Procedure of Direct Hepatic Artery Puncture for the Treatment of Hepatocellular Carcinoma: Two Case Reports

Recently, treatment options for hepatocellular carcinoma (HCC) have expanded due to the development of the tyrosine kinase inhibitor ramucirumab and immune checkpoint inhibitors. Transcatheter arterial chemoembolization is the standard therapy for intermediate-stage HCC; however, in cases with anatomical problems, normal approaches are not possible. In such rare cases, direct hepatic puncture may be considered as an effective therapy and an indispensable treatment. We report our novel method of direct hepatic artery puncture in this case report. In 2011 and 2017, we reported 2 cases in the journal of the Japan Society of Hepatology in Japanese. This therapy is difficult and is associated with a high risk of complications; however, we succeeded in both cases in a similar way. We believe this method may provide an alternative treatment when standard treatment is not possible or when urgent therapy is required. In case 1, direct hepatic artery puncture was performed under ultrasonographic guidance, and we were able to control the disease with percutaneous lipiodol chemotherapy. Case 2 was an emergency case of ruptured HCC. Direct hepatic puncture successfully stopped tumor bleeding; furthermore, tumor necrosis also occurred, as seen on the enhanced computed tomography image. Our new method requires advanced puncture techniques and is not the treatment of choice if there are other safe alternatives available. However, it can be considered as an option if there are no other viable, effective treatments.

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Immunotherapy in Hepatocellular Carcinoma

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00886-5 ◽

2021 ◽

Vol 22 (10) ◽

Cited By ~ 1

Author(s):

Claudia A. M. Fulgenzi ◽

Thomas Talbot ◽

Sam M. Murray ◽

Marianna Silletta ◽

Bruno Vincenzi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Cytotoxic T Lymphocyte ◽

Treatment Options ◽

Predictive Biomarkers ◽

Intermediate Stage ◽

Routine Practice ◽

Advanced Hcc

Opinion statementPatients with hepatocellular carcinoma (HCC) have been traditionally deprived from highly effective systemic therapy options in the past decades. The multi-targeted tyrosine kinase inhibitor sorafenib, approved in 2008, remained the only treatment option for advanced HCC for over a decade. A number of molecularly targeted therapies such as lenvatinib, regorafenib, cabozantinib, and ramucirumab have significantly widened treatment options in patients with advanced HCC. However, emergence of resistance and long-term toxicity from treatment are barriers to long-term survivorship. Immunotherapy is at the focus of intense research efforts in HCC. Whilst targeting of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte 4 (CTLA-4) is associated with radiologically measurable disease-modulating effects in HCC, monotherapies fell short of demonstrating evidence of significant survival extension in advanced disease. Atezolizumab and bevacizumab were the first immunotherapy regimen to demonstrate clear superiority in improving the survival of patients with unresectable HCC compared to sorafenib, paving the way for immunotherapy combinations. As the treatment landscape of HCC rapidly evolves, with immunotherapy integrating within early- and intermediate-stage disease treatment algorithms, lack of level 1 evidence on sequencing of therapeutic strategies and lack of head-to-head comparisons across immunotherapy combinations will affect prescribing of immunotherapy in routine practice. In the absence of predictive biomarkers, choice of immunotherapy over kinase inhibitors will continue to remain an empirical exercise, guided by balancing anti-tumour efficacy with toxicity considerations in the individual patient.

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Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211031141 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110311

Author(s):

Chiun Hsu ◽

Lorenza Rimassa ◽

Hui-Chuan Sun ◽

Arndt Vogel ◽

Ahmed O. Kaseb

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Kinase Inhibitor ◽

Treatment Options ◽

Healthcare Providers ◽

Safety Data ◽

Standard Of Care ◽

Antiangiogenic Agents ◽

Efficacy And Safety ◽

First Line

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

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Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

Vaccines ◽

10.3390/vaccines8030447 ◽

2020 ◽

Vol 8 (3) ◽

pp. 447

Author(s):

Robin Park ◽

Fariha Eshrat ◽

Mohammed Al-Jumayli ◽

Azhar Saeed ◽

Anwaar Saeed

Keyword(s):

Hepatocellular Carcinoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Oncolytic Viruses ◽

Advanced Hepatocellular Carcinoma ◽

T Cell Therapy ◽

Fda Approval ◽

Car T Cell Therapy ◽

Pivotal Study ◽

Extensive Growth

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

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Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design

Future Oncology ◽

10.2217/fon-2020-0283 ◽

2020 ◽

Vol 16 (21) ◽

pp. 1525-1536 ◽

Cited By ~ 2

Author(s):

Robin Kate Kelley ◽

Jennifer W Oliver ◽

Saswati Hazra ◽

Fawzi Benzaghou ◽

Thomas Yau ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Phase Iii ◽

Advanced Hepatocellular Carcinoma ◽

Single Agent Therapy ◽

Treatment Naïve ◽

Phase Iii Study ◽

Immunomodulatory Properties

Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti–PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. ClinicalTrial.gov Registration: NCT03755791

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Diagnosis, Staging, and Patient Selection for Locoregional Therapy to Treat Hepatocellular Carcinoma

Seminars in Interventional Radiology ◽

10.1055/s-0040-1719185 ◽

2020 ◽

Vol 37 (05) ◽

pp. 441-447

Author(s):

Zachary T. Berman ◽

Isabel Newton

Keyword(s):

Hepatocellular Carcinoma ◽

Treatment Options ◽

Intermediate Stage ◽

Family Education ◽

Locoregional Therapy ◽

Stage Disease ◽

Incidence And Mortality ◽

Tumor Boards ◽

Diagnostic Approaches ◽

Locoregional Therapies

AbstractHepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality and the only cancer for which the incidence and mortality are on the rise. Sensitive and specific screening and diagnostic approaches, robust staging regimens, multidisciplinary tumor boards, and patient/family education and engagement in the shared decision-making process help to identify a patient's optimal treatment options. Locoregional therapies have been the mainstay for treating intermediate-stage disease, but they are finding special applications for early and advanced disease. This review discusses the diagnosis of HCC, current accepted staging models, and treatment of HCC, with a focus on locoregional therapies.

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Myopenia as a significant prognostic factor in BCLC-B intermediate-stage hepatocellular carcinoma treated with sorafenib.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15639 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15639-e15639

Author(s):

Mao Okada ◽

Hiroyuki Nakanishi ◽

Masayuki Kurosaki ◽

Sakura Kirino ◽

Leona Osawa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Skeletal Muscle ◽

Prognostic Factor ◽

Kinase Inhibitors ◽

Treatment Options ◽

Intermediate Stage ◽

Significant Prognostic Factor ◽

Poor Prognostic Factor ◽

Skeletal Muscle Index ◽

The Impact

e15639 Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.

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Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16711 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16711-e16711

Author(s):

Erica Villa ◽

Fabio Piscaglia ◽

Rabit Geva ◽

George Dalecos ◽

George Papatheodoridis ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Primary Objective ◽

Response To Treatment ◽

Cyclin Dependent Kinase ◽

Advanced Hcc ◽

Cyclin Dependent Kinase Inhibitor ◽

Secondary Endpoints

e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients. Methods: Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CBR). Results: A total of 31 patients were enrolled and 28 were evaluable for efficacy, of which 14 (50%) completed 6-months of treatment. Milciclib was well-tolerated with manageable toxicities. Eighteen of 31 treated patients had drug-related adverse events (AEs) with most frequent (≥5%) occurrence of drug-related diarrhea, nausea, asthenia, fatigue, retinal hemorrhage, rash and myalgia. No drug-related deaths were recorded. Nine of 14 patients (64%) continued treatment under Compassionate Use after study completion. Seven patients received milciclib until 9, 9, 10, 11, 13, 13 and 16 months. The remaining 2 patients are in the 16th month of treatment. Clinical response to treatment, assessed by mRECIST (independent radiological review), is shown in the Table. Both median TTP and PFS were 5.9 months. Conclusions: Milciclib, acting via a new mechanism, was safe, well-tolerated and met primary and secondary endpoints with 61% CBR. These promising clinical data warrant further evaluation of milciclib. Clinical trial information: NCT03109886 . [Table: see text]

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New advances in the diagnosis and management of hepatocellular carcinoma

BMJ ◽

10.1136/bmj.m3544 ◽

2020 ◽

pp. m3544 ◽

Cited By ~ 1

Author(s):

Ju Dong Yang ◽

Julie K Heimbach

Keyword(s):

Hepatocellular Carcinoma ◽

Systemic Treatment ◽

Early Stage ◽

Treatment Options ◽

Intermediate Stage ◽

Phase Iii ◽

Advanced Hepatocellular Carcinoma ◽

Long Term Outcomes ◽

Stage Disease

ABSTRACT Hepatocellular carcinoma is one of the leading causes of cancer related death in the world. Biannual surveillance for the disease in patients with cirrhosis and in high risk carriers of hepatitis B virus allows early stage cancer detection and treatment with good long term outcomes. Liver ultrasonography and serum α fetoprotein are the most commonly used surveillance tests. If suspicious results are found on the surveillance test, multiphasic computed tomography or magnetic resonance imaging should be undertaken to confirm the diagnosis of hepatocellular carcinoma. If radiologic tests show inconclusive results, liver biopsy or repeat imaging could be considered for confirmation of hepatocellular carcinoma. Management of the disease is complex. Patients should be evaluated by a multidisciplinary team, and the selection of treatment should consider factors such as tumor burden, severity of liver dysfunction, medical comorbidities, local expertise, and preference of patients. Early stage hepatocellular carcinoma is best managed by curative treatment, which includes resection, ablation, or transplantation. Patients with intermediate stage disease often receive locoregional treatment. Systemic treatment is reserved for patients with advanced disease. Several positive, phase III, randomized controlled trials have expanded the systemic treatment options for advanced hepatocellular carcinoma with promising long term outcomes, especially trials using combination treatments, which could also have eventual implications for the treatment of earlier stage disease.

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Clinical Benefits of Immune Checkpoint Inhibitors and Predictive Value of Tumor Mutation Burden in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

10.37766/inplasy2022.1.0008 ◽

2022 ◽

Author(s):

Jiaxi Zheng ◽

◽

Haihua Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Clinical Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Advanced Hepatocellular Carcinoma ◽

Tumor Mutation Burden ◽

Mutation Burden

Review question / Objective: Is immunotherapy associated with beneficial clinical outcomes for hepatocellular carcinoma (HCC) and how can combination immunotherapy be deployed to produce the best benefit? Is tumor mutation burden (TMB) a predictive biomarker for immune‐checkpoint inhibitors? Condition being studied: To this date, about 50 single-arm clinical trials and several randomized control trials (RCTs) presented final or interim results of investigations on the efficacy of PD-1/PD-L1 inhibitors for advanced HCC. In the CheckMate 459, IMbrave 050, and ORIENT-32, immunotherapies were found to significantly improve progression-free survival (PFS) and overall survival (OS) compared with sorafenib (a tyrosine-kinase inhibitor, as standard systemic treatment) in patients with advanced hepatocellular carcinoma. However, these clinical trials were different on clinical phases, sample size, and response evaluation criteria, and inconsistent clinical outcomes were shown in several trials.

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Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13174343 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4343

Author(s):

Sara M. Atwa ◽

Margarete Odenthal ◽

Hend M. El Tayebi

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Cellular Response ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Asia Pacific ◽

Therapeutic Modality ◽

Treatment Modalities

Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.

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