Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells’ exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

Background: Locoregional therapies (LRTs) are commonly used to increase the number of potential candidates for liver transplantation (LT). The aim of this paper is to assess the outcomes of LRTs prior to LT in patients with hepatocellular carcinoma (HCC) beyond the listing criteria. Methods: In accordance with the PRISMA guidelines, we searched the Medline and Web of Science databases for reports published before May 2021. We included papers assessing adult patients with HCC considered for LT and reporting intention-to-treat (ITT) survival outcomes. Two reviewers independently identified and extracted the data and evaluated the papers. Outcomes analysed were drop-out rate; time on the waiting list; and 1, 3 and 5 year survival after LT and based on an ITT analysis. Results: The literature search yielded 3,106 records, of which 11 papers (1874 patients) met the inclusion criteria. Patients with HCC beyond the listing criteria and successfully downstaged presented a higher drop-out rate (OR 2.05, 95% CI 1.45–2.88, p < 0.001) and a longer time from the initial assessment to LT than those with HCC within the listing criteria (MD 1.93, 95% CI 0.91–2.94, p < 0.001). The 1, 3 and 5 year survival post-LT and based on an ITT analysis did not show significant differences between the two groups. Patients with HCC beyond the listing criteria, successfully downstaged and then transplanted, presented longer 3 year (OR 3.77, 95% CI 1.26–11.32, p = 0.02) and 5 year overall survival (OS) (OR 3.08, 95% CI 1.15–8.23, p = 0.02) in comparison with those that were not submitted to LT. Conclusions: Patients with HCC beyond the listing criteria undergoing downstaging presented a higher drop-out rate in comparison with those with HCC within the listing criteria. However, the two groups did not present significant differences in 1, 3 and 5 year survival rates based on an ITT analysis. Patients with HCC beyond the listing, when successfully downstaged and transplanted, presented longer 3 and 5-year OS in comparison with those who were not transplanted.

Immunotherapy and the implementation of more aggressive treatment schemes for locally advanced hepatocellular carcinomas have expanded the boundaries of curative options. Because of these advancements, patients who were once considered beyond the aim of a cure are now eligible for liver transplantation and resection.

Hepatocellular carcinoma (HCC) is the most common liver cancer. The Milan Criteria have stood the test of time and remained the benchmark for selection of candidates for liver transplant (LT). However, it has been proven that a modest expansion of the MC can achieve favorable outcomes. The term downstaging (DS) refers to the application of locoregional therapy (LRT) to tumors outside accepted transplant criteria, with the aim of reducing tumor burden and selecting appropriate candidates for LT. Important factors to consider when assessing the response to DS are: the morphological response; the biological response, usually assessed by the drop in alfa fetoprotein; the stability of disease over time after LRT. Transarterial chemoembolization represents the most used DS approach. Transarterial radioembolization has shown some benefit in downstaging patients with larger tumors and with portal vein tumor thrombosis, which no longer represents an absolute contraindication to the DS protocol. However, several other LRT have been proposed and it is difficult to determine a specific DS method that is more successful than the others. Overall, program specific practices should dictate patient eligibility for DS and individualized treatment decisions must be taken within multidisciplinary teams involving radiologists, hepatologists, surgeons, pathologists and oncologists. Keywords Hepatocellular carcinoma Downstaging Locoregional therapy Liver transplantation Liver resection Liver ablation Transarterial chemoembolization Transarterial radioembolization