Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002–2020)

Haber, Philipp K.; Puigvehí, Marc; Castet, Florian; Lourdusamy, Vennis; Montal, Robert; Tabrizian, Parissa; Buckstein, Michael; Kim, Edward; Villanueva, Augusto; Schwartz, Myron; Llovet, Josep M.

doi:10.1053/j.gastro.2021.06.008

Cited by 141 publications

(128 citation statements)

References 77 publications

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“…Despite the negative impact of NAFLD/NASH on the response to immunotherapy has been confirmed also in pharmacological trials on patients with HCC, a recent meta-analysis considering 3 phase III trials comprising a total of 1656 patients with unresectable HCC found that immunotherapy improved overall survival only in patients with viral HCC compared to non-viral ones [ 71 ]. This evidence was sustained by another meta-analysis involving eight studies comprising more than 3700 patients [ 72 ]. Even worse, the checkpoint inhibition of PD-1/PD-L1 was linked to a decreased survival in patients NAFLD related HCC [ 71 ].…”

Section: Immune-related Therapy In Nafldmentioning

confidence: 85%

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

Lombardi

Piciotti

Dongiovanni

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.

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Section: Immune-related Therapy In Nafldmentioning

confidence: 85%

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

Lombardi

Piciotti

Dongiovanni

et al. 2022

IJMS

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“…The pathogenesis of HCC is a complex multistage process, where angiogenesis plays an important role. For patients with advanced disease, only a handful of kinase inhibitors are approved for therapy, such as cabozantinib, regorafenib, lenvatinib, or sorafenib [ 41 , 42 , 43 , 44 , 45 ]. Anti-angiogenic agents, as well as some monoclonal antibodies, are also approved for use in HCC treatment.…”

Section: Discussionmentioning

confidence: 99%

Bi-Functional Peptides as a New Therapeutic Tool for Hepatocellular Carcinoma

et al. 2021

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Background: The interfering peptides that block protein–protein interactions have been receiving increasing attention as potential therapeutic tools. Methods: We measured the internalization and biological effect of four bi-functional tumor-penetrating and interfering peptides into primary hepatocytes isolated from three non-malignant and 11 hepatocellular carcinomas. Results: These peptides are internalized in malignant hepatocytes but not in non-malignant cells. Furthermore, the degree of peptide internalization correlated with receptor expression level and tumor aggressiveness levels. Importantly, penetration of the peptides iRGD-IP, LinTT1-IP, TT1-IP, and RPARPAR-IP induced apoptosis of the malignant hepatocytes without effect on non-malignant cells. Conclusion: Receptor expression levels correlated with the level of peptide internalization and aggressiveness of the tumor. This study highlights the potential to exploit the expression of tumor-penetrating peptide receptors as a predictive marker of liver tumor aggressiveness. These bi-functional peptides could be developed for personalized tumor treatment.

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“…A recent meta-analysis of eight first-line high-quality phase three randomised clinical trials in advanced HCC (2002–2020) was published, reporting the relationship between aetiology and outcomes after systemic therapies with either TKI, anti-angiogenic, or ICI therapy [ 60 ]. Of these, five trials studied TKI/anti-VEGF (REACH, REACH-2, METIV-HCC, CELESTIAL, and JET-HCC; total of 2083 patients), and three studied immunotherapies (CheckMate-459, Journal Pre-proof 14, IMbrave150 and KEYNOTE-240; with a total of 1656 patients).…”

Section: Could Lenvatinib Compete With Atezolizumab Plus Bevacizumab?mentioning

confidence: 99%

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

Decraecker

Toulouse

Blanc

2021

Cancers

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The systemic treatment of hepatocellular carcinoma is changing rapidly. Three main classes of treatment are now available. Historically, multi-targeted tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib as first-line; regorafenib and cabozantinib as second-line) were the first to show an improvement in overall survival (OS). Anti-vascular endothelial growth factor (anti-VEGF) antibodies can be used in first-line (bevacizumab) or second-line (ramucirumab) combination therapy. More recently, immuno-oncology (IO) has profoundly changed therapeutic algorithms, and the combination of atezolizumab-bevacizumab is now the first-line standard of care. Therefore, the place of TKIs needs to be redefined. The objective of this review was to define the place of TKIs in the therapeutic algorithm at the time of IO treatment in first-line therapy, with a special focus on lenvatinib that exhibits one of the higher anti-tumoral activity among TKI in HCC. We will discuss the place of lenvatinib in first line (especially if there is a contra-indication to IO) but also after failure of atezolizumab and bevacizumab. New opportunities for lenvatinib will also be presented, including the use at an earlier stage of the disease and combination with IOs.

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Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002–2020)

Cited by 141 publications

References 77 publications

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

Bi-Functional Peptides as a New Therapeutic Tool for Hepatocellular Carcinoma

Is There Still a Place for Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma at the Time of Immunotherapies? A Focus on Lenvatinib

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