Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

Tovoli, Francesco; Lorenzo, Stefania De; Barbera, Maria Aurelia; Garajová, Ingrid; Frega, Giorgio; Palloni, Andrea; Pantaleo, Maria Abbondanza; Biasco, Guido; Brandi, Giovanni

doi:10.2217/fon-2017-0166

Cited by 9 publications

(8 citation statements)

References 69 publications

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“…Tailored treatment according to the individual HCC genetic profile could provide therapeutic choices beyond standard sorafenib regimen for liver cancers. 160,161 From this perspective, as galunisertib is not similarly effective in all patients, several studies have been aimed at identifying new potential diagnostics biomarkers for patient stratification. In one study, next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib.…”

Section: Intracellular Level: Signal Transduction Blockade By Recep-mentioning

confidence: 99%

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

et al. 2018

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Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

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Section: Intracellular Level: Signal Transduction Blockade By Recep-mentioning

confidence: 99%

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

et al. 2018

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“…Overall, the results of the CheckMate-459 and KEYNOTE-240 trials suggested that: (1) The design of clinical trials remains a critical point in HCC trials, as seemingly minor pitfalls can determine the failure of the trial [ 21 ]; (2) the safety profile of nivolumab and pembrolizumab was excellent, with an impact on the quality of life significantly lower than that of sorafenib in the CheckMate-459 study [ 11 ]; (3) an objective response could be achieved in 15–20% of cases, leading to a long-term survival in responding patients [ 11 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

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

2020

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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.

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“…As a first point, we demonstrated an improved OS in comparison with matched patients treated with BSC alone. The potential mechanisms of actions of MC have been previously illustrated 26 and include: inhibition of tumor angiogenesis, reduction of the therapeutic resistance of the tumor, and activation of the adaptive and innate immune response 27 , 28 .…”

Section: Discussionmentioning

confidence: 99%

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept

Lorenzo

Tovoli

Barbera

et al. 2018

Sci Rep

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There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naïve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8–9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733–11.267]in MC-patients and 5.1 months [95% CI: 4.098–6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5–6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370–0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations.

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Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

Cited by 9 publications

References 69 publications

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

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

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept

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