Controversies in the management of hepatocellular carcinoma

Forner, Alejandro; Fonseca, Leonardo Gomes da; Díaz-González, Álvaro; Sanduzzi‐Zamparelli, Marco; Reig, María; Bruix, Jordi

doi:10.1016/j.jhepr.2019.02.003

Cited by 47 publications

(41 citation statements)

References 153 publications

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“…Sorafenib is a multitarget tyrosine kinase inhibitor (TKI) currently used for the treatment of hepatocellular carcinoma (HCC) not amenable to surgery or locoregional treatments[1]. Sorafenib significantly prolongs patients' overall survival (OS), but its use is associated with different adverse events (AEs), mainly dermatological, gastrointestinal and cardiovascular[2,3].…”

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confidence: 99%

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

Tovoli

Ielasi

Casadei-Gardini

et al. 2019

Journal of Hepatology

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Background&Aims. Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. The impact of the physicians experience on the management of these AEs and the relative implications on clinical outcomes are unknown. We verified if the AEs management changed over time and if these modifications impacted on treatment duration and overall survival (OS). Methods. We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in three tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n=154), and Group B (2013-2017, n=184). Baseline and follow up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. Results. Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs 568 mg/day, p<0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs 4.1 months, p=0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs 11.0 months, p=0.003) with a sharp increase in the 2-year survival rate (28.1 vs 18.4%, p=0.003) in Group B. The multivariate time-dependent Cox regression confirmed later period of treatment as an independent predictor of survival (HR 0.728, 95%CI 0.581-0.937, p=0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis. Conclusions: experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive.

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confidence: 99%

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

Tovoli

Ielasi

Casadei-Gardini

et al. 2019

Journal of Hepatology

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“…Hepatocellular carcinoma (HCC) is recognized worldwide as a devastating malignancy since it constitutes the second-leading cause of cancer-related mortality, particularly in men [1] and shows a remarkable resistance profile against systemic therapies [2]. In contrast to the optimization of surgical and locoregional therapies driven by the improvement of surveillance of patients at risk, the only available systemic option for the last 10 years was restricted to sorafenib, which is a multi-kinase inhibitor with limited efficacy in patients with unresectable HCC [3].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to the optimization of surgical and locoregional therapies driven by the improvement of surveillance of patients at risk, the only available systemic option for the last 10 years was restricted to sorafenib, which is a multi-kinase inhibitor with limited efficacy in patients with unresectable HCC [3]. Recently, further medications have been approved as additional first-line or second-line treatments of HCC, yet they merely show just a non-inferiority as compared to sorafenib [2]. Collectively, HCC is still broadly recognized as 2 of 21 an aggressive and chemoresistant tumour with the efficacy of systemic HCC treatment remaining disappointingly low.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro

Jakobi

Beyer

Koch

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.

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“…This occurs when the images display the typical combination of arterial phase hyperenhancement and washout appearance in the portal venous and/or delayed phases that are commonly considered in global guidelines . However, there is ongoing controversy regarding biopsy versus follow‐up imaging for indeterminate hepatic nodules (IDNs), which do not meet these criteria when examined by multiphasic contrast‐enhanced computed tomography (CT) or magnetic resonance imaging (MRI) …”

mentioning

confidence: 99%

“…tomography (CT) or magnetic resonance imaging (MRI). (2)(3)(4)(5) The issues that need to be considered before biopsy of an IDN include the risk of complications, such as pain, bleeding, and track seeding of a tumor, and the potential for false-negatives resulting from sampling errors, especially for very small lesions in patients with advanced cirrhosis. (6)(7)(8)(9) In contrast, follow-up imaging without immediate biopsy may entail unnecessary cost and radiation exposure.…”

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confidence: 99%

Hepatocyte‐Specific Magnetic Resonance Imaging–Based Assessment of Indeterminate Hepatic Nodules in the Liver Transplant Evaluation of Patients With Cirrhosis

et al. 2020

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We aimed to determine the identities in explants of indeterminate hepatic nodules (IDNs) that had been scanned by dynamic magnetic resonance imaging (MRI) to establish clinicoradiological parameters predicting which IDNs were hepatocellular carcinomas (HCCs). This study included 88 patients with cirrhosis who underwent gadoxetic acid–enhanced MRI in pre–liver transplantation (LT) workup followed within 90 days by primary LT. The MRI detected 168 hepatic nodules that were classified into 6 benign tumors, 49 HCCs, and 113 IDNs, in 5, 34, and 72 patients, respectively. We compared these pre‐LT radiologic diagnoses and stagings with explant pathology on a per‐lesion basis to enable us to identify features of IDNs related to malignancy. Of the 168 nodules seen on MRI, 119 that were classified radiologically as consisting of 1 benign nodule (33.3%), 46 HCCs (93.9%), and 72 IDNs (63.7%) all turned out to be pathological HCCs. Of 32 patients inside Milan and 54 without HCC staged by MRI, 11 progressed beyond the criteria after LT. High serum alpha‐fetoprotein level (≥20 ng/mL) was the only per‐patient factor significantly associated with malignant IDNs. Per‐tumor analysis of the MRI signals revealed that arterial hyperintensity, hepatobiliary hypointensity, T2‐weighted mild‐to‐moderate intensity, and restricted diffusion‐weighted images were significantly correlated with malignant IDN. A model combining these 4 MRI factors with alpha‐fetoprotein level had the best performance in predicting the identification of IDNs as HCCs in explanted livers. Over 60% of the IDNs seen on dynamic images of cirrhotic livers proved to be HCCs when explanted livers were examined. It may therefore be possible to identify HCCs with reasonable accuracy by means of their hepatocyte‐specific MRI features when patients are being assessed for LT.

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Controversies in the management of hepatocellular carcinoma

Cited by 47 publications

References 153 publications

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro

Hepatocyte‐Specific Magnetic Resonance Imaging–Based Assessment of Indeterminate Hepatic Nodules in the Liver Transplant Evaluation of Patients With Cirrhosis

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