Advances in the Management of Hepatocellular Carcinoma

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editor

Department of Surgery, Duke University Medical Center, 2301 Erwin Rd, Durham, NC, USA
Interests: transplantation; surgical oncology; Hepato-Pancreato-Biliary (HPB) surgery
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with over 750,000 new cases annually and a concomitant increase in the mortality rate. Despite prevention and screening efforts, as well as the development of new technologies for diagnosis and treatment, the incidence of HCC has doubled, and mortality rates have increased in recent decades. Multiple treatment modalities have been proposed for HCC. Liver transplantation (LT) and surgical resection with curative potential are currently the primary treatments. Selection of treatment modality is based on tumor size, tumor location, extrahepatic spread, and underlying liver function. Patients undergoing LT or surgical resection achieve a long-term survival rate of more than 50% at 5 years; however, only a small group of patients with early stage HCC are eligible for these therapies.

Among the staging systems available, the Barcelona Clinic Liver Cancer (BCLC) system has been used widely in the West. According to the BCLC system, resection should be offered only to patients with BCLC-0 and BCLC-A HCC. Nevertheless, these criteria have been considered to be too vague and restrictive, with studies showing heterogeneous outcomes after resection of HCC within the same stage. In addition, several investigators have recently advocated for extending the criteria for resection, acknowledging that certain patients with BCLC-B HCC may benefit more from surgery than other locoregional therapies. The prognostic discrimination as well as the treatment allocation of the revised BCLC classification have been questioned, emphasizing the need for refinement and further subclassification of this system.

Dr. Dimitrios Moris
Collection Editor

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Keywords

  • hepatocellular carcinoma
  • BCLC
  • resection
  • transplantation
  • immunotherapy
  • chemotherapy

Published Papers (23 papers)

2023

Jump to: 2022, 2021, 2020

17 pages, 739 KiB  
Article
Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy
Cancers 2023, 15(13), 3343; https://doi.org/10.3390/cancers15133343 - 25 Jun 2023
Viewed by 1229
Abstract
PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in [...] Read more.
PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p < 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors. Full article
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2022

Jump to: 2023, 2021, 2020

20 pages, 28508 KiB  
Systematic Review
Clinical Outcomes Associated with Monotherapy and Combination Therapy of Immune Checkpoint Inhibitors as First-Line Treatment for Advanced Hepatocellular Carcinoma in Real-World Practice: A Systematic Literature Review and Meta-Analysis
Cancers 2023, 15(1), 260; https://doi.org/10.3390/cancers15010260 - 30 Dec 2022
Cited by 2 | Viewed by 1461
Abstract
Background: Immune checkpoint inhibitors (ICIs)-based therapy has recently been demonstrated to greatly ameliorate survival outcomes in advanced hepatocellular carcinoma (HCC). We aimed to evaluate clinical outcomes of ICIs-based monotherapy and combination therapy as first-line treatment of adults with advanced HCC in real-world practice [...] Read more.
Background: Immune checkpoint inhibitors (ICIs)-based therapy has recently been demonstrated to greatly ameliorate survival outcomes in advanced hepatocellular carcinoma (HCC). We aimed to evaluate clinical outcomes of ICIs-based monotherapy and combination therapy as first-line treatment of adults with advanced HCC in real-world practice by conducting a systematic literature review and meta-analysis. Methods: PubMed, Web of Science, and Embase were searched up to 25 April 2022. Retrospective or prospective real-world studies evaluating progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) of patients with advanced HCC receiving first-line ICIs-based therapy were included. Results: Of 7805 studies retrieved, 38 were deemed eligible for inclusion. For patients receiving first-line ICIs-based therapy in real-world practice, the pooled median PFS and OS were 7.03 (95% CI: 5.55–8.51) and 14.39 (95% CI: 10.91–17.86) months. The ORR and DCR were 0.432 (95% CI: 0.327–0.538) and 0.756 (95% CI: 0.677–0.836), according to mRECIST 1.1, 0.317 (95% CI: 0.218–0.416) and 0.740 (95% CI: 0.644–0.835), judged by RECIST 1.1. The best outcomes of survival and response rate were observed in ICIs-based combination therapy of ICIs, TKIs, plus LRTs. Furthermore, ORR, DCR judged by mRECIST 1.1, and PFS could be potential prognostic factors for OS. Conclusions: This research revealed diversified first-line ICIs-based therapies for advanced HCC in real-world practice. Future studies are needed to adopt prospective, multicentric and comparative designs to test the ICIs-based combination therapies, especially triple therapies of ICIs, TKIs, plus LRTs. Full article
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14 pages, 1324 KiB  
Article
Low Frequency of Cancer-Predisposition Gene Mutations in Liver Transplant Candidates with Hepatocellular Carcinoma
Cancers 2023, 15(1), 201; https://doi.org/10.3390/cancers15010201 - 29 Dec 2022
Cited by 2 | Viewed by 1943
Abstract
Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV [...] Read more.
Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients. Full article
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10 pages, 1556 KiB  
Article
Stereotactic Ablative Radiotherapy for Oligometastatic Hepatocellular Carcinoma: A Multi-Institutional Retrospective Study (KROG 20-04)
Cancers 2022, 14(23), 5848; https://doi.org/10.3390/cancers14235848 - 27 Nov 2022
Cited by 1 | Viewed by 1297
Abstract
We investigated the clinical efficacy of stereotactic ablative radiotherapy (SABR) in patients with oligometastatic hepatocellular carcinoma (HCC). The inclusion criteria were patients receiving definitive treatment for HCC with 1–5 metastatic lesions, <3 metastases in a single organ and receiving radiotherapy with fraction doses [...] Read more.
We investigated the clinical efficacy of stereotactic ablative radiotherapy (SABR) in patients with oligometastatic hepatocellular carcinoma (HCC). The inclusion criteria were patients receiving definitive treatment for HCC with 1–5 metastatic lesions, <3 metastases in a single organ and receiving radiotherapy with fraction doses ≥6 Gy. A total of 100 patients with 121 metastatic lesions were reviewed. The most common site of metastasis was the bones (40%), followed by the lungs (38%). Systemic therapy was administered to 71% of patients. With a median follow-up of 13 months, the median overall survival (OS) was 16 months. The 2-year OS rate was 40%. The prognostic factors in univariate analysis were performance status, Child–Pugh class, primary HCC status, and time interval of metastasis. Performance status and Child–Pugh class remained in multivariate analysis. OS differed significantly depending on the number of prognostic factors: 46 months in patients with both factors (Group 1), 13 months with one factor (Group 2), and 6 months with no risk factor (Group 3) (p < 0.001). Nine patients experienced grade 1 radiation pneumonitis. Given its efficacy and safety, SABR deserves active consideration in the treatment of oligometastatic HCC. Full article
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12 pages, 1677 KiB  
Systematic Review
Hepatocellular Carcinoma Recurrence and Mortality Rate Post Liver Transplantation: Meta-Analysis and Systematic Review of Real-World Evidence
Cancers 2022, 14(20), 5114; https://doi.org/10.3390/cancers14205114 - 19 Oct 2022
Cited by 8 | Viewed by 1486
Abstract
Background: liver transplantation (LT) is the best curative option for eligible patients with hepatocellular carcinoma (HCC), however recurrence remains a major concern. This meta-analysis aimed to investigate the prevalence and risk factors of HCC recurrence. Methods: studies were selected using PubMed, Epistemonikas, and [...] Read more.
Background: liver transplantation (LT) is the best curative option for eligible patients with hepatocellular carcinoma (HCC), however recurrence remains a major concern. This meta-analysis aimed to investigate the prevalence and risk factors of HCC recurrence. Methods: studies were selected using PubMed, Epistemonikas, and Google Scholar databases published from inception to 15 May 2022 and a meta-analysis of the proportions was conducted. Observational studies reporting the prevalence of recurrent HCC after an LT were included, with the analysis being stratified by an adherence to the Milan criteria (MC), geographical region, AFP levels, and donor type. Results: out of 4081 articles, 125 were included in the study. The prevalence of recurrent HCC was 17% (CI: 15–19). Patients beyond the MC were more likely to recur than patients within the MC. Asian populations had the greatest prevalence of HCC recurrence (21%; CI: 18–24), whereas North American populations had the lowest recurrence (10%; CI: 7–12). The mortality rate after HCC recurrence was 9%; CI: 8–11. North American populations had the greatest prevalence of mortality with 11% (CI: 5–17). Conclusions: the recurrence, overall survival, and mortality rates among patients with HCC post-LT remains high, with substantial differences between regions. Full article
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13 pages, 1556 KiB  
Article
Modified Albumin–Bilirubin Model for Stratifying Survival in Patients with Hepatocellular Carcinoma Receiving Anticancer Therapy
Cancers 2022, 14(20), 5083; https://doi.org/10.3390/cancers14205083 - 17 Oct 2022
Viewed by 1275
Abstract
Albumin–bilirubin (ALBI) grade is an objective and reproducible model for evaluating overall survival (OS) in patients with hepatocellular carcinoma (HCC). However, the original ALBI grade was established for patients with Child–Pugh classes A–C. HCC patients with Child–Pugh class C or poor performance status [...] Read more.
Albumin–bilirubin (ALBI) grade is an objective and reproducible model for evaluating overall survival (OS) in patients with hepatocellular carcinoma (HCC). However, the original ALBI grade was established for patients with Child–Pugh classes A–C. HCC patients with Child–Pugh class C or poor performance status (Barcelona Clinic Liver Cancer (BCLC) stage D) usually receive hospice care. Thus, optimized cutoffs for the ALBI grade for stratifying OS in HCC patients receiving anticancer therapy are pertinent for accurate prognostication. This study retrospectively enrolled 2116 patients with BCLC stages A–C HCC after the exclusion of those ineligible for receiving anticancer therapy. The modified ALBI (mALBI) grades were: an ALBI score ≤−3.02 for mALBI grade 1, an ALBI score >−3.02 to ≤−2.08 for mALBI grade 2, and an ALBI score >−2.08 for mALBI grade 3. The original ALBI and mALBI grades were independent predictors of OS in all the enrolled patients and those receiving transarterial chemoembolization. In patients receiving curative therapy (radiofrequency ablation and surgical resection), the mALBI grade (grade 2 vs. 1 and grade 3 vs. 2) was an independent predictor of OS. Original ALBI grade 2 vs. 1 was an independent predictor of OS but not ALBI grade 3 vs. 2. The mALBI model can differentiate between patients with early, intermediate, or advanced HCC who received anticancer therapy into three prognostic groups. External validation of the proposed mALBI grade is warranted. Full article
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19 pages, 1144 KiB  
Article
Surgical Resection Is Superior to TACE in the Treatment of HCC in a Well Selected Cohort of BCLC-B Elderly Patients—A Retrospective Observational Study
Cancers 2022, 14(18), 4422; https://doi.org/10.3390/cancers14184422 - 12 Sep 2022
Cited by 3 | Viewed by 1324
Abstract
Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection [...] Read more.
Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection (SR) according to a more complex evaluation, to establish its safety and efficacy. A total of 186 selected HCC patients (median age 73.2 yrs), submitted to SR between January 2005 and January 2021, were retrospectively analyzed. Of which, 166 were staged 0, A, B according to the BCLC system, while 20 with a single large tumor (>5 cm) were classified as stage AB. No perioperative mortality was recorded; complications occurred in 48 (25.80%) patients, and all but two were Clavien–Dindo grade I–II. Median follow-up was 9.2 years. Subsequently, 162 recurrent patients (87,1%) were selected for new treatments. Comparable overall survival rates (OS) were observed at 1, 3, 5, and 10 years in 0, A, B and AB stages (p = 0.2). Eventually, the BCLC-B group was matched to 40 BCLC-B patients treated (2015-2021) with TACE. Significant differences in baseline characteristics (p <0.0001) and in OS were observed at 1 and 3 years (p <0.0001); a significant difference was also observed in oncological outcomes, in terms of the absence, residual, or relapse of disease (p <0.05). Surgery might be a valid treatment in HCC for patients affected by chronic liver disease in a condition of compensation, up to BCLC-B stage. Surgical indication for liver resection in case of HCC should be extensively revised. Full article
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13 pages, 968 KiB  
Article
Individualized Approach in the Surgical Management of Hepatocellular Carcinoma: Results from a Greek Multicentre Study
Cancers 2022, 14(18), 4387; https://doi.org/10.3390/cancers14184387 - 09 Sep 2022
Cited by 3 | Viewed by 1655
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of death worldwide. The management of HCC is complex, with surgical treatment providing long-term survival in eligible patients. This study aims to present the experience of aggressive [...] Read more.
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of death worldwide. The management of HCC is complex, with surgical treatment providing long-term survival in eligible patients. This study aims to present the experience of aggressive surgical management of HCC in Greece. Methods: This is a retrospective multicentre clinical study with 242 patients. Results: Most patients were male (79%) and had a median age of 71 yrs. According to the most recent BCLC criteria, 172 patients (71.1%) were classified as BCLC 0-A stage, 33 patients (13.6%) were classified as BCLC B, and 37 (15.3%) were classified as BCLC C. A total of 54% of the patients underwent major hepatectomy. Major postoperative morbidity was 15.6%, and the 90-day postoperative mortality rate was 4.5%. The median follow-up was 33.5 months. Three- and five-year overall survival was 65% and 48%, respectively. The median overall survival was 55 months. Significantly, five-year survival was 55% for BCLC A, and 34% and 21% for BCLC B and C, respectively. In univariate analysis, cirrhosis, type of resection (R status), and BCLC stage were associated with overall survival. Multivariate analysis indicated that R1 and R2 resections compared to R0, and BCLC C compared to BCLC 0-A, were independently associated with increased mortality. Conclusions: Aggressive surgical treatment of HCC offers satisfactory long-term survival prospects. A significant percentage (29%) of HCCs that underwent liver resection were of the intermediate and advanced BCLC stage. The management of patients with HCC should be discussed in multidisciplinary tumour board meetings on a case-by-case basis to be more effective. Full article
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15 pages, 5121 KiB  
Systematic Review
Innovation for the Sake of Innovation? How Does Robotic Hepatectomy Compare to Laparoscopic or Open Resection for HCC—A Systematic Review and Meta-Analysis
Cancers 2022, 14(14), 3359; https://doi.org/10.3390/cancers14143359 - 11 Jul 2022
Cited by 9 | Viewed by 1569
Abstract
Robot-assisted hepatectomy is a novel approach to treat liver tumors. HCC is on the rise as the cause of cancer and mortality and is often preceded by cirrhosis. Robot-assisted hepatectomy has been suggested to offer benefits to cirrhotic patients. We aimed to evaluate [...] Read more.
Robot-assisted hepatectomy is a novel approach to treat liver tumors. HCC is on the rise as the cause of cancer and mortality and is often preceded by cirrhosis. Robot-assisted hepatectomy has been suggested to offer benefits to cirrhotic patients. We aimed to evaluate current evidence for robot-assisted hepatectomy for HCC and compare it to open and laparoscopic approaches. This systematic review and meta-analysis has been conducted in accordance with most recent PRISMA recommendations and the protocol has been registered at PROSPERO (CRD42022328544). There were no randomized controlled trials available and no study focused on cirrhotic patients exclusively. Robot-assisted hepatectomy was associated with less major complications than the laparoscopic approach, but comparable with open hepatectomy. No difference was seen in overall or minor complications, as well as liver specific or infectious complications. Cumulative survivals were similar in robot-assisted hepatectomy and laparoscopic or open approaches. There is a clear lack of evidence to suggest particular benefits for robot-assisted hepatectomy in cirrhotic patients. Otherwise, the robot-assisted approach has similar complication rates as open or laparoscopic methods. Non-industry driven randomized controlled trials are needed to evaluate the efficacy of robot-assisted liver surgery. Full article
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23 pages, 975 KiB  
Review
Emerging Therapies for Hepatocellular Carcinoma (HCC)
Cancers 2022, 14(11), 2798; https://doi.org/10.3390/cancers14112798 - 04 Jun 2022
Cited by 78 | Viewed by 8938
Abstract
Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for [...] Read more.
Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment. Full article
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12 pages, 2972 KiB  
Article
Surgical Resection plus Intraoperative Radiofrequency Ablation versus Chemoembolization for the Treatment of Intermediate-Stage (BCLC B) Hepatocellular Carcinoma with Preserved Liver Function: A Propensity Score-Matched Analysis
Cancers 2022, 14(10), 2440; https://doi.org/10.3390/cancers14102440 - 15 May 2022
Cited by 1 | Viewed by 1602
Abstract
The purpose of this study was to compare the efficacy and safety of surgical resection (SR) plus intraoperative radiofrequency ablation (IORFA) with transarterial chemoembolization (TACE) in patients with intermediate-stage HCC and Child–Pugh class A liver function. Treatment-naïve patients who received SR plus IORFA [...] Read more.
The purpose of this study was to compare the efficacy and safety of surgical resection (SR) plus intraoperative radiofrequency ablation (IORFA) with transarterial chemoembolization (TACE) in patients with intermediate-stage HCC and Child–Pugh class A liver function. Treatment-naïve patients who received SR plus IORFA (n = 104) or TACE (n = 513) were retrospectively evaluated. Patients were subjected to a maximum 1:3 propensity score matching (PSM), yielding 95 patients who underwent SR plus IORFA and 252 who underwent TACE. Evaluation of the entire study population showed that progression-free survival (PFS) and overall survival (OS) were significantly better in the SR plus IORFA than in the TACE group. After PSM, the median PFS (18.4 vs. 15.3 months) and OS (88.6 vs. 56.2 months) were significantly longer, and OS rate significantly higher (HR: 0.65, p = 0.026), in the SR plus IORFA group than in the TACE group. Stratified Cox regression analysis and doubly robust estimation revealed that treatment type was significantly associated with both OS and PFS. Rates of major complications were similar in the SR plus IORFA and TACE groups. In conclusion, SR plus IORFA showed better survival outcomes than TACE. SR plus IORFA may provide curative treatment to patients with intermediate-stage HCC with ≤4 tumors and Child–Pugh class A. Full article
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15 pages, 1926 KiB  
Article
Conventional Therapies Do Not Prolong the Prognosis of Hepatocellular Carcinoma Patients with Extrahepatic Metastases under Receiving of Tyrosine Kinase Inhibitors
Cancers 2022, 14(3), 752; https://doi.org/10.3390/cancers14030752 - 31 Jan 2022
Viewed by 1818
Abstract
Background: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase [...] Read more.
Background: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase inhibitor (TKI) treatment. Methods: We retrospectively investigated 127 HCC patients with extrahepatic metastases, who were divided into the non-TKI (conventional therapies) and TKI groups and further subdivided into the TKI alone and TKI plus conventional therapies groups. Conventional therapies included transcatheter arterial chemoembolization, cisplatin-based chemotherapy, radiation, surgery, and UFT, an oral chemotherapeutic agent. Results: The median of the overall survival (OS) of the 127 patients with extrahepatic metastases was 7.0 months. Meanwhile, the median OS of the TKI and non-TKI groups was 12.1 and 4.1 months, respectively. Imitating TKI after diagnosing metastases promoted a favorable increase in OS. Among the TKI group, the median OS in the TKI alone group was 8.9 months. TKI plus conventional therapies promoted no improvement in OS after adjusting for the patients’ background data. Conclusion: TKI promoted a better OS in HCC patients with extrahepatic metastases compared to conventional therapies. However, TKI plus conventional therapies promoted no improvement in the prognosis of such patients. Full article
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12 pages, 1765 KiB  
Article
External Validation of the FSAC Model Using On-Therapy Changes in Noninvasive Fibrosis Markers in Patients with Chronic Hepatitis B: A Multicenter Study
Cancers 2022, 14(3), 711; https://doi.org/10.3390/cancers14030711 - 29 Jan 2022
Cited by 2 | Viewed by 1494
Abstract
Antiviral therapy (AVT) induces the regression of non-invasive fibrosis markers (NFMs) and reduces hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients. We externally validated the predictive performance of the FSAC prediction model for HCC using on-therapy NFM responses. Our multicenter study [...] Read more.
Antiviral therapy (AVT) induces the regression of non-invasive fibrosis markers (NFMs) and reduces hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients. We externally validated the predictive performance of the FSAC prediction model for HCC using on-therapy NFM responses. Our multicenter study consecutively recruited treatment-naïve CHB patients (n = 3026; median age, 50.0 years; male predominant (61.3%); cirrhosis in 1391 (46.0%) patients) receiving potent AVTs for >18 months between 2007 and 2018. During follow-up (median 64.0 months), HCC developed in 303 (10.0%) patients. Patients with low FIB-4 or APRI levels at 12 months showed significantly lower HCC risk than those with high NFM levels at 12 months (all p < 0.05). Cumulative 3-, 5-, and 8-year HCC probabilities were 0.0%, 0.3% and 1.2% in the low-risk group (FSAC ≤ 2); 2.1%, 5.2%, and 11.1% in the intermediate-risk group (FSAC 3−8); and 5.2%, 15.5%, and 29.8% in the high-risk group (FSAC ≥ 9) (both p < 0.001 between each adjacent pair). Harrell’s c-index value for FSAC score (0.770) was higher than those for PAGE-B (0.725), modified PAGE-B (0.738), modified REACH-B (0.737), LSM-HCC (0.734), and CAMD (0.742). Our study showed that the FSAC model, which incorporates on-therapy changes in NFMs, had better predictive performance than other models using only baseline parameters. Full article
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13 pages, 2047 KiB  
Article
A New Tumor Burden Score and Albumin–Bilirubin Grade-Based Prognostic Model for Hepatocellular Carcinoma
Cancers 2022, 14(3), 649; https://doi.org/10.3390/cancers14030649 - 27 Jan 2022
Cited by 17 | Viewed by 1737
Abstract
The prognosis of hepatocellular carcinoma (HCC) varies widely due to variable tumor extent and liver reserve. We aimed to develop and validate a new prognostic model based on tumor burden score (TBS) and albumin–bilirubin (ALBI) grade for HCC. We prospectively identified 3794 HCC [...] Read more.
The prognosis of hepatocellular carcinoma (HCC) varies widely due to variable tumor extent and liver reserve. We aimed to develop and validate a new prognostic model based on tumor burden score (TBS) and albumin–bilirubin (ALBI) grade for HCC. We prospectively identified 3794 HCC patients who were randomized into derivation and validation groups. Survival predictors were evaluated by a multivariate Cox model. The TBS–ALBI system allocated two points for high TBS and ALBI grade 3, and one point each for the presence of ascites, serum α-fetoprotein ≥ 400 ng/mL, vascular invasion or distant metastasis, performance status 2–4, medium TBS, and ALBI grade 2, with a maximal score of 8 points. Significant survival differences were found across different TBS–ALBI score groups in the validation cohort (all p < 0.001). The TBS–ALBI system had the lowest corrected Akaike information criterion (AICc) and the highest homogeneity compared with other proposed staging models. The discriminative ability of the TBS–ALBI system was consistently stable across different viral etiologies, cancer stages, and treatment strategies. Conclusions: This new TBS–ALBI system is a feasible and robust prognostic system in comparison with other systems; it is a user-friendly tool for long-term outcome assessment independent of treatment modality and cancer stage in HCC. Full article
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13 pages, 791 KiB  
Article
The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab
Cancers 2022, 14(2), 343; https://doi.org/10.3390/cancers14020343 - 11 Jan 2022
Cited by 17 | Viewed by 1919
Abstract
Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus [...] Read more.
Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus bevacizumab were identified, including first-line, second-line, third-line, and later-line settings. In these patients, the median progression-free survival (PFS) was 5.0 months, including 5.0 months for the first-line treatment, not reached for the second-line treatment, and 2.5 months for the third line and later line treatment. The objective response rate and disease control rate to atezolizumab plus bevacizumab were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. The ratios of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) were used to predict PFS in these patients. The optimal cutoff values of NLR and PLR were 3 and 230, and NLR and PLR were independent prognostic factors for superior PFS in the univariate and multivariate analyses. Our study confirms the efficacy and safety of atezolizumab plus bevacizumab in uHCC patients in clinical practice and demonstrates the prognostic role of NLR and PLR for PFS in these patients. Full article
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2021

Jump to: 2023, 2022, 2020

12 pages, 796 KiB  
Review
Locoregional Therapies for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis
Cancers 2021, 13(21), 5430; https://doi.org/10.3390/cancers13215430 - 29 Oct 2021
Cited by 11 | Viewed by 3157
Abstract
Hepatocellular carcinoma is the fourth leading cause of cancer worldwide, and the fastest increasing cause of cancer mortality in the United States. Its propensity for vascular invasion leads to the presence of portal vein tumor thrombus in up to half of patients. PVTT [...] Read more.
Hepatocellular carcinoma is the fourth leading cause of cancer worldwide, and the fastest increasing cause of cancer mortality in the United States. Its propensity for vascular invasion leads to the presence of portal vein tumor thrombus in up to half of patients. PVTT results in a classification of advanced disease, given the risk recurrence secondary to intravascular spread, and formal guidelines recommend systemic therapy in these patients. However, recent advances in locoregional therapies including TACE, TARE, and ablation have demonstrated the potential to drastically improve overall survival in patients with HCC complicated by PVTT. Full article
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15 pages, 1039 KiB  
Review
Cure the Incurable? Recent Breakthroughs in Immune Checkpoint Blockade for Hepatocellular Carcinoma
Cancers 2021, 13(21), 5295; https://doi.org/10.3390/cancers13215295 - 22 Oct 2021
Cited by 8 | Viewed by 2583
Abstract
HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, [...] Read more.
HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, the use of ICI therapy has revolutionized the systemic treatment of advanced HCC. For the first time, clinical trials testing ICIs, anti-CTLA-4 and anti-PD1/PDL1 reported a survival benefit in patients with sorafenib resistance. However, it took four more years to find the right combination regimen to use ICI in combination with the anti-angiogenic agent bevacizumab to substantially prolong overall survival (OS) of patients with advanced HCC after sorafenib. This review provides a comprehensive history of ICI therapy in HCC, up-to-date information on the latest ICI clinical trials, and discusses the recent development of novel ICIs that would potentially lead to a new checkpoint blockade therapy for advanced HCC. Full article
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11 pages, 1072 KiB  
Article
Risk Score Model for Microvascular Invasion in Hepatocellular Carcinoma: The Role of Tumor Burden and Alpha-Fetoprotein
Cancers 2021, 13(17), 4403; https://doi.org/10.3390/cancers13174403 - 31 Aug 2021
Cited by 7 | Viewed by 1899
Abstract
Microvascular invasion (MVI) is a significant risk factor for the recurrence of hepatocellular carcinoma, but it is a histological feature that needs to be confirmed after hepatectomy or liver transplantation. The preoperative prediction of MVI can optimize the treatment plan of HCC, but [...] Read more.
Microvascular invasion (MVI) is a significant risk factor for the recurrence of hepatocellular carcinoma, but it is a histological feature that needs to be confirmed after hepatectomy or liver transplantation. The preoperative prediction of MVI can optimize the treatment plan of HCC, but an easy and widely applicable model is still lacking. The aim of our study was to predict the risk of MVI using objective preoperative factors. We retrospectively collected 1153 patients who underwent liver resection for HCC, and MVI was found to be associated with significantly poor disease-free survival. The patients were randomly split in a 3:1 ratio into training (n = 864) and validation (n = 289) datasets. The multivariate analysis of the training dataset found preoperative total tumor volume (TTV) and alpha-fetoprotein (AFP) to be independent risk factors for MVI. We built a risk score model with cutoff points of TTV at 30, 60, and 300 cm3 and AFP at 160 and 2000 ng/mL, and the model stratified the risk of MVI into low risk (14.1%), intermediate risk (36.4%), and high risk (60.5%). The validation of the risk score model with the validation dataset showed moderate performance (the concordance statistic: 0.731). The model comprised simple and objective preoperative factors with good applicability, which can help to guide treatment plans for HCC and future study design. Full article
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16 pages, 1688 KiB  
Systematic Review
Adjuvant Transarterial Chemoembolization Following Curative-Intent Hepatectomy Versus Hepatectomy Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Cancers 2021, 13(12), 2984; https://doi.org/10.3390/cancers13122984 - 15 Jun 2021
Cited by 19 | Viewed by 2349
Abstract
The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the [...] Read more.
The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the overall survival (OS) and recurrence-free survival (RFS) of patients with resectable HCC undergoing hepatectomy followed by adjuvant TACE vs. hepatectomy alone in randomized controlled trials (RCTs). The risk of bias was assessed using the Risk of Bias 2.0 tool. Meta-regression analyses were performed to explore the effect of hepatitis B viral status, microvascular invasion, type of resection (anatomic vs. parenchymal-sparing), and tumor size on the outcomes. Ten eligible RCTs, reporting on 1216 patients in total, were identified. The combination of hepatectomy and adjuvant TACE was associated with superior OS (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.52 to 0.85; p < 0.001) and RFS (HR: 0.70, 95% CI: 0.56 to 0.88; p < 0.001) compared to hepatectomy alone. There were significant concerns regarding the risk of bias in most of the included studies. Overall, adjuvant TACE may be associated with an oncologic benefit in select HCC patients. However, the applicability of these findings may be limited to Eastern Asian populations, due to the geographically restricted sample. High-quality multinational RCTs, as well as predictive tools to optimize patient selection, are necessary before adjuvant TACE can be routinely implemented into standard practice. PROSPERO Registration ID: CRD42021245758. Full article
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10 pages, 1259 KiB  
Article
Three-Dimensional Radiological Assessment of Ablative Margins in Hepatocellular Carcinoma: Pilot Study of Overlay Fused CT/MRI Imaging with Automatic Registration
Cancers 2021, 13(6), 1460; https://doi.org/10.3390/cancers13061460 - 23 Mar 2021
Cited by 5 | Viewed by 2036
Abstract
Background: We investigate the feasibility of image fusion application for ablative margin assessment in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and possible causes for a wrong initial evaluation of technical success through a side-by-side comparison. Methods: A total of 467 patients with [...] Read more.
Background: We investigate the feasibility of image fusion application for ablative margin assessment in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and possible causes for a wrong initial evaluation of technical success through a side-by-side comparison. Methods: A total of 467 patients with 1100 HCCs who underwent RFA were reviewed retrospectively. Seventeen patients developed local tumor progressions (LTPs) (median size, 1.0 cm) despite initial judgments of successful ablation referring to contrast-enhanced images obtained in the 24 h after ablation. The ablative margins were reevaluated radiologically by overlaying fused images pre- and post-ablation. Results: The initial categorizations of the 17 LTPs had been grade A (absolutely curative) (n = 5) and grade B (relatively curative) (n = 12); however, the reevaluation altered the response categories to eight grade C (margin-zero ablation) and nine grade D (existence of residual HCC). LTP occurred in eight patients re-graded as C within 4 to 30.3 months (median, 14.3) and in nine patients re-graded as D within 2.4 to 6.7 months (median, 4.2) (p = 0.006). Periablational hyperemia enhancements concealed all nine HCCs reevaluated as grade D. Conclusion: Side-by-side comparisons carry a risk of misleading diagnoses for LTP of HCC. Overlay fused imaging technology can be used to evaluate HCC ablative margin with high accuracy. Full article
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15 pages, 516 KiB  
Article
Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis
Cancers 2021, 13(3), 521; https://doi.org/10.3390/cancers13030521 - 29 Jan 2021
Cited by 6 | Viewed by 2238
Abstract
Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) [...] Read more.
Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was performed on a panel of 597 selected genes. Images of the patients who underwent MRI with hepatospecific contrast media during the study period were retrospectively re-evaluated (imaging was not part of the prospective study). cfDNA was detected in the plasma of 36 patients with LC. NGS-based analyses identified 20 variants in different combinations. Re-evaluation of the MRI images that were available for a proportion of the patients (n = 27) confirmed the absence of lesions in 8 cases carrying cfDNA without variants. In 6 of 19 patients with identified variants and MRI images available, MRI revealed a precursor lesion compatible with HCC and new lesions were discovered at follow-up in two patients. These precursor lesions were amenable for curative treatments. Mutation analysis revealed selective HCC related gene mutations in a subset of patients with LC, raising the suspect that these patients were at an increased risk for HCC development. MRI findings confirmed suspect nodular lesions of early stage HCC not detected with current standard screening procedures, which were only seen in patients carrying cfDNA variants. This opens a perspective for an HCC screening strategy combining both liquid biopsy and MRI in patients with LC. Full article
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Graphical abstract

2020

Jump to: 2023, 2022, 2021

14 pages, 3111 KiB  
Article
Establishment of an Immunocompetent Metastasis Rat Model with Hepatocyte Cancer Stem Cells
Cancers 2020, 12(12), 3721; https://doi.org/10.3390/cancers12123721 - 11 Dec 2020
Cited by 2 | Viewed by 5435
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future. Full article
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9 pages, 654 KiB  
Brief Report
Using Hepatocellular Carcinoma Tumor Burden Score to Stratify Prognosis after Liver Transplantation
Cancers 2020, 12(11), 3372; https://doi.org/10.3390/cancers12113372 - 14 Nov 2020
Cited by 23 | Viewed by 1942
Abstract
Liver transplantation (LT) remains a mainstay of treatment for hepatocellular carcinoma (HCC). Tumor factors such as size and number of tumors define eligibility for LT using the Milan criteria. The tumor burden score (TBS) incorporates both tumor number and size into a single [...] Read more.
Liver transplantation (LT) remains a mainstay of treatment for hepatocellular carcinoma (HCC). Tumor factors such as size and number of tumors define eligibility for LT using the Milan criteria. The tumor burden score (TBS) incorporates both tumor number and size into a single continuous variable and has been used to differentiate prognosis among patients undergoing resection for HCC. The objective of the present study was to evaluate the ability of the TBS to predict overall and recurrence-free survival in patients undergoing LT for HCC. The Scientific Registry of Transplant Recipients (SRTR) was used to analyze all liver transplants for HCC, with initial tumor size data from 2004 to 2018. There were 12,486 patients in the study period. In the unadjusted analyses, patients with a high TBS had worse overall (p < 0.0001) and recurrence-free (p < 0.0001) survival. In the adjusted analyses, a high TBS was associated with a greater hazard ratio (HR) of death (HR = 1.21; 95%CI, [1.13–1.30]; p < 0.001) and recurrence (HR = 1.49; 95%CI [1.3–1.7]; p < 0.001). When we superimposed the TBS on the Milan criteria, we saw that a higher TBS was associated with a higher hazard of recurrence at values that were either all within (HR = 1.20; 95%CI, [1.04–1.37]; p = 0.011) or variably within (HR = 1.53; 95%CI, [1.16–2.01]; p = 0.002) the Milan criteria. In conclusion, the TBS is a promising tool in predicting outcomes in patients with HCC after LT. Full article
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