Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

Roderburg, Christoph; Özdirik, Burcin; Wree, Alexander; Demir, Münevver; Tacke, Frank

doi:10.2217/hep-2020-0004

Cited by 33 publications

(32 citation statements)

References 54 publications

(60 reference statements)

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“…Although ICIs showed limited efficacy as single agents, combined therapies have revolutionized the treatment regimens of advanced HCC. 108 Importantly, HCC does not respond to classical cytotoxic chemotherapy. Different mechanisms of resistance to chemotherapy have been proposed, such as reduced drug uptake and increased drug efflux/metabolism, increased DNA repair mechanisms, decreased DNA-damage-induced cell-cycle arrest, impaired apoptosis and enhanced survival pathways (e.g., phosphatidylinositol 3-kinase [PI3K]/AKT/ mTOR), activation of autophagy, and deregulation of the epigenetic machinery to promote stem cell epigenetic signatures.…”

Section: Systemic Therapies For Advanced Hccmentioning

confidence: 99%

The therapeutic landscape of hepatocellular carcinoma

Gallage

García‐Beccaria

Szydlowska

et al. 2021

Med

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The liver is endowed with an amazing regenerative capacity that allows it to withstand an enormous amount of damage. Nevertheless, it is precisely this highly regenerative capacity that renders it susceptible to dysplasia and liver cancer. Liver cancer is not only one of the most common cancers but also one of the deadliest. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 70%-90% of all cases, but treatment options for advanced stages remain scarce. Therefore, a great deal of effort has gone into identifying early diagnostic markers as well as novel therapies, both local and systemic, for the treatment of this deadly disease. In this review, we aim to shed light into the current therapeutic landscape of HCC with an emphasis on the available treatments, ranging from surgical and local-ablative therapy for early and intermediate stages of the disease to systemic therapies for advanced cancer treatments. We will also address the molecular mechanisms and limitations of currently available systemic therapies and the causes of treatment resistance and finally summarize the emerging future avenues and novel concepts that are promising.

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Section: Systemic Therapies For Advanced Hccmentioning

confidence: 99%

The therapeutic landscape of hepatocellular carcinoma

Gallage

García‐Beccaria

Szydlowska

et al. 2021

Med

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“…However, the study was recently halted after the completion of an interim futility analysis [ 155 ]. Further studies employing other therapeutic agents, combinations of treatments and adjuvants and in different stages of disease are on the way (e.g., NCT03203005 and NCT03071094) [ 156 ].…”

Section: Immunological Therapeutic Approachesmentioning

confidence: 99%

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Lurje

Hammerich

Tacke

2020

IJMS

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Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.

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“…Most recently, it was demonstrated that patients with PD-L1 positive gastric cancer show improved response rates and improved survival compared to patients without PD-L1 expression [ 19 ]. While the same was true, e.g., for patients with non-small cell lung cancer [ 20 ], PD-L1 tumor expression was neither predictive nor prognostic in other tumor entities such as hepatocellular carcinoma (HCC) [ 21 ]. In terms of circulating biomarkers for ICI therapy, data are scarce; some authors have suggested that serum lactate dehydrogenase (LDH) levels [ 22 , 23 ] and the neutrophil/lymphocyte ratio (NLR) might correlate with an unfavorable prognosis in patients with melanoma and/or NSCLC treated with ICI.…”

Section: Discussionmentioning

confidence: 99%

Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy

Loosen

Bosch

Gorgulho

et al. 2021

JCM

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Background: Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. Methods: We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. Results: While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (−3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<−6.18 mm2/cm) or a strongly decreasing ∆MMA (<−0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below −6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). Conclusion: Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.

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Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

Cited by 33 publications

References 54 publications

The therapeutic landscape of hepatocellular carcinoma

The therapeutic landscape of hepatocellular carcinoma

Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer

Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy

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