs included fatigue, hand and foot syndrome, and hypertension. Significantly better survival outcomes were shown in the Child–Pugh A group compared to other patients. Conclusions: These results suggest that Sorafenib and Regorafenib treatments offer a survival advantage in patients with relapsed HCC post-transplantation. However, individualized treatment strategies and close follow-up are crucial for optimizing outcomes. Further studies are needed to refine therapeutic protocols and enhance the care of this specific patient group. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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13 pages, 845 KiB  
Article
Patient Outcomes in Resected Combined Hepatocellular Cholangiocarcinoma (cHCC-ICC) and Intrahepatic Cholangiocarcinoma: A Single Center Study
by Rick Y. Lin, Doga Kahramangil, Muhammet Ozer, Thomas J. George, Ibrahim Nassour, Steven J. Hughes, Ali Zarrinpar and Ilyas Sahin
Cancers 2024, 16(22), 3878; https://doi.org/10.3390/cancers16223878 - 20 Nov 2024
Viewed by 1081
Abstract
Background/Objectives: Combined hepatocellular cholangiocarcinoma (cHCC-ICC) is a rare malignancy that involves a combination of features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) and exhibits a more aggressive clinical course; however, its risk factors and outcomes remain largely undefined. Methods: This study is a [...] Read more.
Background/Objectives: Combined hepatocellular cholangiocarcinoma (cHCC-ICC) is a rare malignancy that involves a combination of features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) and exhibits a more aggressive clinical course; however, its risk factors and outcomes remain largely undefined. Methods: This study is a single-center retrospective study of 82 patients diagnosed with ICC or cHCC-ICC who underwent surgical resection from June 2011 to January 2023. Our analysis included 70 patients with resected ICC and 12 with resected cHCC-ICC. Results: The overall survival (OS) for the entire cohort was 21.6 months, with a recurrence-free survival (RFS) of 11.8 months. The cHCC-ICC group had significantly higher levels of AST and ALT (AST median 206 U/L vs. 46 U/L; ALT median 165.5 U/L vs. 48 U/L; p = 0.012 and p = 0.013, respectively), whereas the ICC group had higher alkaline phosphatase (median 66 U/L vs. 104 U/L; p = 0.03). CA 19-9 values (76 U/mL vs. 22 U/mL; p = 0.02) were higher in the ICC group, while AFP values were higher in the cHCC-ICC group (7.3 ng/mL vs. 3.2 ng/mL; p = 0.0004). The cHCC-ICC group had a significantly higher rate of recurrence (83% vs. 47%, p = 0.028) with a significantly decreased RFS (4.7 months vs. 12.4 months; log-rank p = 0.007). In multivariate analysis, patients with resected ICC had a significantly reduced risk of recurrence by 73% compared to their counterparts (HR 0.27 [0.10–0.73], p = 0.01). Conclusions: cHCC-ICC is a rare entity that needs to be further studied to improve patient outcomes. Further studies are warranted and may suggest the need for more aggressive initial treatment strategies in patients diagnosed with cHCC-ICC. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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Review

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22 pages, 589 KiB  
Review
Hepatocellular Carcinoma After HCV Eradication with Direct-Acting Antivirals: A Reappraisal Based on New Parameters to Assess the Persistence of Risk
by Eduardo Fassio, Luis Colombato, Gisela Gualano, Soledad Perez, Miguel Puga-Tejada and Graciela Landeira
Cancers 2025, 17(6), 1018; https://doi.org/10.3390/cancers17061018 - 18 Mar 2025
Viewed by 417
Abstract
Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although [...] Read more.
Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although ameliorated, the risk of developing hepatocellular carcinoma (HCC) persists, particularly among patients with pre-treatment advanced fibrosis/cirrhosis. Current guidelines recommend indefinite HCC surveillance in these patients. However, a recent Markov model evaluation shows that HCC surveillance is cost-effective only for patients with cirrhosis but not so for those with F3 fibrosis, a finding which points out the need to better define the risk of HCC in hepatitis C patients after cure and further characterize pre- and post-treatment factors that might affect the incidence of HCC in this setting. We reviewed the literature analyzing this aspect. Here we summarize the main findings: male gender and older age are independent predictors of increased risk of post-cure HCC development. Moreover, non-invasive tests for hepatic fibrosis, namely FIB4, APRI, and liver stiffness, measured before and after treatment and their post-therapy change, contribute to better stratifying the risk of HCC occurrence. Furthermore, low serum albumin, as well as an AFP above 7 ng/mL prior to and after DAA therapy, also constitute independent predictors of HCC development. Considering these findings, we propose to classify patients with HCV viral eradication and advanced fibrosis/cirrhosis into groups of low, medium, or high risk of HCC and to adopt adequate surveillance strategies for each group, including protocols for abbreviated magnetic resonance imaging (MRI) for those at the highest risk. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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Graphical abstract

28 pages, 1260 KiB  
Review
Next-Generation Immunotherapy for Hepatocellular Carcinoma: Mechanisms of Resistance and Novel Treatment Approaches
by Shabnam Eghbali and Thatcher Ross Heumann
Cancers 2025, 17(2), 236; https://doi.org/10.3390/cancers17020236 - 13 Jan 2025
Cited by 1 | Viewed by 2605
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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10 pages, 679 KiB  
Review
Radiation Segmentectomy for the Treatment of Hepatocellular Carcinoma: A Practical Review of Evidence
by Sophia N. Mourad, Cynthia De la Garza-Ramos and Beau B. Toskich
Cancers 2024, 16(3), 669; https://doi.org/10.3390/cancers16030669 - 4 Feb 2024
Cited by 3 | Viewed by 3089
Abstract
Radiation segmentectomy is a versatile, safe, and effective ablative therapy for early-stage hepatocellular carcinoma. Advances in radiation segmentectomy patient selection, procedural technique, and dosimetry have positioned this modality as a curative-intent and guideline-supported treatment for patients with solitary HCC. This review describes key [...] Read more.
Radiation segmentectomy is a versatile, safe, and effective ablative therapy for early-stage hepatocellular carcinoma. Advances in radiation segmentectomy patient selection, procedural technique, and dosimetry have positioned this modality as a curative-intent and guideline-supported treatment for patients with solitary HCC. This review describes key radiation segmentectomy concepts and summarizes the existing literary knowledgebase. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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Other

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12 pages, 1691 KiB  
Systematic Review
Evaluation of Overall Survival by Restricted Mean Survival Time of Advanced Biliary Tract Cancer treated with Immunotherapy: A Systematic Review and Meta-Analysis
by Ezequiel Mauro, Marco Sanduzzi-Zamparelli, Tamara Sauri, Alexandre Soler, Gemma Iserte, Marta Fortuny and Alejandro Forner
Cancers 2024, 16(11), 2077; https://doi.org/10.3390/cancers16112077 - 30 May 2024
Viewed by 2775
Abstract
Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier [...] Read more.
Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. Methods: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. Results: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49–1.93), p < 0.001, I2 = 0%]. Conclusions: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment (2nd Edition))
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