Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/µL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.

Prevention of hepatitis B reactivation in patients with hematologic malignancies treated with novel systemic therapies: Who and Why?

The risk of reactivation in patients with chronic or past/resolved hepatitis B virus (HBV) infection receiving chemotherapy or immunosuppressive drugs is a well-known possibility. The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy. Though the advent of new drugs is occurring in all the field of medicine, in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment. As novel therapies, there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging. Moreover, patients are often treated with a combination of different drugs, so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult. First results are now available, but further studies are still needed. Patients with chronic HBV infection [hepatitis B surface antigen (HBsAg) positive] are reasonably all treated. Past/resolved HBV patients (HBsAg negative) are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.

Comparative Analysis of Subclassification Systems in Patients with Intermediate-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Classification B) Receiving Systemic Therapy.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. METHODS: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. RESULTS: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). CONCLUSIONS: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems.

Current guidelines for diagnosis and management of hepatic involvement in hereditary hemorrhagic teleangiectasia.

Hereditary hemorrhagic teleangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is the most common cause of hepatic vascular malformations in adults. Different vascular shunts (arteriovenous, arterioportal or portovenous) lead to different clinical manifestations. Even though no hepatic-related symptoms are reported in the majority of cases, the severity of liver disease could lead to refractory medical conditions, in some cases requiring liver transplantation. The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.

Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma.

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.

TKIs in combination with immunotherapy for hepatocellular carcinoma.

INTRODUCTION: The treatment landscape of hepatocellular carcinoma (HCC) has significantly changed over the last 5 years with multiple options in the frontline, second line, and beyond. Tyrosine kinase inhibitors (TKIs) were the first approved systemic treatments for the advanced stage of HCC; however, thanks to the increasing knowledge and characterization of the immunological features of the tumor microenvironment, the systemic treatment of HCC has been further expanded with the immune checkpoint inhibitor (ICI) approach and the following evidence of the higher efficacy obtained with combined treatment with atezolizumab plus bevacizumab over sorafenib. AREAS COVERED: In this review, we look at rationale, efficacy, and safety profiles of current and emerging ICI/TKI combination treatments and discuss the available results from other clinical trials using similar combinatorial therapeutic approaches. EXPERT OPINION: Angiogenesis and immune evasion are the two key pathogenic hallmarks of HCC. While the pioneering regimen of atezolizumab/bevacizumab is consolidating as the first-line treatment of advanced HCC, it will be essential, in the near future, to determine the best second-line treatment options and how to optimize the selection of the most effective therapies. These points still need to be addressed by future studies that are largely warranted to enhance the treatment's effectiveness and ultimately to tackle down HCC lethality.

Validation of the easy-to-use lenvatinib prognostic index to predict prognosis in advanced hepatocellular carcinoma patients treated with lenvatinib.

AIM: The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first-line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. METHODS: Data of Eastern and Western patients treated with lenvatinib as first-line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The "low risk" group includes patients with prognostic nutritional index (PNI) >43.3 and with previous transarterial chemoembolization. The "medium risk" group includes patients with PNI >43.3, but without previous transarterial chemoembolization and patients with PNI <43.3, albumin-bilirubin grade 1 and Barcelona Clinic Liver Cancer stage B. The "high risk" group includes patients with PNI <43.3, albumin-bilirubin grade 2, and patients with PNI <43.3, albumin-bilirubin grade 1 and Barcelona Clinic Liver Cancer stage C. RESULTS: A total of 717 patients were included. The median overall survival was 20.7 months (95% CI 16.1-51.6) in patients with low risk (n = 223), 16.7 months (95% CI 13.3-47.0) in patients with medium risk (n = 264), and 10.7 months (95% CI 9.3-12.2) in patients with high risk (n = 230; HR 1, 1.29, and 1.92, respectively; p < 0.0001). Median progression-free survival was 7.3 months (95% CI 6.3-46.5) in patients with low risk, 6.4 months (95% CI 5.3-8.0) in patients with medium risk ,and 4.9 months (95% CI 4.3-5.5) in patients with high risk (HR 1, 1.07, 1.47 respectively; p = 0.0009). CONCLUSION: The lenvatinib prognostic index confirms its prognostic value on an external cohort of hepatocellular carcinoma patients treated with Lenvatinib.

Surveillance for hepatocellular carcinoma: current status and future perspectives for improvement.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a globally relevant medical problem. Fortunately, risk factors for this tumor have been identified, and surveillance protocols developed. Patients with liver cirrhosis have the highest risk of developing HCC and have historically been included in surveillance programs. Special categories have also emerged in recent years, especially patients with eradicated HCV infection or nonalcoholic fatty liver disease. Novel serum biomarkers and magnetic resonance imaging protocols are currently being proposed to refine existing surveillance protocols. AREAS COVERED: We discuss the rationale of surveillance programs for HCC and report the most recent recommendations from international guidelines about this topic. Gray areas, such as nonalcoholic fatty liver disease and the role of intrahepatic cholangiocellular carcinoma, are also discussed. EXPERT OPINION: Surveillance is recognized as a tool to favor early diagnosis of HCC, access to curative treatment, and increase survival, even if the supporting evidence is mainly based on observational studies. As new randomized clinical trials are difficult to propose, future challenges will include optimizing implementation in the primary care setting and a more personalized approach, balancing the opportunities and risks of overdiagnosis of novel techniques and biomarkers.

Not long after its development, ultrasound (US) has been used to identify liver cancer in patients with liver cirrhosis. Consequently, US-based semiannual surveillance programs have been implemented in recent decades to facilitate an early diagnosis of liver cancer and increase chances of successful radical treatment. The efficacy of these protocols has been recognized in observational studies and clinical trials. However, recent years have shown the appearance of new categories of patients with chronic liver disease. Also, imaging innovations and putative novel biomarkers appeared on the stage. This review discusses the current knowledge and future perspective of these surveillance programs for liver cancer.

Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders.

Case-control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child-Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543-0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.