Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC.

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Embolization versus embolization and systemic therapy in patients with hepatocellular carcinoma and metastatic disease: A retrospective analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.363 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 363-363 ◽

Cited By ~ 4

Author(s):

Sunnie Kim ◽

Karen T. Brown ◽

Yuman Fong ◽

Stephen Barnett Solomon ◽

Joanne F. Chou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Retrospective Analysis ◽

Systemic Therapy ◽

Survival Benefit ◽

Combined Modality Therapy ◽

Locally Advanced ◽

Arterial Embolization ◽

Combined Modality ◽

Kaplan Meier

363 Background: Transarterial chemoembolization (TACE) provides a survival benefit in a subset of patients with unresectable hepatocellular carcinoma (HCC). Even though data are lacking, patients with metastatic HCC (mHCC) are sometimes treated with transarterial therapies to address the hepatic disease. Sorafenib is a standard treatment for patients with mHCC. Methods: A retrospective analysis was conducted on patients diagnosed with HCC who had undergone hepatic arterial embolization (HAE) between 2006 and until 2013. Overall survival (OS) was calculated from date of HAE to date of death and estimated by Kaplan Meier Methods. Patients alive at their last follow up date were censored. Results: Of 243 patients who had undergone HAE at MSKCC during the study period, 36 patients had mHCC on initial diagnosis. Of these, 22 received HAE only, while 14 received HAE plus systemic therapy at some time during their whole treatment course. Conclusions: Patients with mHCC who underwent HAE alone had a poor OS. These data suggest that there maybe a survival benefit in patients with mHCC treated with transarterial therapies add to systemic therapy that is given at some time during their whole treatment course. These results contrast with recent data on the use of combined modality in locally advanced disease. Further studies of combined modality therapy in the setting of mHCC may be warranted. [Table: see text]

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PHARMACOLOGICAL THERAPY OF HEPATOCELLULAR CANCER PRACTICAL ISSUES AND SOLUTIONS

Medical Council ◽

10.21518/2079-701x-2017-14-11-23 ◽

2017 ◽

pp. 11-23

Author(s):

V. V. Breder ◽

K. K. Laktionov ◽

M. I. Davydov

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Hepatocellular Cancer ◽

Pharmacological Therapy ◽

Second Line Therapy ◽

Clinical Issue ◽

Pharmaceutical Therapy ◽

Hepatocellular Carcinomas ◽

Strategic Goal

Pharmaceutical therapy of hepatocellular carcinoma represents a major clinical issue of debate in modern oncology. Until now, Sorafenib remains the only option for the management of locally advanced and metastatic hepatocellular carcinomas, which increases the overall survival of patients. In the absence of alternative treatment, the oncologist understanding of the place, time, the strategic goal and tactical objectives of the pharmaceutical therapy of hepatocellular carcinoma at different stages of cancer is of great importance. The article considers the practical aspects of the Sorafenib therapy of hepatocellular cancer in various clinical situations, and proposes algorithms of accompanying therapy for the underlying liver pathology. It presents the results of Regorafenib therapy, a new multi-kinase inhibitor, which significantly increases survival in the second line therapy of sorafenib-resistant hepatocellular carcinoma. The options of pharmaceutical therapy for hepatocellular carcinoma using cytotoxic and molecular-directed medicines, prospects of modern immunotherapy are discussed.

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Current locoregional therapies and treatment strategies in hepatocellular carcinoma

Current Oncology ◽

10.3747/co.27.7171 ◽

2020 ◽

Vol 27 (S3) ◽

Author(s):

L. Cardarelli-Leite ◽

A. Hadjivassiliou ◽

D. Klass ◽

J. Chung ◽

S.G.F. Ho ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Biology ◽

Treatment Strategies ◽

Current Evidence ◽

Percutaneous Ablation ◽

Transarterial Radioembolization ◽

Combined Use ◽

Liver Morphology ◽

Locoregional Therapies ◽

Bridging To Transplant

Locoregional therapies (LRT) play an important role in the treatment of hepatocellular carcinoma (HCC), with the aim of increasing overall survival while preserving liver function. Different forms of LRT are available and choosing which one is best will depend on technical aspects, liver morphology, tumor biology, and patient’s symptoms. The purpose of this review article is to provide an overview of the current evidence regarding the use of percutaneous ablation, transarterial chemoembolization and transarterial radioembolization for the curative or palliative treatment of HCC. Special situations are also reviewed, including the combined use of systemic therapy with LRT; indications and techniques for bridging to transplant and downstaging; and the use of LRT to treat patients with HCC and macrovascular invasion.

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Tumor Marker-Based Definition of the Transarterial Chemoembolization-Refractoriness in Intermediate-Stage Hepatocellular Carcinoma: A Multi-Cohort Study

Cancers ◽

10.3390/cancers11111721 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1721 ◽

Cited By ~ 1

Author(s):

Jun Sik Yoon ◽

Dong Hyun Sinn ◽

Jeong-Hoon Lee ◽

Hwi Young Kim ◽

Cheol-Hyung Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cohort Study ◽

Tumor Marker ◽

Systemic Therapy ◽

Transarterial Chemoembolization ◽

External Validation ◽

Intermediate Stage ◽

Prognostic Impact ◽

High Baseline ◽

Definition Of

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

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CDKN2A is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

Bioscience Reports ◽

10.1042/bsr20211103 ◽

2021 ◽

Author(s):

Jun-peng Luo ◽

Jing Wang ◽

Jin-hua Huang

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Immune Cell ◽

Kinase Inhibitor ◽

Prognostic Biomarker ◽

Disease Free Survival ◽

Cyclin Dependent Kinase ◽

Strong Correlations ◽

Immune Infiltration ◽

Cyclin Dependent Kinase Inhibitor

Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is an essential regulator of immune cell functionality, but the mechanisms whereby it drives immune infiltration in hepatocellular carcinoma (HCC) remain unclear. In the current study, we studied the association with CDKN2A expression and immune invasion with the risk of developing HCC. A totally of 2207 different genes were found between HCC and adjacent liver tissues from TCGA and GEO databases. CDKN2A was highly expressed in HCC and associated with poorer overall survival and disease-free survival. Notably, CDKN2A expression was positively correlated with infiltrating levels into purity, B cell, CD+8 T cell, CD+4 T cell, macrophage, neutrophil, and dendritic cells in HCC. CDKN2A expression showed strong correlations between diverse immune marker sets in HCC. These findings suggest that CDKN2A expression potentially contributes to regulation of tumor-associated macrophages and can be used as a prognostic biomarker for determining prognosis and immune infiltration in HCC.

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Liver Transplantation for Locally Advanced Hepatocellular Carcinoma

Digestive Disease Interventions ◽

10.1055/s-0040-1702996 ◽

2020 ◽

Vol 04 (01) ◽

pp. 003-012

Author(s):

Norio Kawamura ◽

Akinobu Taketomi

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Liver Transplant ◽

Early Stage ◽

Locally Advanced ◽

Tumor Biology ◽

Locoregional Therapy ◽

Milan Criteria ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc

AbstractSince the Milan criteria were accepted as the gold standard, liver transplantation has been widely performed as a curative treatment for early-stage hepatocellular carcinoma (HCC). The outcome of liver transplantation in early-stage HCC is excellent; however, the Milan criteria are strict, and therefore, only limited numbers of patients can benefit from liver transplantation. Many HCC patients are diagnosed at an advanced stage, which falls outside the Milan criteria, so it has been proposed over the last two decades that liver transplant surgeons should perform liver transplantation in locally advanced HCC, when presenting without recurrence. Several trials exploring the upper limits of liver transplantation have been performed, and extensive research on tumor biology has enabled the expansion of liver transplant indication for HCC. Simultaneously, locoregional therapy for advanced HCC was found to be an effective procedure when used to distinguish potentially transplantable patients. This treatment approach, known as a downstaging strategy, has been developed over the last two decades and became an essential treatment option for locally advanced HCC. In this article, the current strategies of liver transplantation for the treatment of locally advanced HCC are reviewed.

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Phase II Study of the Mitogen-Activated Protein Kinase 1/2 Inhibitor Selumetinib in Patients With Advanced Hepatocellular Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.9432 ◽

2011 ◽

Vol 29 (17) ◽

pp. 2350-2356 ◽

Cited By ~ 104

Author(s):

Bert H. O'Neil ◽

Laura W. Goff ◽

John Sae Wook Kauh ◽

Jonathan R. Strosberg ◽

Tanios S. Bekaii-Saab ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Protein Kinase ◽

Phase Ii ◽

Systemic Therapy ◽

Single Agent ◽

Locally Advanced ◽

Mitogen Activated Protein Kinase ◽

Advanced Hepatocellular Carcinoma ◽

Time To Progression ◽

Mitogen Activated Protein

Purpose Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. Patients and Methods Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. Conclusion In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.

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Selection of Patients with Hepatocellular Carcinoma for Sorafenib

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2009.0028 ◽

2009 ◽

Vol 7 (4) ◽

pp. 397-403 ◽

Cited By ~ 21

Author(s):

Ghassan K. Abou-Alfa

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Phase Iii ◽

Vegf Receptor ◽

Raf Kinase ◽

Advanced Cirrhosis ◽

Phase Iii Studies ◽

Selection Of Patients ◽

Selection Of

Sorafenib, a multitargeted anti-VEGF receptor and raf kinase inhibitor, was recently approved by the FDA for treating unresectable hepatocellular carcinoma (HCC) based on 2 randomized phase III studies. In addition, a phase II study evaluating sorafenib in patients with HCC and Child-Pugh A and B and a phase I study evaluating sorafenib in patients with organ dysfunction have provided insight about the safety and efficacy of sorafenib in patients with HCC and more advanced cirrhosis, and any difference in outcome based on etiology of HCC. The lack of objective responses observed in the sorafenib arm in the SHARP study also raises practical issues about how to assess response or efficacy of the therapy and thus how long a patient should receive sorafenib. This article addresses these questions on the use of sorafenib in HCC, both in the locally advanced and metastatic settings, in addition to the potential future applications and uses of sorafenib.

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Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.tps541 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. TPS541-TPS541

Author(s):

Neeraj Agarwal ◽

Ulka N. Vaishampayan ◽

Bradley Alexander McGregor ◽

Marjorie C. Green ◽

Nehal Mohamed ◽

...

Keyword(s):

Disease Progression ◽

Dose Escalation ◽

Immune Cell ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Antiangiogenic Therapy ◽

Objective Response ◽

Locally Advanced ◽

Clinical Activity ◽

Phase 1B

TPS541 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

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Therapy of Intermediate-Stage Hepatocellular Carcinoma: Current Evidence and Clinical Practice

Seminars in Interventional Radiology ◽

10.1055/s-0040-1719186 ◽

2020 ◽

Vol 37 (05) ◽

pp. 456-465

Author(s):

Nathan X. Chai ◽

Julius Chapiro

Keyword(s):

Hepatocellular Carcinoma ◽

Thermal Ablation ◽

Clinical Evidence ◽

Checkpoint Inhibitors ◽

Intermediate Stage ◽

Locoregional Therapy ◽

Current Evidence ◽

Locoregional Treatment ◽

Wide Range ◽

Bland Embolization

AbstractIntermediate-stage Hepatocellular Carcinoma (HCC) represents a wide range of disease burden. Patients with different levels of liver function, tumor size, and number of lesions may all have intermediate-stage disease according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Several minimally invasive image-guided locoregional therapies are available for the treatment of intermediate-stage HCC, including conventional transarterial chemoembolization (cTACE), drug-eluting bead TACE (DEB-TACE), yttrium-90 radioembolization (Y-90 RE), thermal ablation, bland embolization, and combination therapy. Available clinical evidence points to cTACE as the current gold standard for the locoregional treatment of intermediate-stage HCC. DEB-TACE is at best non-inferior to cTACE in terms of survival benefit. Y-90 RE is a maturing therapy, and some institutions have adopted it as first-line therapy for intermediate-stage HCC. Thermal ablation combined with TACE may be used in select patients, while bland embolization has only limited evidence for its use. The combination of locoregional therapy with VEGF inhibitors or immune checkpoint inhibitors has also been explored. This article will examine in detail the clinical evidence supporting available locoregional treatment options for intermediate-stage HCC.

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