Adjuvant therapy for hepatocellular carcinoma:Dilemmas at the start of a new era

Approximately 50%-70%of patients with hepatocellular carcinoma experience recurrence within five years after curative hepatic resection or ablation.As a result,many patients receive adjuvant therapy after curative resection or ablation in order to prolong recurrence-free survival.The therapy recommended by national guidelines can differ,and guidelines do not specify when to initiate adjuvant therapy or how long to continue it.These and other unanswered questions around adjuvant therapies make it difficult to optimize them and determine which may be more appropriate for a given type of patient.These questions need to be addressed by clinicians and researchers.

Efficacy of hepatic resection vs transarterial chemoembolization for solitary huge hepatocellular carcinoma

AIM: To compare the efficacy of hepatic resection(HR) and transarterial chemoembolization(TACE) for patients with solitary huge(≥ 10 cm) hepatocellular carcinoma(HCC).METHODS: Records were retrospectively analyzed of 247 patients with solitary huge HCC, comprising 180 treated by HR and 67 by TACE. Long-term overall survival(OS) was compared between the two groups using the Kaplan-Meier method, and independent predictors of survival were identified by multivariate analysis. These analyses were performed using all patients in both groups and/or 61 pairs of propensity score-matched patients from the two groups. RESULTS: OS at 5 years was significantly higher in the HR group than the TACE group, across all patients(P = 0.002) and across propensity score-matchedpairs(36.4% vs 18.2%, P = 0.039). The two groups showed similar postoperative mortality and morbidity. Multivariate analysis identified alpha-fetoprotein ≥ 400 ng/m L, presence of vascular invasion and TACE treatment as independent predictors of poor OS.CONCLUSION: Our findings suggest that HR can be safe and more effective than TACE for patients with solitary huge HCC.

Is laparoscopic hepatectomy superior to open hepatectomy for hepatocellular carcinoma?

The low perioperative morbidity and shorter hospital stay associated with laparoscopic hepatectomy have made it an often-used option at many liver centers, despite the fact that many patients with hepatocellular carcinoma have cirrhosis, which makes the procedure more difficult and dangerous. Type of surgical procedure proves not to be a primary risk factor for poor outcomes after hepatic resection for hepatocellular carcinoma, the available evidence clearly shows that laparoscopic hepatectomy is an effective alternative to the open procedure for patients with early-stage hepatocellular carcinoma, even in the presence of cirrhosis. Whether the same is true for patients with intermediate or advanced disease is less clear, since laparoscopic major hepatectomy remains a technically demanding procedure.

Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection

Significant advances have been made in nucleos(t)ideanalogue(NA) therapy to treat chronic hepatitis B,and this therapy reduces the risk of hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC) in somepatients.However,whether NAs can also prevent recurrence after radical resection of HBV-related HCC remains controversial and is an important question,giventhat most patients will experience recurrence within afew years of curative surgery.Here we systematicallyreviewed the literature since 2004 on outcomes afteradministering NAs to patients with HBV-related HCCfollowing radical resection.We focused on treatmentindications,duration,effects on recurrence-free survivaland overall survival,and the management of NA resistance.We find that patients with HCC should stronglyconsider NA therapy if they are positive for HBV-DNA,and that the available evidence suggests that postoperative NA therapy can increase both recurrence-free andoverall survival.To minimize drug resistance,cliniciansshould opt for potent analogues with higher resistancebarriers,and they should monitor the patient carefully for emergence of NA-resistant HBV.

Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after surgery: A comment for moving forward

Recurrence rate of hepatocellular carcinoma remains quite high even after surgery,and no postoperative therapies have been definitively shown to prevent hepatocellular carcinoma recurrence.A previous study showed that therapy with nucleos(t)ide analogues given to such patients after surgery significantly improved survival.However,many questions still exist about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery.

Adjuvant sorafenib in hepatocellular carcinoma: A cautionary comment of STORM trial

Recurrence rate of hepatocellular carcinoma(HCC) is very high even after curative surgery, and no postoperative therapies have been definitively shown to prevent HCC recurrence. Sorafenib is proved to be effective for advanced HCC by two large randomized controlled trials in 2008 and 2009. Therefore it stands to reason to expect that adjuvant sorafenib may improve post-surgery outcomes of patients with HCC. However, many questions still exist about the value of sorafenib for patients with HCC after surgery or transarterial chemoembolization. In this editorial, we complehensively reviewed the safety and efficacy of adjuvant sorafenib for patients with hepatocellar carcinoma after surgery or transarterial chemoembolization. We emphasized the positive and negative role of sorafenib.

Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment:Several Unanswered Questions

Most patients with hepatocellular carcinoma(HCC)have a poor prognosis.Hepatectomy and local ablation are the main curative treatments for HCC.Nevertheless,the recurrence rate after hepatectomy or ablation is up to 70%,which seriously affects patient prognosis.Several adjuvant therapies have been explored to reduce postoperative recurrence.However,although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival,a standard consensus of national HCC guidelines for adjuvant treatment is lacking.Therefore,there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines.A variety of adjuvant treatment methods,such as antiviral therapy,transarterial chemoembolization or traditional Chinese medicine,are recommended by the Chinese HCC guidelines.However,Western guidelines make few recommendations other than antiviral therapy.Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines.This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.

Systematic treatment in unresectable hepatocellular carcinoma:The most concerns

The most frequent causes of hepatocellular carcinoma(HCC)are chronic infection with hepatitis B or C virus,alcoholic liver disease,and fatty liver disease[1].The molecular pathological heterogeneity of HCC is obvious,which may be the main reason for the great difference in efficacy of different patients after receiving systematic therapy.

New Evidence and Perspectives on the Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus

Portal vein tumor thrombosis (PVTT) is an intractable condition but common phenomenon in hepatocellular carcinoma (HCC).HCC patients with PVTT may have worse liver function,a higher chance of comorbidity related to portal hypertension,lower tolerance to treatment and poorer prognoses.In Western guidelines,patients are offered palliative treatment with sorafenib or other systemic agents because HCC with PVTT is grouped together with metastatic HCC during the planning of its management.In recent years,various treatment options have become available for patients with HCC and PVTT.Therapy has also shifted toward evidencebased treatment.However,policies for the management of HCC with PVTT have not been established.This comprehensive literature review aims to present current and available management options for patients with HCC and PVTT.Evidence is mainly based on studies published after 2010.

Treatments of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus:Current Status and Controversy

The proportions of patients with hepatocellular carcinoma(HCC)involving portal vein tumor thrombus(PVTT)varies greatly in different countries or regions,ranging from 13%to 45%.The treatment regimens for PVTT recommended by HCC guidelines in different countries or regions also vary greatly.In recent years,with the progress and development of surgical concepts,radiotherapy techniques,systematic therapies(for example,VEGF inhibitors,tyrosine kinase inhibitors and immune checkpoint inhibitors),patients with HCC involving PVTT have more treatment options and their prognoses have been significantly improved.To achieve the maximum benefit,both clinicians and patients need to think rationally about the indications of treatment modalities,the occurrence of severe adverse events,and the optimal fit for the population.In this review,we provide an update on the treatment modalities available for patients with HCC involving PVTT.Trials with large sample size for patients with advanced or unresectable HCC are also reviewed.

Predictors and long-term prognosis of early and late recurrence for patients undergoing hepatic resection of hepatocellular carcinoma: a large-scale multicenter study

Recurrence is common among patients undergoing hepatic resection for hepatocellular carcinoma(HCC),which greatly limits long-term survival.We aimed to identify predictors and long-term prognosis of early and late recurrence after HCC resection.Methods:Multicenter data of patients who underwent HCC resection between 2002 and 2016 were analyzed.Recurrence was divided into early(≤2 years)and late recurrence(>2 years after surgery).Predictors of early and late recurrence,and prognostic factors of post-recurrence survival(PRS)were identified by univariate and multivariate analyses.Results:Among 1,426 patients,554(38.8%)and 348(24.4%)developed early and late recurrence,respectively.Independent predictors associated with early recurrence included preoperative alpha-fetoprotein level>400μg/L,resection margin<1 cm,and tumor size>5.0 cm,multiplicity,macrovascular and microvascular invasion,and satellites of the initial tumor at the first diagnosis of HCC;independent predictors associated with late recurrence included male,cirrhosis,and tumor size>5.0 cm,multiplicity,macrovascular and microvascular invasion,and satellites of the initial tumor.Patients with early recurrence had a lower likelihood of undergoing potentially curative treatments for recurrence(37.2%vs.48.0%,P<0.001)and a worse median PRS(13.5 vs.36.6 months,P<0.001)vs.patients who had late recurrence.Multivariate analysis revealed that early recurrence and irregular postoperative surveillance were independently associated with worse PRS[hazard ratio(HR)=1.250,95%CI:1.016-1.538,P=0.035;and HR=1.983,95%CI:1.677-2.345,P<0.001].Conclusions:Predictors associated with early and late recurrence after curative resection for patients with HCC were generally same,although several did differ.Patients with late recurrence had better long-term survival than patients with early recurrence.

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease:Current Progresses and Challenges

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease(NAFLD),leading to an increase in cases of NAFLD-related hepatocellular carcinoma(HCC).To provide an updated literature review detailing epidemiology,risk factors,pathogenic pathways,and treatment strategies linked to NAFLD-related HCC,we conducted a literature search on PubMed from its inception to December 31,2021.About 25%of the global population suffers from NAFLD.The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years.Older age,male sex,metabolic comorbidities,unhealthy lifestyle habits(such as smoking and alcohol consumption),physical inactivity,genetic susceptibility,liver fibrosis,and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC.Therefore,low-calorie diet,moderate-intensity exercise,treatment of metabolic comorbidities,and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC.In addition,all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC.Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC.Hepatic resection,liver transplantation,ablation,transarterial chemoembolization,radiotherapy,targeted drugs,and immune checkpoint inhibitors are used to treat NAFLD-related HCC.Lenvatinib treatment may lead to better overall survival,while immune checkpoint inhibitors may lead to worse overall survival.Given the specific risk factors for NAFLD-related HCC,primary prevention is key.Moreover,the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

Analysis of Clinicopathological Characteristics and Prognosis of Young Patients with Hepatocellular Carcinomaafter Hepatectomy

Background and Aims:This study was designed to analyze the effects of age and clinicopathological characteristics on prognosis of Chinese patients with hepatocellular carcinoma(HCC).Methods:The clinical data of 2032 HCC patients who were first diagnosed with HCC and underwent curative hepatectomy in our hospital between January 2006 and January 2011 were retrospectively analyzed.Results:Younger HCC patients(age<40 years,n=465)had a significantly higher hepatitis B infection rate,larger tumors,higher alpha-fetoprotein levels,higher preoperative liver function,and more frequent vascular invasions than older patients.Most younger patients were suitable for anatomical hepatectomy,and their tumors were found to be at a highly advanced stage.The recurrence-free survival and overall survival rates of younger HCC patients were significantly worse than those of older patients but this difference disappeared after propensity score matching.Multivariate analysis of pre-matched samples showed that age≤40 years was one of the independent risk factors associated with poor overall survival.Conclusions:Younger patients showed different clinicopathological characteristics than older patients,such as higher rates of hepatitis B infection and advanced tumors.The recurrence-free survival and overall survival rates of younger HCC patients after hepatectomy may be similar to those of older patients.

The upward trend in the immunotherapy utilization for hepatobiliary cancers

Hepatobiliary cancers(HBCs)include those of the liver[mainly hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma]and biliary tract(extrahepatic cholangiocarcinoma and gallbladder cancer).Based on the 2020 global cancer statistics,liver cancer ranks seventh in incidence and third in mortality among all malignant tumors,while gallbladder cancer ranks 25th in incidence and 21st in mortality(1).Due to the lack of typical symptoms and signs at the early stages,HBCs are often diagnosed at intermediate or advanced stages,and thus the opportunity of curative surgical interventions is missed(2).Therefore,most patients with HBC can only be treated with noncurative treatments,including immunotherapy.Several immunotherapeutic approaches have been attempted for HBCs,including oncolytic viruses,tumor vaccines,adoptive immunotherapy,and immune checkpoint inhibitors(ICIs;Figure 1).

Controversies of hepatectomy and adjuvant therapy for hepatocellular carcinoma: moving forward

Due to the prevelence of hepatitis B virus(HBV)and hepatitis C virus(HCV),occurrence of hepatocellular carcinoma(HCC)is increasing in many countries/regions,including China[1].

Potential Role and Clinical Value of PPP2CA in Hepatocellular Carcinoma

Background and Aims:Protein phosphatase 2A(PP2A)is associated with many cancers.This study aimed to clarify whether PPP2CA,which encodes the alpha isoform of the catalytic subunit of PP2A,plays a role in hepatocellular carcinoma(HCC)and to identify the potential underlying molecular pathways.Methods:Based on bioinformatics,public databases and our in-house RNA-Seq database,we analyzed the clinical value and molecular mechanism of PPP2CA in HCC.Results:Data were analyzed from 2,545 patients with HCC and 1,993 controls without HCC indexed in The Cancer Genome Atlas database,the Gene Expression Omnibus database and our in-house RNA-Seq database.PPP2CA expression was significantly higher in HCC tissue than in non-cancerous tissues(standardized mean difference:0.69,95%confidence interval[CI]:0.50–0.89).PPP2CA expression was able to differentiate HCC from non-HCC,with an area under the summary receiver operator characteristic curve of 0.79(95%CI:0.75–0.83).Immunohistochemistry of tissue sections confirmed that PPP2CA protein was up-regulated in HCC tissues.High PPP2CA expression in HCC patients was associated with shorter overall,progression-free and disease-free survival.Potential molecular pathways through which PPP2CA may be involved in HCC were determined using miRWalk 2.0 as well as analysis of Gene Ontology categories,Kyoto Encyclopedia of Genes and Genomes pathways,and protein-protein interaction networks.Conclusions:PPP2CA is up-regulated in HCC and higher expression correlates with worse prognosis.PPP2CA shows potential as a diagnostic marker for HCC.Future studies should examine whether PPP2CA contributes to HCC through the candidate microRNAs,pathways and hub genes identified in this study.