Impact of guideline adherence on the prognosis of Barcelona clinic liver cancer stage B hepatocellular carcinoma

BACKGROUND Patients with Barcelona clinic liver cancer(BCLC)stage B hepatocellular carcinoma(HCC)are considerably heterogeneous in terms of tumor burden,liver function,and performance status.To improve the poor survival outcomes of these patients,treatment approaches other than transarterial chemoembolization(TACE),which is recommended by HCC guidelines,have been adopted in realworld clinical practice.We hypothesize that this non-adherence to treatment guidelines,particularly with respect to the use of liver resection,improves survival in patients with stage B HCC.AIM To assess guideline adherence in South Korean patients with stage B HCC and study its impact on survival.METHODS A retrospective analysis was conducted using data from 2008 to 2016 obtained from the Korea Central Cancer Registry.Patients with stage B HCC were categorized into three treatment groups,guideline-adherent,upward,and downward,based on HCC guidelines recommended by the Asian Pacific Association for the Study of the Liver(APASL),the European Association for the Study of the Liver(EASL),and the American Association for the Study of Liver Diseases(AASLD).The primary outcome was HCC-related deaths;tumor recurrence served as the secondary outcome.Survival among the groups was compared using the Kaplan-Meier method and the log-rank test.Predictors of survival outcomes were identified using multivariable Cox regression analysis.RESULTS In South Korea, over the study period from 2008 to 2016, a notable trend was observed in adherence to HCCguidelines. Adherence to the EASL guidelines started relatively high, ranging from 77% to 80% between 2008 and2012, but it gradually declined to 58.8% to 71.6% from 2013 to 2016. Adherence to the AASLD guidelines began at71.7% to 75.9% from 2008 to 2010, and then it fluctuated between 49.2% and 73.8% from 2011 to 2016. In contrast,adherence to the APASL guidelines remained consistently high, staying within the range of 90.14% to 94.5%throughout the entire study period. Upward treatment, for example with liver resection, liver transplantation, orradiofrequency ablation, significantly improved the survival of patients with BCLC stage B HCC compared to thatof patients treated in adherence to the guidelines (for patients analyzed according to the 2000 EASL guidelines, the5-year survival rates were 63.4% vs 27.2%, P < 0.001), although results varied depending on the guidelines.Progression-free survival rates were also significantly improved upon the use of upward treatments in certaingroups. Patients receiving upward treatments were typically < 70 years old, had platelet counts > 105/μL, andserum albumin levels ≥ 3.5 g/dL.CONCLUSIONAdherence to guidelines significantly influences survival in South Korean stage B HCC patients. Curativetreatments outperform TACE, but liver resection should be selected with caution due to disease heterogeneity.

Real impact of tumor marker AFP and PIVKA-II in detecting very small hepatocellular carcinoma(≤2 cm,Barcelona stage 0)-assessment with large number of cases

BACKGROUND In hepatocellular carcinoma(HCC),detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites.AIM To examine the impact of the tumor marker alpha-fetoprotein(AFP)or PIVKA-II in detecting very small HCC nodules(≤2 cm in maximum diameter,Barcelona stage 0)in the large number of very small HCC.The difference in the behavior of these tumor markers in HCC development was also examined.METHODS A total of 933 patients with single-nodule HCC were examined.They were subdivided into 394 patients with HCC nodules≤2 cm in maximum diameter and 539 patients whose nodules were>2 cm.The rates of patients whose AFP and PIVKA-II showed normal values were examined.RESULTS The positive ratio of the marker PIVKA-II was significantly different(P<0.0001)between patients with nodules≤2 cm in diameter and those with nodules>2 cm,but there was no significant difference in AFP(P=0.4254).In the patients whose tumor was≤2 cm,50.5%showed normal levels in AFP and 68.8%showed normal levels in PIVKA-II.In 36.4%of those patients,both AFP and PIVKA-II showed normal levels.The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size.In contrast,the positivity in AFP was increased gradually and slowly.CONCLUSION In the surveillance of very small HCC nodules(≤2 cm in diameter,Barcelona clinical stage 0)the tumor markers AFP and PIVKA-II are not so useful.

Usefulness of staging systems and prognostic scores for hepatocellular carcinoma treatments

Therapeutic management of hepatocellular carcinoma(HCC) is quite complex owing to the underlying cirrhosis and portal vein hypertension. Different scores or classification systems based on liver function and tumoral stages have been published in the recent years. If none of them is currently "universally" recognized, the Barcelona Clinic Liver Cancer(BCLC) staging system has become the reference classification system in Western countries. Based on a robust treatment algorithm associated with stage stratification, it relies on a high level of evidence. However, BCLC stage B and C HCC include a broad spectrum of tumors but are only matched with a single therapeutic option. Some experts have thus suggested to extend the indications for surgery or for transarterial chemoembolization. In clinical practice, many patients are already treated beyond the scope of recommendations. Additional alternative prognostic scores that could be applied to any therapeutic modality have been recently proposed. They could represent complementary tools to the BCLC staging system and improve the stratification of HCC patients enrolled in clinical trials, as illustrated by the NIACE score. Prospective studies are needed to compare these scores and refine their role in the decision making process.

Reverse time-dependent effect of alphafetoprotein and disease control on survival of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma

AIM To characterize the survival of cirrhotic patients with Barcelona Clinic Liver Cancer(BCLC) stage C hepatocellular carcinoma(HCC) and to ascertain the factors predicting the achievement of disease control(DC).METHODS The cirrhotic patients with BCLC stage C HCC evaluated by the Hepatocatt multidisciplinary group were subjected to the investigation. Demographic, clinical and tumor features, along with the best tumor response and overall survival were recorded. RESULTS One hundred and ten BCLC stage C patients were included in the analysis; the median overall survival was 13.4 mo(95%CI: 10.6-17.0). Only alphafetoprotein(AFP) serum level > 200 ng/m L and DC could independently predict survival but in a time dependent manner, the former was significantly associated with increased risk of mortality within the first 6 mo of follow-up(HR = 5.073, 95%CI: 2.159-11.916, P = 0.0002), whereas the latter showed a protective effect against death after one year(HR = 0.110, 95%CI: 0.038-0.314, P < 0.0001). Only patients showing microvascular invasion and/or extrahepatic spread recorded lower chances of achieving DC(OR = 0.263, 95%CI: 0.111-0.622, P = 0.002).CONCLUSION The BCLC stage C HCC includes a wide heterogeneous group of cirrhotic patients suitable for potentially curative treatments. The reverse and time dependent effect of AFP serum level and DC on patients' survival confers them as useful predictive tools for treatment management and clinical decisions.

Clinical stages of recurrent hepatocellular carcinoma: A retrospective cohort study

BACKGROUND Hepatocellular carcinoma(HCC)is the second leading cause of cancer-related death worldwide,and has relatively high recurrence rates.Few studies have been published on the clinical stages of recurrent HCC.AIM To assess the applicability of the Barcelona Clinic Liver Cancer(BCLC)staging for recurrent HCC and the need to establish clinical stage criteria for recurrent HCC.METHODS The clinicopathological data of 81 patients with recurrent HCC who were admitted to the Hospital of Guangxi Zhuang Autonomous Region from January 2013 to December 2017 were collected.The patients were divided into three groups according to the BCLC staging system as follows:(1)Group A with BCLC stage A,51 patients;(2)Group B with BCLC stage B,14 patients;and(3)Group C with BCLC stage C,16 patients.The median time to tumor recurrence and the median overall survival were compared.RESULTS The median time to tumor recurrence in groups A,B,and C was 16±1.5 mo,10±2.8 mo,and 6±0.5 mo,respectively,with a statistically significant difference among them(χ^(2)=70.144,P<0.05);no statistically significant difference was noted between group A and group B(χ^(2)=2.659,P>0.05),although there were statistically significant differences between group A and group C and between group B and group C(χ^(2)=62.110,and 19.972,P<0.05).The median overall survival in groups A,B,and C were 42±5.1 mo,22±3.1 mo,and 13±1.8 mo,respectively,with a statistically significant difference among them(χ2=38.949,P<0.05);there were statistically significant differences between group A and group B,group A and group C,and group B and group C(χ2=9.577,37.172,and 7.183,respectively;P<0.05).CONCLUSION There are different prognoses in recurrent HCC patients according to the BCLC staging.Therefore,BCLC staging is applicable to recurrent HCC and it is essential to formulate clinical stage criteria for recurrent HCC.

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.

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.

A nomogram predicting the recurrence of hepatocellular carcinoma in patients after laparoscopic hepatectomy

Background:Patients with hepatocellular carcinoma(HCC)undergoing surgical resection still have a high 5-year recurrence rate(~60%).With the development of laparoscopic hepatectomy(LH),few studies have compared the efficacy between LH and traditional surgical approach on HCC.The objective of this study was to establish a nomo-gram to evaluate the risk of recurrence in HCC patients who underwent LH.Methods:The clinical data of 432 patients,pathologically diagnosed with HCC,underwent LH as initial treatment and had surgical margin>1 cm were collected.The significance of their clinicopathological features to recurrence-free survival(RFS)was assessed,based on which a nomogram was constructed using a training cohort(n=324)and was internally validated using a temporal validation cohort(n=108).Results:Hepatitis B surface antigen(hazard ratio[HR],1.838;P=0.044),tumor number(HR,1.774;P=0.003),tumor thrombus(HR,2.356;P=0.003),cancer cell differentiation(HR,0.745;P=0.080),and microvascular tumor invasion(HR,1.673;P=0.007)were found to be independent risk factors for RFS in the training cohort,and were used for con-structing the nomogram.The C-index for RFS prediction in the training cohort using the nomogram was 0.786,which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification(C-index,0.698)and the Barcelona Clinic Liver Cancer staging system(C-index,0.632).A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve.An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis,which was also confirmed in the validation cohort compared to other systems.Conclusions:We constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients,which can be clinically implemented in assisting the planification of individual postoperative surveil-lance protocols.

Living donor liver transplantation can be a rescue treatment for hepatocellular carcinoma

For intermediate-stage hepatocellular carcinoma(HCC)in the Barcelona Clinic Liver Cancer(BCLC),transarterial chemoembolization(TACE)is advised as the initial treatment.The term“BCLC intermediate-stage HCC”(BCLC stage B)refers to a group of patients with varying liver functions and single big nodules or many nodules that do not have distant metastases or vascular invasion(1).In general,tumors beyond the Milan criteria(single tumor>5 cm or≥4 nodules)are classified as BCLC intermediate-stage HCC.Consequently,not every patient with intermediate-stage HCC in BCLC is a good candidate for TACE alone;this is especially true for patients who have a substantial tumor bulk,multinodular dissemination,or decreased liver function.TACE refractory cases cannot get full TACE treatment.