Combination approaches in hepatocellular carcinoma:How systemic treatment can benefit candidates to locoregional modalities

The management of hepatocellular carcinoma(HCC)is challenging because most patients have underlying cirrhosis,and the treatment provides,historically,a limited impact on the natural history of patients with advanced-stage disease.Additionally,recurrence rates are high for those patients who receive local and locoregional modalities,such as surgical(resection and transplantation)or imageguided(ablation and intra-arterial)therapies.Translational research has led to new concepts that are reshaping the current clinical practice.Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis.This has primed a successful incorporation of novel agents with different targets,such as anti-angiogenic drugs,targeted-therapies,and immune-checkpoint inhibitors.Although clinical trials have proven efficacy of systemic agents in advanced stage disease,there is no conclusive evidence to support their use in combination with loco-regional therapy.While novel local modalities are being incorporated(e.g.,radioembolization,microwave ablation,and irreversible electroporation),emerging data indicate that locoregional treatments may induce tumor microenvironment changes,such as hyperexpression of growth factors,release of tumor antigens,infiltration of cytotoxic lymphocytes,and modulation of adaptative and innate immune response.Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement.Current efforts are directed to investigate the role of immunotherapy-based regimens in this context.The present review aims to describe the current landscape of systemic and locoregional treatments for HCC,present evidence to support combination approaches,and address future perspectives.

Trial eligibility in advanced hepatocellular carcinoma: Does it support clinical practice in underrepresented subgroups?

Although hepatocellular carcinoma is considered a highly lethal malignancy,recent therapeutic advances have been achieved during the last 10 years.This scenario resulted in an unprecedented improvement in survival for patients with advanced hepatocellular carcinoma,almost reaching 20-26 mo of overall survival after first-second line sequential treatment.The advent of the combination of atezolizumab with bevacizumab showed,for the first time,superiority over sorafenib with improvement in overall survival.However,first and second-line trials were correctly based on the premise that a strict selection of patients enhances the power to capture the positive effect of treatment by excluding competing risks for mortality such as liver failure,decompensated cirrhosis or other underlying medical conditions.As a result,the inclusion criteria used in clinical trials do not support the use of novel therapies in several real-world scenarios involving underrepresented subgroups,such as patients with unpreserved liver function,other comorbid conditions,a history of solid-organ transplantation,autoimmune disorders and those with a high risk of bleeding.The present text aims at discussing treatment strategies in these subgroups.