scholarly journals Challenges in the Current Management of Hepatocellular Carcinoma

2021 ◽  
Vol 6 (04) ◽  
pp. 269-274
Author(s):  
Soumya Jogi ◽  
Radha Varanasi ◽  
Sravani S Bantu ◽  
Sudha Saduvala ◽  
Ashish Manne
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Staging System ◽  
Convincing Evidence ◽  
Locoregional Therapy ◽  
Vegf Inhibitors ◽  
Stereotactic Radiation

Management of hepatocellular carcinoma (HCC) is complicated. Barcelona Clinic Liver Cancer (BCLC) staging system is widely used in risk stratifying HCC. It is different from anatomic staging (TNM) used in other cancers and is based on the liver function (Child-Pugh Score) and performance status at diagnosis along with tumor characteristics like size/number of primary, vascular invasion, and distant metastasis. Guidelines proposed by various liver societies help the treating physician select first-line therapy, but there are many limitations to them. Lack of reliable biomarkers that give objective information to monitor the response other than alpha-fetoprotein or radiological response is hurting the management strategies. There are no ideal predictors for recurrence and residual microscopic disease, especially after locoregional therapy (LRT) like surgical resection, ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic radiation therapy (SBRT). Also, there is no convincing evidence to use adjunct therapy along with LRT in localized HCC. There is a need to identify the subset of HCC that would benefit from peri-procedural therapy. Recommendations for treating advanced HCC with macrovascular invasion is not uniform across the guidelines. Some propose LRT (TACE and/or TARE) or recommend systemic therapy only like tyrosine-kinase inhibitors (TKI) or Immune-checkpoint inhibitors (ICI). A considerable portion of patients have poor liver function (Child-Pugh Score C) at diagnosis. In this era of medicine, we should give them options other than supportive care, but unfortunately, it is the preferred option. This population needs special attention in trials. In current practice, there only 2-3 classes of drugs available like TKI, ICI, and vascular endothelial growth factor (VEGF) inhibitors. There is a need to explore more classes of liver-friendly drugs in treating HCC, and the enrolment of patients in clinical trials must be advised in the guidelines.

scholarly journals Treatment of Advanced Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Mahmoud Aryan ◽  
Ellery Altshuler ◽  
Xia Qian ◽  
Wei Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Performance Status ◽  
Staging System ◽  
Tumor Burden ◽  
Systemic Review ◽  
Locoregional Therapy ◽  
Treatment Modalities ◽  
Advanced Hcc ◽  
The Past

Hepatocellular Carcinoma (HCC) is the fifth most common cancer and represents the fourth most common cause of cancer related death worldwide. Treatment of HCC is dictated based upon cancer stage, with the most universally accepted staging system being the Barcelona Clinic Liver Cancer (BCLC) staging system. This system takes into account tumor burden, active liver function, and patient performance status. BCLC stage C HCC is deemed advanced disease, which is often characterized by preserved liver function (Child-Pugh A or B) with potential portal invasion, extrahepatic spread, cancer related symptoms, or decreased performance status. Sorafenib has been the standard treatment for advanced HCC over the past decade; however, its use is limited by low response rates, decreased tolerance, and limited survival benefit. Researchers and clinicians have been investigating effective treatment modalities for HCC over the past several years with a focus on systemic regimens, locoregional therapy, and invasive approaches. In this systemic review, we discuss the management of advanced HCC as well as the ongoing research on various treatment opportunities for these patients.

scholarly journals Emerging Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

2019 ◽  
Author(s):  
Vito Longo ◽  
Oronzo Brunetti ◽  
Antonio Gnoni ◽  
Antonella Licchetta ◽  
Sabina Del Curatolo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Primary Liver Cancer ◽  
Single Agent ◽  
Locoregional Therapy ◽  
First Line ◽  
Dismal Prognosis

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.

Transition of molecular target agent therapy in advanced hepatocellular carcinoma: A multicenter, retrospective study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 317-317
Author(s):  
Kazufumi Kobayashi ◽  
Sadahisa Ogasawara ◽  
Aya Takahashi ◽  
Yuya Seko ◽  
Satoshi Tsuchiya ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retrospective Study ◽  
Performance Status ◽  
Progression Free Survival ◽  
Staging System ◽  
Sequential Therapy ◽  
Molecular Target ◽  
Advanced Hepatocellular Carcinoma ◽  
Entire Cohort ◽  
Significant Difference

317 Background: There have been considerable advances in systemic chemotherapy for hepatocellular carcinoma (HCC) in recent times. Currently, four molecular target agents (MTA) are available for HCC treatment in Japan. Sequential therapy using multiple MTAs is being considered as the gold standard of treatment. However, the effectiveness of the treatment strategy transition for HCC remains unclear. The present study aimed to clarify the current practical use of MTAs and its effectiveness in HCC treatment. Methods: In this multicenter, retrospective study, we collected and analyzed the clinical data of 877 patients who underwent MTA therapy for HCC from June 2009 to March 2019 at several institutes in Japan. The patients were classified into 3 groups as per the period of initial MTA treatment beginning (period 1: 2009–2012, n = 267; period 2: 2013–2016, n = 352; period 3: 2017–2019, n = 258). These 3 periods were defined to have approximately same term. Period 3 means the era of multiple MTAs because of the approval of regorafenib in Japan in 2017. We assessed the patient characteristics, MTA use, and prognosis of the 3 groups. Results: The proportion of patients with advanced-stage HCC, defined according to the Barcelona Clinic Liver Cancer staging system, in each period was 70.1%, 66.5%, and 62.0% in period 1, 2, and 3, respectively. MTA use for intermediate stages increased with the passage of time ( p = 0.052). The proportion of multiple MTAs use was remarkably increased in the 3 groups (1.1%, 10.2%, and 42.6%, respectively, p < 0.0001). Child-Pugh score, proportion of macrovascular invasion, extrahepatic metastasis, and α-fetoprotein (AFP) ≥400 ng/mL showed no significant difference among the 3 groups. The median overall survival was 11.9 months for the entire cohort and 10.4, 11.3, and 15.2 months, for period 1, 2, and 3, respectively. It is noteworthy that the prognosis of patients with HCC improved over time ( p = 0.016). With respect to progression-free survival, the median value was 3.0 months for the entire cohort and 2.7, 2.8, and 4.7 months for period 1, 2, and 3, respectively ( p < 0.0001). The treatment duration was also prolonged with time (2.7, 3.2, and 6.6 months for period 1, 2, and 3, respectively; p < 0.0001). Multivariate analysis using Cox proportional hazard model showed that HCV infection, Child-Pugh score, performance status, α-fetoprotein ≥400 ng/mL, presence of macrovascular invasion, and period 3 for initial MTA introduction were independent prognostic factors. Conclusions: Sequential therapy with multiple MTAs has gained popularity with time and is considered to improve patient prognosis. The development of MTA therapy for HCC is expected to continue. Therefore, further studies are needed to help determine the appropriate drugs, the sequence of MTA use, and the precise transition time.

Cancer Immunotherapy-Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

2021 ◽  
Vol 16 ◽  
Author(s):  
Jing Bai ◽  
Ping Liang ◽  
Qian Li ◽  
Rui Feng ◽  
Jiang Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Locoregional Therapy ◽  
Incidence And Mortality

: Hepatocellular Carcinoma (HCC) is one of the most common malignancies, the incidence and mortality of which are increasing worldwide. Cancer immunotherapy has revolutionized cancer treatment in recent years. In particular, Immune Checkpoint Inhibitors (ICIs) as new therapeutic tools have demonstrated encouraging antitumor activity and manageable tolerability in HCC. Immunologic checkpoint blockade with antibodies targeting Programmed cell Death-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), and Cytotoxic T Lymphocyte-Associated protein-4 (CTLA-4) strengthens tumor immunity by restoring exhausted T cells. Although the efficacy of combination treatment strategies using ICIs combined with other ICIs, molecular targeted agents, systemic therapy, or locoregional therapy has been well documented in numerous preclinical and clinical studies on several types of cancers, most HCC patients do not benefit from ICI treatment. This review highlights recent developments and potential opportunities related to ICIs and their combination in the management of HCC. The present article also includes recent patent review coverage on this topic.

scholarly journals Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 21 (17) ◽  
pp. 6302
Author(s):  
Michela Guardascione ◽  
Giuseppe Toffoli
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Antiangiogenic Agents ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.

scholarly journals Baseline and Early Predictors of Good Patient Candidates for Second-Line after Sorafenib Treatment in Unresectable Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1256 ◽  
Author(s):  
Hitomi Takada ◽  
Masayuki Kurosaki ◽  
Kaoru Tsuchiya ◽  
Yasuyuki Komiyama ◽  
Jun Itakura ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Tumor Burden ◽  
Second Line ◽  
Inclusion Criteria ◽  
Sorafenib Treatment ◽  
Unresectable Hepatocellular Carcinoma ◽  
Early Predictors

Background: Recent advances in the development of tyrosine kinase inhibitors (TKIs) have enabled patients with unresectable hepatocellular carcinoma (HCC) to receive multiple TKIs in sequence. The aim of this study was to identify predictors of good candidates for second-line treatment after disease progression during sorafenib treatment. Methods: This is a retrospective cohort study of 190 consecutive HCC patients who were treated with sorafenib in our hospital. Three criteria of good candidates for second-line TKI at the time of disease progression during sorafenib treatment were defined as follows: criterion 1 was the same as the inclusion criteria of the regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE) study, criterion 2 was the inclusion criteria of the RESORCE study plus Child–Pugh score 5, and criterion 3 was the inclusion criteria of the RESORCE study plus albumin–bilirubin (ALBI) grade 1. Factors at baseline and at week 4 during sorafenib treatment were used to predict patients fulfilling each of these three criteria. Results: The distribution of patients was 29%, 13%, and 6% in criteria 1, 2, and 3, respectively. Significant factors for meeting criterion 1 was the combination of baseline albumin >3.7 g/dL (odds ratio (OR) 2.7) plus degree of decrease in albumin (Δalbumin) at week 4 <0.2 g/dL (OR 2.6), or the combination of baseline ALBI score <−2.33 (OR 2.5) and ΔALBI at week 4 <0.255 (OR 4.9). For criterion 2, the value of baseline albumin and ALBI score was identical to criterion 1; however, Δalbumin (<0.1 g/dL) and ΔALBI score (<0.19) became stricter. For criterion 3, the value of baseline albumin (>3.8 g/dL) and ALBI (<−2.55) became stricter, as did Δalbumin (<0.1 g/dL) and ΔALBI (<0.085). Furthermore, tumor burden (>11) was selected as an additional predictor (OR 5.4). Conclusion: Predictors to satisfy the RESORCE study inclusion criteria were as follows: preserved liver function at baseline, as reflected by albumin or ALBI score, and small deterioration of liver function early during sorafenib therapy, as reflected by Δalbumin or ΔALBI at week 4. Liver function at baseline and degree of change in liver function during sorafenib treatment need to be stricter for better outcomes of liver function with disease progression.

scholarly journals Immunotherapy with Checkpoint Inhibitors for Hepatocellular Carcinoma: Where Are We Now?

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 578
Author(s):  
Francesco Tovoli ◽  
Stefania De Lorenzo ◽  
Franco Trevisani
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Randomised Clinical Trial ◽  
Immune Mediated ◽  
Long Time ◽  
Tumour Escape ◽  
Programmed Death Protein 1

Immune checkpoint inhibitors (ICIs) are beginning to show promise in the clinical management of hepatocellular carcinoma (HCC). Most recently, the anti-programmed death protein-1 (PD-1) agent atezolizumab combined with bevacizumab demonstrated superiority to sorafenib in a Phase 3 randomised clinical trial in the frontline setting. Other ongoing trials of immunotherapy for HCC are exploring different drug combinations, such as a double checkpoint blockade with PD-1 and anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents or with tyrosine kinase inhibitors. Moreover, ICIs are being tested in the adjuvant and neoadjuvant settings trying to resolve long-time unmet needs in HCC. The results of the ongoing trials will be critical to understanding the extent of the therapeutic role of ICIs in the complex and multifaceted clinical scenario of HCC. Still, there are some critical points which need further attention to clarify the best use of ICIs in HCC patients. For instance, the actual eligibility rate of patients in the real-life scenario, the prompt identification and correct management of immune-mediated adverse events, the identification of biomarkers predicting response or resistance, and strategies to prevent the tumour escape from ICI effect.

Assessment of radioembolization among patients who met the inclusion criteria for Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14654-e14654 ◽  
Author(s):  
Bruno Sangro ◽  
Livio Carpanese ◽  
Roberto Cianni ◽  
Daniele Gasparini ◽  
Rita Golfieri ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Liver Function ◽  
Median Overall Survival ◽  
Performance Status ◽  
Advanced Hepatocellular Carcinoma ◽  
Inclusion Criteria ◽  
Ecog Performance Status ◽  
Advanced Hcc ◽  
Good Liver Function

e14654 Background: SHARP was pivotal in determining the safety and efficacy of sorafenib in advanced hepatocellular carcinoma (HCC) in patients with predominately good liver function. In practice, many patients with advanced HCC receive radioembolization (RE). Investigators from the European Network on RE with yttrium-90 resin microspheres (ENRY) group conducted an analysis of safety and survival among consecutive patients who met the SHARP inclusion criteria. Methods: 58% of patients (189 of 325) who had received RE between 09/2003 and 12/2009 were considered SHARP-equivalents. Of these, 11.6% received sorafenib 4.7 months (median) after RE for a median duration of 2.8 months. Safety and tolerability analyses were conducted up to day 90 post RE; changes from baseline were recorded and transitions in CTCAE grades >3 tested. Statistical analyses used SAS (SAS, Cary NC) version 9.2 XP Pro. Results: Like the SHARP sorafenib cohort, most patients had advanced HCC (BCLC stage C: 72.5%), good liver function (Child–Pugh class A: 100%) and ECOG performance status (0–1: 90.5%). Macroscopic vascular invasion (MVI), extrahepatic spread (EHD) or both was present in 33.9%. 20.1% had received prior surgical procedures, 8.5% prior ablative procedures and 33.3% prior vascular [chemo]embolization. RE was predominantly a single whole-liver procedure (median activity 1.7 GBq). Median overall survival was 10.8 months (95% CI: 8.8–12.8) in the SHARP-equivalent cohort, 10.2 months (8.3–11.8) in patients with MVI/EHD, 9.7 months (7.6–10.9) in advanced HCC (BCLC stage C) and 16.6 months (11.2–22.8) in intermediate HCC (BCLC stage B). Treatment-related adverse events (all grades; grade >3) were: fatigue (50.3%; 2.1%), abdominal pain (25.9%; 2.1%), nausea/vomiting (31.2%; 0.5%) and GI ulcer (3.2%; 1.0%). At baseline, raised bilirubin (all grades) was present in 20.3%, increasing to 49.4% of patients evaluated up to day 90. Bilirubin grade was unchanged in 58.1% and increased in 37.8%; 4.0% had ≥grade 3 events. Conclusions: In patients matching the inclusion criteria for SHARP, RE was well tolerated with a median overall survival which compares favorably with sorafenib.

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