The potential impact of direct-acting antivirals (DAAs) in patients with Barcelona Clinic Liver Cancer (BCLC)-B/C stage hepatocellular carcinoma (HCC) is understudied. Patients with HCC have been ...systematically excluded from randomised controlled trials evaluating the effectiveness of DAAs. Thus, the benefits of DAAs in patients with HCC are less well defined. The presence of active HCC before the initiation of DAA treatment is reported to be a predictor of DAA failure, and studies in patients without HCC have demonstrated that improvements in cirrhosis complications were lower or absent after DAA failure. Even if viral eradication is achieved using DAAs, reversal of liver function impairment may take longer than the development of end-stage cancer status. Additionally, the impact of DAAs on HCC recurrence is still a controversial topic. Thus, the decision of whether to use DAAs should be made on a patient-by-patient basis, and each patient should be informed of all the potential risks and benefits associated with their usage. This document summarises the current data on the usage of DAAs in BCLC-B/C patients, discusses the concept of “the point of no return” in the setting of DAAs, and proposes tools for deciding the best option for each patient profile. If liver function improvement overlaps with symptomatic HCC progression, the benefits of DAAs could be minimised, worsened, or fully counterbalanced. If the BCLC stage is defined using only liver dysfunction, the decision to prioritise DAA treatment should be based on the option (or lack thereof) of liver transplantation and/or the HCC stage. We propose applying a shared decision-making approach, informing each patient of all the potential risks and benefits of the proposed medical intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, ...replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for ...these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•DAAs improve survival in patients with HCV-related early HCC that has been successfully treated.•The improvement in survival seems to be caused by a reduction in hepatic ...decompensation.•DAAs did not impact on HCC recurrence.
The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation.
We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared.
In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio HR 0.39; 95% CI0.17–0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR0.70; 95% CI0.44–1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR0.32; 95% CI0.13–0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00–0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11–0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02–0.38; p = 0.02).
In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment.
We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Hepatocellular carcinoma(HCC)is a major health problem with a high incidence and mortality all over the world.Natural history of HCC is severe and extremely variable,and prognostic factors ...influencing outcomes are incompletely defined.Over time,many staging and scoring systems have been proposed for the classification and prognosis of patients with HCC.Currently,the non-ideal predictive performance of existing prognostic systems is secondary to their inherent limitations,as well as to a non-universal reproducibility and transportability of the results in different populations.New serological and histological markers are still under evaluation with promising results,but they require further evaluation and external validation.The aim of this review is to highlight the main tools for assessing the prognosis of HCC and the main concerns,pitfalls and warnings regarding its staging systems currently in use.
Knowing the spontaneous outcome of hepatocellular carcinoma (HCC) is important for designing randomized controlled trials (RCTs) of new therapeutic approaches; however, survival of patients in the ...absence of treatment is highly variable, and prognostic factors influencing outcomes are incompletely defined. The aims of this meta‐analysis were to estimate the 1‐year and 2‐year survival rates of untreated HCC patients enrolled in RCTs of palliative treatments, and to identify prognostic factors. RCTs evaluating therapies for HCC with placebo or no‐treatment arms were identified on MEDLINE through April 2009. Data were combined in a random effect model. Primary outcomes were 1‐year and 2‐year survival. Thirty studies met the inclusion criteria. The pooled estimates of the survival rates were 17.5% at 1 year (95% confidence interval 95%CI, 11%‐27%; range, 0%‐75%) and 7.3% at 2 years (95%CI, 3.9%‐13%; range, 0%‐50%). Heterogeneity among studies was highly significant (P < 0.0001) both for 1‐year and 2‐year survival, and persisted when RCTs were stratified according to all patient and study features. Through meta‐regression, impaired performance status, Child‐Pugh B‐C class, and presence of portal vein thrombosis were all independently associated with shorter survival. Ascites was strongly linked to a worse outcome in intermediate/advanced Barcelona Clinic Liver Cancer stages. Conclusion: This meta‐analysis confirms the heterogeneity of behavior of untreated HCC and provides a sound basis for stratifying patients with HCC according to expected survival in future trials of new anti‐cancer agents. (HEPATOLOGY 2010.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, 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, SAZU, SBCE, SBMB, UL, UM, UPUK
•HBP-hypointense nodules without APHE may contain a HBP-hyperintense nodule-in-nodule.•Hyperintensity of the inner nodule becomes visible on 3-minute transitional phase.•The nodule-in-nodule may ...precede the appearance of APHE on subsequent MRI.•The nodule-in-nodule architecture on HBP likely represents a focus of progressed HCC.
To investigate the clinical implications and natural history of observations showing a “nodule-in-nodule” architecture on hepatobiliary phase (HBP) in a cirrhotic population.
This is an IRB-approved retrospective study conducted in a single institution. We identified 20 patients (11 men and 9 women, mean age 71 years, range 51–83 years) who had a hyperintense nodule on HBP arising within a larger HBP-hypointense nodule without arterial phase hyperenhancement (APHE) at gadoxetate disodium-enhanced MRI. Size and signal intensity of the nodules were evaluated in all sequences, along with the evolution of the nodules at serial MRI studies.
Twenty-four nodules were analyzed in 20 patients. Mean diameter of the inner hyperintense nodule on HBP was 1.1 cm (range 0.6–1.8 cm) and that of the outer hypovascular hypointense nodule was 2.1 cm (range 1.2–4.1 cm). All intranodular foci were hyperintense on HBP and showed a typical pattern for hepatocellular carcinoma (HCC) with APHE and washout on portal venous phase (PVP) (n = 11, 46%), washout only (n = 7, 29%) or APHE with no washout (n = 6, 25%). The hyperintensity on 3-, 5- and 10-minute phases was seen in 21%, 58% and 83% of the nodules, respectively. In twelve out of sixteen (75%) nodules with subsequent imaging available the hyperintensity on HBP occurred before either the appearance of APHE or washout on PVP.
HBP-hypointense nodules without APHE may contain a hyperintense smaller nodule-in-nodule on HBP that can precede the appearance of either APHE or washout on PVP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.
This multicentric ...study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS).
A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts.
PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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