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.

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.

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.

Transarterial chemoembolization in Barcelona Clinic Liver Cancer Stage 0/A hepatocellular carcinoma

AIM: To evaluate the clinical characteristics of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 and A hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE).

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.

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.

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.

End-stage liver disease score and future liver remnant volume predict post-hepatectomy liver failure in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is the world’s sixth most common malignant tumor and the third cause of cancer death.Although great progress has been made in hepatectomy,it is still associated with a certain degree of risk of posthepatectomy liver failure(PHLF),which extends the length of hospital stay and remains the leading cause of postoperative death.Studies have shown that assessment of hepatic functional reserve before hepatectomy is beneficial for reducing the incidence of PHLF.AIM To assess the value of model for end-stage liver disease(MELD)score combined with standardized future liver remnant(sFLR)volume in predicting PHLF in patients undergoing hepatectomy for HCC.METHODS This study was attended by 238 patients with HCC who underwent hepatectomy between January 2015 and January 2018.Discrimination of sFLR volume,MELD score,and sFLR/MELD ratio to predict PHLF was evaluated according to the area under the receiver operating characteristic curve.RESULTS The patients were divided into two groups according to whether PHLF occurred after hepatectomy.The incidence of PHLF was 8.4%in our research.The incidence of PHLF increased with the decrease in sFLR volume and the increase in MELD score.Both sFLR volume and MELD score were considered independent predictive factors for PHLF.Moreover,the cut-off value of the sFLR/MELD score to predict PHLF was 0.078(P<0.001).This suggests that an sFLR/MELD≥0.078 indicates a higher incidence of PHLF than an sFLR/MELD<0.078.CONCLUSION MELD combined with sFLR is a reliable and effective PHLF predictor,which is superior to MELD score or sFLR volume alone.

Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease

AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.

The growth rate of hepatocellular carcinoma is different with different TNM stages at diagnosis

Background: Hepatocellular carcinoma(HCC) progresses fast and has a poor prognosis, but the growth rate in different TNM stages is not clear. The present study was to estimate the growth rate of HCC with different TNM stages at diagnosis. Methods: Baseline demographics and tumor characteristics were analyzed for 10145 patients in Surveillance, Epidemiology, and End Results(SEER) Program-registered HCC. Multiple linear regression models were used for age adjustment with patient race, sex, marital status, and HCC grade. Results: The age at diagnosis was younger in Caucasians and males. The adjusted average age of patients with stage I HCC was 65.26 years. The adjusted age of patients with stage II, IIIA, IIIB, and IIIC was-0.17,-0.25,-0.29, and-0.55 adjusted-year younger compared with patients with stage I HCC(all P < 0.001). The adjusted average age of patients with T1 was 65.26 years. The age adjustment was-0.17,-0.26, and-0.55 respectively(all P < 0.001) for T2, T3 or T4 tumors without distant metastases. Conclusions: These findings demonstrated that the more advanced the HCC stage at diagnosis, the younger the age at diagnosis and the faster the HCC growth from tumor occurrence.

Noninvasive imaging of hepatocellular carcinoma: From diagnosis to prognosis

Hepatocellular carcinoma(HCC) is the most common primary liver cancer and a major public health problem worldwide. Hepatocarcinogenesis is a complex multistep process at molecular, cellular, and histologic levels with key alterations that can be revealed by noninvasive imaging modalities. Therefore, imaging techniques play pivotal roles in the detection, characterization, staging, surveillance, and prognosis evaluation of HCC. Currently, ultrasound is the first-line imaging modality for screening and surveillance purposes. While based on conclusive enhancement patterns comprising arterial phase hyperenhancement and portal venous and/or delayed phase wash-out, contrast enhanced dynamic computed tomography and magnetic resonance imaging(MRI) are the diagnostic tools for HCC without requirements for histopathologic confirmation. Functional MRI techniques, including diffusion-weighted imaging, MRI with hepatobiliary contrast agents, perfusion imaging, and magnetic resonance elastography, show promise in providing further important information regarding tumor biological behaviors. In addition, evaluation of tumor imaging characteristics, including nodule size, margin, number, vascular invasion, and growth patterns, allows preoperative prediction of tumor microvascular invasion and patient prognosis. Therefore, the aim of this article is to review the current state-of-the-art and recent advances in the comprehensive noninvasive imaging evaluation of HCC. We also provide the basic key concepts of HCC development and an overview of the current practice guidelines.

Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers worldwide. Surgery, percutaneous ablation and liver transplantation are the only curative treatment modalities for HCC. However, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options for patients with advanced HCC are required. In advanced HCC, according to current international guidelines, sorafenib, a molecular targeted agent, is the standard treatment. However, alternative treatment modalities are required because of the low response rates and unsuitability of molecular agents in real practice. In various treatment modalities, mostly in Asia, hepatic arterial infusion chemotherapy(HAIC) has been applied to advanced HCC with a view to increasing the therapeutic efficacy. HAIC provides direct drug delivery into the tumor feeding vessels and also minimizes systemic toxicities through a greater first-pass effect in the liver. However, the sample sizes of studies on HAIC have been small and large randomized trials are still lacking. In this article, we describe the treatment efficacy of HAIC for advanced stage HCC and discuss future therapeutic possibilities.

The prognostic significance of clinical and pathological features in hepatocellular carcinoma

The prognosis of patients with HCC still remains dismal. The life expectancy of HCC patients is hard to predict because of the high possibility of postoperative recurrence. Many factors, such as patient's general conditions, macroscopic tumor morphology, as well as tumor histopathology features, have been proven of prognostic significance. Female HCC patient often has a better prognosis than male patient, which might be due to the receptor of sex hormones. Younger patients often have tumors with higher invasiveness and metastatic potentials, and their survival and prognosis are worse than the older ones. Co-existing hepatitis status and hepatic functional reserve have been confirmed as risk factors for recurrence. Serum alpha-fetoprotein (AFP) is useful not only for diagnosis, but also as a prognostic indicator for HCC patients. AFP mRNA has been proposed as a predictive marker of HCC cells disseminated into the circulation and for metastatic recurrence. Many pathologic features, such as tumor size, number, capsule state, cell differentiation, venous invasion, intrahepatic spreading, and advanced pTNM stage, are the best-established risk factors for recurrence and important aspects affecting the prognosis of patients with HCC. Marked inflammatory cell infiltration in the tumor could predict a better prognosis. Clinical stage is still the most important factor influencing on the prognosis. Extratumor spreading and lymph nodal metastasis are independent predictors for poor outcome. Some new predictive systems have recently been proposed. Different strategies of treatment might have significant different effects on the patients' prognosis. To date, surgical resection is still the only potentially curative treatment for HCC, including localized postoperative recurrences. Extent of resection, blood transfusion, occlusion of porta hepatis, and blood loss affect the survival and prognosis of HCC patients. Regional therapies provide alternative ways to improve the prognosis of HCC patients who have no opportunity to receive surgical treatment or postoperative recurrence. The combination of these treatment modalities is hopeful to further improve the prognosis. The efficacies of neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy or chemoembolization in preventing recurrence and on the HCC prognosis still remain great controversy, and deserve further evaluation. Biotherapy, including IFN-alpha therapy, will play more important role in preventing recurrence and metastasis of HCC after operation.

Inflammation scores predict survival for hepatitis B virus-related hepatocellular carcinoma patients after transarterial chemoembolization

AIM:To compare the prognostic ability of inflammation scores for patients with hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC)undergoing transarterial chemoembolization(TACE).METHODS:Data of 224 consecutive patients who underwent TACE for unresectable HBV-related HCC from September 2009 to November 2011 were retrieved from a prospective database.The association of inflammation scores with clinicopathologic variables and overall survival(OS)were analyzed,and receiver operating characteristic curves were generated,and the area under the curve(AUC)was calculated to evaluate the discriminatory ability of each inflammation score and staging system,including tumor-node-metastasis,Barcelona Clinic Liver Cancer,and Cancer of the Liver Italian Program(CLIP)scores.RESULTS:The median follow-up period was 390 d,the one-,two-,and three-year OS were 38.4%,18.3%,and 11.1%,respectively,and the median OS was 390d.The Glasgow Prognostic Score(GPS),modifed GPS,neutrophil-lymphocyte ratio,and Prognostic Index were associated with OS.The GPS consistently had a higher AUC value at 6 mo(0.702),12 mo(0.676),and24 mo(0.687)in comparison with other inflammation scores.CLIP consistently had a higher AUC value at6 mo(0.656),12 mo(0.711),and 24 mo(0.721)in comparison with tumor-node-metastasis and Barcelona Clinic Liver Cancer staging systems.Multivariate analysis revealed that alanine aminotransferase,GPS,and CLIP were independent prognostic factors for OS.The combination of GPS and CLIP(AUC=0.777)was superior to CLIP or GPS alone in prognostic ability for OS.CONCLUSION:The prognostic ability of GPS is superior to other inflammation scores for HCC patients undergoing TACE.Combining GPS and CLIP improved the prognostic power for OS.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

BACKGROUND： Combined hepatocellular carcinoma and cholangiocarcinoma （cHCC-CC） is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma （HCC） and cholangiocarcinoma （CC）. Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. METHODS： The dinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual （6th ed.）. Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. RESULTS： Significant differences were observed in clinico- pathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease- free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC;but significantly poorer than those with HCC. In subanalysis of patients with stage Ⅱ, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. CONCLUSION： Patients with cHCC-CC showed similar dinico- pathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage Ⅱ.

Staging systems for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient's underlying liver disease and liver functional reserve. Moreover, thereis considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.

Staging systems for predicting survival of patients with hepatocellular carcinoma after surgery

AIM: To compare the staging systems for stratifying and predicting the prognosis of patients with hepatocel-lular carcinoma (HCC) after partial hepatectomy (PH). METHODS: Clinical data about 438 HCC patients who underwent PH from January 1991 to December 2004 at our hospital were retrospectively analyzed. Tumor stage was evaluated following the Chinese tumor node me-tastasis (TNM) and barcelona clinic liver cancer (BCLC) staging systems, respectively. Survival curves for the HCC patients were plotted using the Kaplan-Meier method and differences were compared by the log-rank test. The accuracy of each system for predicting death of HCC patients was evaluated by calculating the area under the receiver operating characteristic curve. RESULTS: The HCC patients were classified into stag-es Ⅰ-Ⅲ, stages Ⅰ-Ⅳ and stages A-C, according to the 3 staging systems, respectively. Log-rank test showed that the cumulative survival rate was significantly dif-ferent for the HCC patients at 3 Chinese system stag-es, TNM stages Ⅰ and Ⅱ, TNM stages Ⅲ and Ⅳ, and 3 BCLC stages (P < 0.05). However, no significant differ-ence was found in the HCC patients at TNM stages Ⅱ and Ⅲ. The accuracy of the Chinese and BCLC staging systems was higher than that of the TNM staging sys-tem for predicting the survival rate of HCC patients. CONCLUSION: The Chinese and BCLC staging systems are better for stratifying and predicting the prognosis of HCC patients after PH than the TNM staging system.

Emerging role of ^(18)F-fluorodeoxyglucose positron emission tomography for guiding management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of major causes of cancer mortality worldwide. For decades, ^(18)F-fluorodeoxyglucose(FDG) positron emission tomography(PET) has been widely used for staging, predicting prognosis, and detecting cancer recurrence in various types of malignant diseases. Due to low sensitivity of FDG PET for detecting intrahepatic HCC lesions, the clinical value of FDG PET in HCC patients has been limited. However, recent studies with diverse analytic methods have shown that FDG PET has promising role in aiding management of HCC patients. In this review, we will discuss the clinical role of FDG PET for staging, predicting prognosis, and evaluating treatment response in HCC. Further, we will focus on recent clinical studies regarding implication of volumetric FDG PET parameters, the significance of FDG uptake in HCC for selecting treatment and predicting treatment response, and the use of radiomics of FDG PET in HCC.

Grey zone in the Barcelona Clinic Liver Cancer Classification for hepatocellular carcinoma: Surgeons' perspective

Hepatocellular carcinoma(HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. The Barcelona Clinic Liver Cancer(BCLC) classification has been endorsed as the optimal staging system and treatment algorithm for HCC by the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. However, in real life, the majority of patients who are not considered ideal candidates based on the BCLC guideline still were performed hepatic resection nowadays, which means many hepatic surgeons all around the world do not follow the BCLC guidelines. The accuracy and application of the BCLC classification has constantly been challenged by many clinicians. From the surgeons' perspectives, we herein put forward some comments on the BCLC classification concerning subjectivity of the assessment criteria, comprehensiveness of the staging definition and accuracy of the therapeutic recommendations. We hope to further discuss with peers and colleagues with the aim to make the BCLC classification more applicable to clinical practice in the future.

Validation of modified albumin-bilirubin-TNM score as a prognostic model to evaluate patients with hepatocellular carcinoma

BACKGROUND An ideal staging system for hepatocellular carcinoma(HCC)should rely on the hepatic reserve function and tumor burden.With the improvement in diagnostic and treatment strategies for HCC,in addition to recent treatment of viral hepatitis,finding a suitable assessment tool for hepatic reserve has become mandatory.AIM To validate a recently proposed modified albumin-bilirubin-TNM(mALBI-T)grade as a prognostic model for patients with HCC in Egypt.METHODS For patients diagnosed with HCC,Child-Turcotte-Pugh(CTP)score,Barcelona Clinic Liver Cancer(BCLC)stage,albumin-bilirubin(ALBI),plateltetalbumin– bilirubin(PALBI),ALBI-based BCLC,ALBI-T and mALBI-T grades were estimated.Patients were followed from time of diagnosis to date of death or date of data collection if they remained alive.Overall survival and received treatments were determined.Survival data were analyzed.RESULTS A total of 1910 patients were included(mean age,57 years;1575 males).At presentation,50.6%had CTP A,36.1%had CTP B and 13.4%had CTP C;12%had ALBI grade 1,62.3%had ALBI grade 2 and 24.7%had ALBI grade 3.Overall median survival was 13 mo;survival was better in patients with ALBI 1 than in those with ALBI 2 and 3(28.6 vs 14 and 5.8 mo,respectively,P<0.001).Patients with ALBI-T grades 0 and 1 had better survival than those with ALBI-T grades 2,3,4 and 5(P<0.001).The modified ALBI-T showed better stratification and significant improvement in prediction of survival.CONCLUSION ALBI-T grade is a superior prognostic tool that selects patients with HCC who have better liver reservoir and tumor stage.mALBI-T is a better prognostic model in patients with HCC.