Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Rethinking the Barcelona clinic liver cancer guidelines:Intermediate stage and Child-Pugh B patients are suitable for surgery?

According to Barcelona Clinic Liver Cancer recommendations,intermediate stage hepatocellular carcinomas(stage B)are excluded from liver resection and are referred to palliative treatment.Moreover,Child-Pugh B patients are not usually candidates for liver resection.However,many hepatobiliary centers in the world manage patients with intermediate stage hepatocellular carcinoma or Child-Pugh B cirrhosis with liver resection,maintaining that hepatic resection is not contraindicated in selected patients with non–early-stage hepatocellular carcinoma and without normal liver function.Several studies demonstrate that resection provides the best survival benefit for selected patients in very early/early and even in intermediate stages of Barcelona Clinic Liver Cancer classification,and this treatment gives good results in the setting of multinodular,large tumors in patients with portal hypertension and/or Child-Pugh B cirrhosis.In this review we explore this controversial topic,and we show through the literature analysis how liver resection may improve the short-and long-term survival rate of carefully selected Barcelona Clinic Liver Cancer B and Child-Pugh B hepatocellular carcinoma patients.However,other large clinical studies are needed to clarify which patients with intermediate stage hepatocellular carcinoma are most likely to benefit from liver resection.

Idarubicin vs doxorubicin in transarterial chemoembolization of intermediate stage hepatocellular carcinoma

BACKGROUND Liver cancer is the fifth most common cancer and the second cause of cancerrelated deaths worldwide.Transarterial chemoembolization(TACE)is the best treatment of intermediate hepatocellular carcinoma(HCC).Doxorubicin is the most commonly used drug despite a low level of evidence.AIM To compare the objective response rate of idarubicin-based TACE(Ida-TACE)against doxorubicin-based TACE(Dox-TACE)in intermediate stage HCC.METHODS Between January 2012 and December 2014,all patients treated with TACE at our academic hospital were screened.Inclusion criteria were patients with Child-Pugh score A or B,a performance status below or equal to 1,and no prior TACE.Either lipiodol TACE or drug-eluting beads TACE could be performed with 10 mg of idarubicin or 50 mg of doxorubicin.Each patient treated with idarubicin was matched with two doxorubicin-treated patients.The TACE response was assessed by independent radiologists according to the mRECIST criteria.RESULTS Sixty patients were treated with doxorubicin and thirty with idarubicin.There were 93%and 87%of cirrhotic patients and 87%and 70%of Child-Pugh A in the doxorubicin and idarubicin groups,respectively.The median number of HCC per patient was two in both groups with 31%and 26%of single nodules in doxorubicin and idarubicin groups,respectively.Objective response rate after first TACE was 76.7%and 73.3%(P=0.797)with 41.7%and 40.0%complete response in doxorubicin and idarubicin groups,respectively.Progression-free survival was 7.7 mo in both groups,and liver transplant-free survival was 24.9 mo and 21.9 mo in doxorubicin and idarubicin groups,respectively.Safety profiles were similar in both groups,with grade 3-4 adverse events in 35%of Dox-TACE and 43%of Ida-TACEs.CONCLUSION Ida-TACE and Dox-TACE showed comparable results in terms of efficacy and safety.Ida-TACE may represent an interesting alternative to Dox-TACE in the management of patients with intermediate stage HCC.

Living donor liver transplantation for Barcelona clinic liver cancer (BCLC) intermediate-stage hepatocellular carcinoma

Background:Barcelona clinic liver cancer(BCLC)stage B(intermediate stage)hepatocellular carcinoma(HCC)is highly heterogeneous;thus,identifying the most effective treatment for individual patients represents a significant clinical challenge.However,transarterial chemoembolization(TACE)is the only recommended treatment option.Therefore,we aimed to investigate the patient characteristics and outcomes of living donor liver transplantation(LDLT)for BCLC stage B HCC.Methods:A total of 516 patients with BCLC stage B HCC who underwent LDLT(n=104)or did not undergo LDLT(non-LDLT;n=412)between 2004 to 2018 were analyzed by propensity score matching(PSM;1:4)analysis.Factors influencing overall survival(OS)and recurrence were analyzed using Cox’s proportional hazards models.Results:Patients treated with LDLT achieved better OS than the non-LDLT group,including liver-and non-liver related survival(all P<0.001).Multivariate Cox regression analysis showed age>60 years(P=0.006),a neutrophil-lymphocyte ratio(NLR)>4(P=0.016)and>3 locoregional therapies(LRT)before LDLT(P<0.001)were independent risk factors for HCC recurrence.In addition,age>60 years(P<0.001)and>3 LRT before LDLT(P=0.001)were independent risk factors for OS.Using a combination of age,NLR,and LRT before liver transplantation(LT),the patients can be divided into low-risk(none of risk),intermediate-risk(one of risk),and high risk(more than two of risk)groups.There were significant differences in the cumulative HCC recurrence(P<0.001)and mortality(P<0.001)rates among the three groups.Conclusions:LDLT may represent a valuable therapeutic option for selected patients with BCLC stage B HCC.

Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation:Where do we stand?

Liver transplantation (LT) for hepatocellular carcinoma (HCC) within Milan criteria is a widely accepted optimal therapy. Neo-adjuvant therapy before transplantation has been used as a bridging therapy to prevent dropout during the waiting period and as a down-staging method for the patient with intermediate HCC to qualify for liver transplantation. Transarterial chemoembolization and radiofrequency ablation are the most commonly used method for locoregional therapy. The data associated with newer modalities including drug-eluting beads, radioembolization with Y90, stereotactic radiation therapy and sorafenib will be discussed as a tool for converting advanced HCC to LT candidates. The concept &#x0201c;ablate and wait&#x0201d; has gained the popularity where mandated observation period after neo-adjuvant therapy allows for tumor biology to become apparent, thus has been recommended after down-staging. The role of neo-adjuvant therapy with conjunction of &#x0201c;ablate and wait&#x0201d; in living donor liver transplantation for intermediate stage HCC is also discussed in the paper.

Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy

The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall survival.Recently,the efficacy of multiple MTAs,including lenvatinib,in practice has been reported,and therapeutic strategies for Barcelona Clinic Liver Cancer(BCLC)intermediate stage HCC are undergoing major changes.Based on these results,lenvatinib could be recommended for patients with transcatheter arterial chemoembolization(TACE)-refractory,ALBI grade 1,within the up-to-seven criteria in the BCLC intermediate stage.Lenvatinib provides a more favorable outcome than TACE,even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A.When patients meet the definitions of TACE-refractory or TACE-unsuitable,switching to systemic chemotherapy,including lenvatinib,is for favorable for preserving liver function.If initial treatment,including MTA,has a significant therapeutic effect and downstaging of HCC is obtained,additional TACE or surgical resection should be considered.Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug.Furthermore,a significant therapeutic effect is expected in tumors with more than 50%liver involvement or main portal vein invasion,which have traditionally been considered to have a poor prognosis in patients.This suggests that at the start of lenvatinib treatment,HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.