During the last decades, further knowledge of hepatocellular carcinoma (HCC) molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors (TKIs) ...and immunotherapy. In this review, we describe first and second line systemic treatment options for advanced HCC. Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab (specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.
Role of antiviral treatment for HCC prevention Colombo, Massimo; Iavarone, Massimo, MD, PhD
Baillière's best practice & research. Clinical gastroenterology,
10/2014, Volume:
28, Issue:
5
Journal Article
Peer reviewed
Abstract Chemoprevention of hepatocellular carcinoma (HCC) is listed as a yet highly debated long-term benefit of a successful treatment of patients with chronic viral hepatitis. In the hepatitis B ...virus (HBV) arena, the retrospective scrutiny of both interferon and nucleos(t)ide analogues (NUC) studies failed to provide robust evidence for HCC chemoprevention, due to a number of confoundings in the studies that were originally designed to assess the antiviral activity of interferon therapy. However, the reanalysis of outcomes following patients stratification for risk factors of HCC, provided a clue to find an association between NUC therapy and a reduced risk of liver cancer in non cirrhotic patients, only. In the hepatitis C scenario, a meta analysis of 30 observational studies of patients treated with interferon demonstrated a more than 70% reduction of HCC risk occurring independently of severity of underlying liver fibrosis which was less pronounced in aged patients and those with more advanced liver fibrosis. While the reasons for the residual risk of HCC in virological responders remain largely unexplained, international societies recommend surveillance for HCC of both HBV and HCV responders to antiviral therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to ...survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800‐mg/d sorafenib therapy. Treatment was down‐dosed or interrupted according to drug label. Two hundred ninety‐six patients (88% Child‐Pugh A, 75% Barcelona Clinic Liver Cancer BCLC‐C, and 25% BCLC‐B) received sorafenib for 3.8 months (95% CI 3.3‐4.4). Two hundred sixty‐nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC‐C versus 20.6 months in BCLC‐B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half‐dosed sorafenib may have implications for tailored therapy. (HEPATOLOGY 2011)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, ...a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF‐A, VEGF‐C and VEGFR‐1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression‐free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF‐A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF‐C alleles T of rs4604006, G of rs664393, VEGFR‐2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.
What's new?
The tyrosine kinase inhibitor sorafenib, which is directed against vascular endothelial growth factor (VEGF), is considered to be the standard of treatment for hepatocellular carcinoma (HCC). Nevertheless, some tumors fail to respond to the drug, possibly owing to variations in the VEGF gene. Here, investigation of single nucleotide polymorphisms (SNPs) in VEGF and VEGFR in HCC patients who received sorafenib reveals that certain SNPs are significant predictors of progression free survival and overall survival. The identified SNPs may represent valuable assets in the identification of HCC patients who are likely to benefit from sorafenib treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background/Aims Liver biopsy for hepatocellular carcinoma (HCC) detection is largely restricted to small hepatocellular lesions, which are often morphologically challenging, requiring careful ...distinction between dysplastic nodules (high-grade) and well-differentiated HCC. Methods We investigated the diagnostic accuracy of a panel of markers (HSP70 GPC3 and GS), previously tested in resection specimens, in a series of liver biopsies of large regenerative nodules ( n = 13), low-grade dysplastic nodules ( n = 21), high-grade dysplastic nodules ( n = 50), very well-differentiated (VWD) ( n = 17), well-differentiated (WD-G1) ( n = 40) and G2-3 ( n = 35) HCC. Results Almost all cases of large regenerative and low-grade dysplastic nodules did not stain while high-grade dysplastic nodules showed 1 marker (22%) but never 2 or 3. For HCC detection the overall accuracy of marker combination was 60.8% (3 markers) and 78.4% (2 markers) with 100% specificity. When restricted to VWD + WD-G1 HCC the accuracy was 57% (3 markers) and 72.9% (2 markers) with 100% specificity. Conclusions This panel proved useful to detect well-differentiated HCC in biopsy. Two immunoreactive markers (out of 3) are recommended as the most valuable diagnostic combination for HCC detection. The diagnostic accuracy of the panel could be improved using additional markers, as suggested by studies of expression profiling in other human models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The hepatitis B virus (HBV) plays a dominant role in the 749,000 new cases and 692,000 deaths related to hepatocellular carcinoma (HCC) that are estimated to occur each year worldwide. Chronic ...infection with HBV is responsible for 60% of HCCs in Asia and Africa and at least 20% of the tumors in Europe, Japan, and the United States. This article discusses the pathogenic role of HBV and the risk of HCC. Tumors almost invariably develop in the context of chronic hepatitis or cirrhosis, which makes early diagnosis the only practical approach to improve prognosis. The treatment options are also discussed.
Aim
Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with ...hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC.
Methods
All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI.
Results
A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash‐out in the late phase was marked in 24% of nodules.
Conclusions
CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs ...not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The American College of Radiology (ACR) released the Liver Imaging Report and Data System (LI-RADS) scheme, which categorizes hepatic nodules in risk classes from LR-1 to LR-5 (according to the ...degree of risk to be HCC) and LR-M (probable malignancy not specific for HCC). The aim of this study was to test whether HCC with different LR patterns on CEUS have different overall survival (OS) and recurrence-free survival (RFS). We retrospectively enrolled 167 patients with the first definitive diagnosis of single HCC (by using CT/MRI or histological techniques if CT/MRI were inconclusive) for whom CEUS examination was available. The median size of HCC lesions was 2.2 cm (range 1.0-7.2 cm). According to CEUS LI-RADS classification, 28 patients were in LR-3, 48 in LR-4, 83 in LR-5, and 8 in LR-M. Patient liver function and nodule characteristics were not statistically different between CEUS LI-RADS classes. Using univariate analysis, CEUS LI-RADS class was not found to be a predictor of survival (
= 0.347). In conclusion, HCC showing the CEUS LI-RADS classes LR-3 and LR-4 have no better clinical outcome than typical HCC. Such data support the EASL policy, aimed at conclusive diagnostic investigations of indeterminate nodules up to obtaining histological proof to avoid leaving aggressive HCC not timely treated.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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