Sorafenib and Regorafenib in HBV- or HCV-positive hepatocellular carcinoma patients: Analysis of RESORCE and SHARP trials

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Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: Results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment

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

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)

Profile of lenvatinib in the treatment of hepatocellular carcinoma: design, development, potential place in therapy and network meta-analysis of hepatitis B and hepatitis C in all Phase III trials

Purpose: Sorafenib is the only approved drug in first-line treatment for hepatocellular carcinoma. Recently, the Phase III REFLECT trial proved lenvatinib not inferior to sorafenib, potentially establishing a new standard of care in this setting. The study showed that both have similar overall survivals, yet with longer time to progression for lenvatinib. Currently, the selection of one or other is not based on clinical or biological parameters for this reason we performed a network meta-analysis and we also analyzed the REFLECT trial and its implications in the current and future clinical practice. Materials and methods: We performed the meta-analysis according to the Prisma statement recommendations. HR was the measure of association for time to progression and overall survival. The pooled analysis of HR was performed using a random effect model, fixing a 5% error as index of statistical significance. Results: For HBV-positive patients, there was a clear trend in favor of lenvatinib over sorafenib (HR 0.82 95% credible interval [CrI] 0.60\u20131.15). For HCV-positive no differences between lenvatinib and sorafenib were observed (HR 0.91 95% CrI 0.41\u20132.01). The data showed that lenvatinib could be the best drug for HBV-positive patients in 59% of cases compared to only 1% of patients treated with sorafenib. Conclusion: The identification of clinical or biological markers that could predict response or resistance to treatments is needed to guide treatment decision. This network meta-analysis demonstrates that the etiology is a good candidate and this result should be validated in a specific trial.Purpose: Sorafenib is the only approved drug in first-line treatment for hepatocellular carcinoma. Recently, the Phase III REFLECT trial proved lenvatinib not inferior to sorafenib, potentially establishing a new standard of care in this setting. The study showed that both have similar overall survivals, yet with longer time to progression for lenvatinib. Currently, the selection of one or other is not based on clinical or biological parameters for this reason we performed a network meta-analysis and we also analyzed the REFLECT trial and its implications in the current and future clinical practice.Materials and methods: We performed the meta-analysis according to the Prisma statement recommendations. HR was the measure of association for time to progression and overall survival. The pooled analysis of HR was performed using a random effect model, fixing a 5% error as index of statistical significance.Results: For HBV-positive patients, there was a clear trend in favor of lenvatinib over sorafenib (HR 0.82 95% credible interval [CrI] 0.60-1.15). For HCV-positive no differences between lenvatinib and sorafenib were observed (HR 0.91 95% CrI 0.41-2.01). The data showed that lenvatinib could be the best drug for HBV-positive patients in 59% of cases compared to only 1% of patients treated with sorafenib.Conclusion: The identification of clinical or biological markers that could predict response or resistance to treatments is needed to guide treatment decision. This network meta-analysis demonstrates that the etiology is a good candidate and this result should be validated in a specific trial

Radiofrequency Ablation of hepatocellular carcinoma: a meta-analysis of overall survival and recurrence-free survival

Background and aims So far, no randomized trial or meta-analysis has been conducted on overall survival (OS) and recurrence-free survival (RFS) factors in patients treated with radiofrequency ablation (RFA) alone. The purpose of this meta-analysis was to evaluate prognostic factors of OS and RFS in patients treated with RFA. Methods A primary analysis was planned to evaluate the clinical prognostic factor of OS. RFS was the secondary aim. Thirty-four studies published from 2003 to 2017 were analyzed. They included 11,216 hepatocellular carcinoma patients. Results The results showed that Child\u2013Pugh B vs Child\u2013Pugh A (HR =2.32; 95% CI: 2.201\u20132.69; P<0.0001) and albumin\u2013bilirubin score 1 vs 0 (HR =2.69; 95% CI: 2.10\u20133.44; P<0.0001) were predictive of poor OS. Tumor size as a continuous variable was not predictive of OS, although it was predictive of OS when we considered the size as a cutoff value (.2 cm vs <2 cm: HR =1.41; 95% CI: 1.23\u20131.61; P<0.0001; >3 cm vs <3 cm: HR =1.43; 95% CI: 1.17\u20131.74; P<0.0001) and in presence of >1 nodule (HR =1.59; 95% CI: 1.46\u20131.74; P<0.0001). Alpha-fetoprotein >20 ng/mL (HR =1.46; 95% CI: 1.25\u20131.70; P<0.0001) was the only predictive factor of poor prognosis. Conclusion Our meta-analysis highlighted that the maximum benefit of RFA in terms of OS and RFS is reached in the presence of Child\u2013Pugh A, albumin\u2013bilirubin score 1, single-nodule tumor sized <2 cm, and alpha-fetoprotein <20 ng/mL

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation

Purpose: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). Methods: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Results: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5\u201311.6) vs 5.0 (4.2\u20135.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8\u201312.9) vs. 5.8 (4.8\u20136.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5\u201324.1) vs. 7.8 (5.2\u201310.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. Conclusions: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression

Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals

Background: Unexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy. Aims: We evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting. Methods: In this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score. Results: In patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05\u20135.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85\u20131.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01\u20131.09) was significantly associated with a risk of recurrence. Conclusion: ALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs

Antiangiogenic agents after first line and sorafenib plus chemoembolization: A systematic review

Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage, although the combination of TACE with sorafenib may theoretically benefit HCC patients in intermediate stage. Owing to the significant antiangiogenic effect of sorafenib and the limitation of TACE, it is rational to combine them. Though the strategy of combining TACE and sorafenib has been increasingly used in patients with unresectable HCC but the current evidence is controversial and its clinical role has not been determined yet. In first-line therapy, patients receiving sorafenib had increased overall survival and progression free survival. Therefore several antiangiogenic agents have entered clinical studies on HCC, many with negative results. This review discusses the current drug development for patients with HCC and role of TACE plus sorafenib

Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) since 2007 and numerous studies have investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC