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In this Expert Opinion, we thoroughly analyse the Barcelona Clinic Liver Cancer (BCLC) staging and treatment algorithm for hepatocellular carcinoma (HCC) that, since 1999, has standardised HCC management, offering a structured approach for the prognostic evaluation and treatment of patients with HCC. The first part of the article presents the strengths and evolutionary improvements of the BCLC staging system. Nevertheless, both patient characteristics and available treatments have changed in the last two decades, limiting the role of the BCLC criteria for treatment allocation in a growing number of patients. As therapeutic options expand and become more effective, the stage-linked treatment decision-making algorithm may lead to undertreatment and suboptimal outcomes for patients with disease beyond early-stage HCC. Consequently, strict adherence to BCLC criteria is limited in expert centres, particularly for patients diagnosed beyond early-stage HCC. Although the BCLC system remains the benchmark against which other therapeutic frameworks must be judged, the era of precision medicine calls for patient-tailored therapeutic decision-making (by a multidisciplinary tumour board) rather than stage-dictated treatment allocation. Acknowledging this conceptual difference in clinical management, the second part of the article describes a novel "multiparametric therapeutic hierarchy", which integrates a comprehensive assessment of clinical factors, biomarkers, technical feasibility, and resource availability. Lastly, considering the increasing efficacy of locoregional and systemic treatments, the concept of "converse therapeutic hierarchy" is introduced. These treatments can increase the feasibility (conversion approach) and effectiveness (adjuvant approach of systemic therapy) of potentially curative approaches to greatly improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background The 2022 Barcelona Clinic Liver Cancer (BCLC) algorithm does not recommend liver resection (LR) in BCLC A patients with oligo-nodular (two or three nodules ≤3   cm) hepatocellular carcinoma (HCC). This sharply contrasts with the therapeutic hierarchy concept, implying a precise treatment order exists within each BCLC stage. This study aimed to compare the outcomes of LR versus radiofrequency ablation (RFA) or trans-arterial chemoembolization (TACE) in BCLC A patients. Methods A meta-analysis adhering to PRISMA guidelines and the Cochrane Handbook was performed. All RCT, cohort and case–control studies that compared LR versus RFA or TACE in oligo-nodular BCLC A HCC published between January 2000 and October 2023 were comprehensively searched on PubMed, Embase, the Cochrane Library and China Biology Medicine databases. Primary outcomes were overall survival (OS) and disease-free survival (DFS) at 3 and 5 years. Risk ratio (RR) was computed as a measure of treatment effect (OS and DFS benefit) to calculate common and random effects estimates for meta-analyses with binary outcome data. Results 2601 patients from 14 included studies were analysed (LR = 1227, RFA = 686, TACE = 688). There was a significant 3- and 5-year OS benefit of LR over TACE (RR = 0.55, 95% c.i. 0.44 to 0.69, P < 0.001 and RR 0.57, 95% c.i. 0.36 to 0.90, P = 0.030, respectively), while there was no significant 3- and 5-year OS benefit of LR over RFA (RR = 0.78, 95% c.i. 0.37 to 1.62, P = 0.452 and RR 0.74, 95% c.i. 0.50 to 1.09, P = 0.103, respectively). However, a significant 3- and 5-year DFS benefit of LR over RFA was found (RR = 0.70, 95% c.i. 0.54 to 0.93, P = 0.020 and RR 0.82, 95% c.i. 0.72 to 0.95, P = 0.015, respectively). A single study comparing LR and TACE regarding DFS showed a significant superiority of LR. The Newcastle–Ottawa Scale quality of studies was high in eight (57%) and moderate in six (43%). Conclusions In BCLC A oligo-nodular HCC patients, LR should be preferred to RFA or TACE (therapeutic hierarchy concept). Additional comparative cohort studies are urgently needed to increase the certainty of this evidence. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non‐transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR. Methods: From the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up‐to‐seven criteria were compared between patients with HCC <4 and ≥4 cm. Results: During a median follow‐up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up‐to‐seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence‐free survival and overall survival. HCC size ≥4 cm and high alpha‐fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up‐to‐seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non‐transplantable recurrence. Conclusions: Despite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long‐term survival. Non‐transplantable recurrence is predicted by HCC size and AFP levels, among pre‐operatively available variables. High‐risk patients could be considered for frontline LT or listed for transplantation even before recurrence. [ABSTRACT FROM AUTHOR]

Worldwide, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly increases mortality and morbidity. The Coronavirus Disease 2019 (COVID-19) outbreak has had a considerable impact on healthcare systems all around the world, having a significant effect on planned patient activity and established care pathways, in order to meet the difficult task of the global pandemic. Patients with hepatocellular carcinoma (HCC) are considered a particularly susceptible population and conceivably at increased risk for severe COVID-19 because of two combined risk factors: chronic advanced liver disease and HCC itself. In these challenging times, it is mandatory to reshape clinical practice in a prompt way to preserve the highest standards of patient care and safety. However, due to the stay-at-home measures instituted to stop the spread of COVID-19, HCC surveillance has incurred a dramatic drop, and care for HCC patients has been rearranged by refining the algorithm for HCC treatment to the COVID-19 pandemic, permitting these patients to be safely managed by identifying those most at risk of neoplastic disease progression. [ABSTRACT FROM AUTHOR]

Background: Long-term survival after liver transplantation (LT) for hepatocellular cancer (HCC) continues to increase along with the modification of inclusion criteria. This study aimed at identifying risk factors for 5- and 10-year overall and HCC-specific death after LT. Methods: A total of 1,854 HCC transplant recipients from 10 European centers during the period 1987–2015 were analyzed. The population was divided in three eras, defined by landmark changes in HCC transplantability indications. Multivariable logistic regression analyses were used to evaluate the significance of independent risk factors for survival. Results: Five- and 10-year overall survival (OS) rates were 68.1% and 54.4%, respectively. Two-hundred forty-two patients (13.1%) had HCC recurrence. Five- and 10-year recurrence rates were 16.2% and 20.3%. HCC-related deaths peaked at 2 years after LT (51.1% of all HCC-related deaths) and decreased to a high 30.8% in the interval of 6 to 10 years after LT. The risk factors for 10-year OS were macrovascular invasion (OR = 2.71; P = 0.001), poor grading (OR = 1.56; P = 0.001), HCV status (OR = 1.39; P = 0.001), diameter of the target lesion (OR = 1.09; P = 0.001), AFP slope (OR = 1.63; P = 0.006), and patient age (OR = 0.99; P = 0.01). The risk factor for 10-year HCC-related death were AFP slope (OR = 4.95; P < 0.0001), microvascular (OR = 2.13; P < 0.0001) and macrovascular invasion (OR = 2.32; P = 0.01), poor tumor grading (OR = 1.95; P = 0.001), total number of neo-adjuvant therapies (OR = 1.11; P = 0.001), diameter of the target lesion (OR = 1.11; P = 0.002), and patient age (OR = 0.97; P = 0.001). When analyzing survival rates in function of LT era, a progressive improvement of the results was observed, with patients transplanted during the period 2007–2015 showing 5- and 10-year death rates of 26.8% and 38.9% (vs. 1987–1996, P < 0.0001; vs. 1997–2006, P = 0.005). Conclusions: LT generates long-term overall and disease-free survival rates superior to all other oncologic treatments of HCC. The role of LT in the modern treatment of HCC becomes even more valued when the follow-up period reaches at least 10 years. The results of LT continue to improve even when prudently widening the inclusion criteria for transplantation. Despite the incidence of HCC recurrence is highest during the first 5 years post-transplant, one-third of them occur later, indicating the importance of a life-long follow-up of these patients. [ABSTRACT FROM AUTHOR]

Background: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. Methods: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. Results: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). Conclusions: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAPIII maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10--1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is the most frequent liver tumor and is associated with chronic liver disease in 90% of cases. In selected cases, liver transplantation represents an effective therapy with excellent overall survival. Since the introduction of Milan criteria in 1996, numerous alternative selection systems to LT for HCC patients have been proposed. Debate remains about how best to select HCC patients for transplant and how to prioritize them on the waiting list. The selection of the best scoring system to propose in the context of LT for HCC is far to be identified. In this review, we analyze and categorize the various selection systems, assessing their roles in the different decisional phases. [ABSTRACT FROM AUTHOR]

Background: Dichotomous models like Milan Criteria represent the routinely used tools for predicting the outcome of patients with hepatocellular carcinoma (HCC). However, a paradigm shift from a dichotomous to continuous prognostic stratification should represent a good strategy for improving the prediction process. Recently, the tumor burden score (TBS) has been proposed for selecting patients with colorectal liver metastases. To date, TBS has not been validated in a large HCC population. The main objective of this study was to evaluate the prognostic power of TBS in an HCC population treated with different curative and palliative modalities.Methods: Prospectively collected data from consecutive HCC patients managed in 24 institutions participating in the ITA.LI.CA group between Jan 2002 and Mar 2015 were analyzed (n = 4759). A sub-analysis focused on 3909 patients with the radiological evidence of vascular invasion or metastatic disease was also performed.Results: TBS demonstrated the best discriminative ability when compared to MC and other tumor-specific scores. At multivariable Cox regression analysis, TBS was an independent risk factor of overall survival, with a 6% increased risk for patient death for each point increase in TBS. At survival analysis, when TBS ≥ 8 was connected with MELD ≥ 15 and alpha-fetoprotein ≥ 1000 ng/mL, patients presenting all these three risk factors presented the worst results (p value < 0.0001).Conclusions: Survival prediction of HCC patients was very well done using TBS model, even stratifying the population in relation to the presence of metastases and/or vascular invasion. TBS model was the best in terms of discriminatory ability and goodness of fit when compared with other continuous or binary variables. Its incorporation in a model composed by tumor- and liver function-related variables further increases its survival prediction. [ABSTRACT FROM AUTHOR]

Aims This multicentre cohort study evaluated the role of ageing on clinical characteristics, treatment allocation and outcome of new hepatocellular carcinomas ( HCCs), in clinical practice. Material & Methods From September 2008, 541 patients >70 years old (elderly group), and 527 ≤70 years old (non-elderly group) with newly diagnosed HCC were consecutively enrolled in 30 Italian centres. Differences in clinical characteristics and treatment allocation between groups were described by a multivariable logistic regression model measuring the inverse probability weight to meet the elderly group. Survival differences were measured by unadjusted and adjusted (by inverse probability weight) survival analysis. Results Elderly patients were mainly females, hepatitis C virus infected and with better conserved liver function ( P<.001). At presentation, HCC median size was similar in both groups while, in youngers, HCC was more frequently multinodular ( P=.001), and associated with neoplastic thrombosis ( P=.009). Adjusted survival analysis showed that age did not predict short-mid-term survival (within 24 months), while it was a significant independent predictor of long-term survival. Moreover, age had a significant long-term survival impact mainly on early HCC stages (Barcelona Clinic for Liver Cancer [ BCLC] 0-A), its impact on BCLC B stage was lower, while it was negligible for advanced-terminal stages. Conclusions Age per se does not impact on short-mid-term prognosis (≤24 months) of HCC patients, and should not represent a limitation to its management. [ABSTRACT FROM AUTHOR]

Background: Hemoperitoneum is a possible complication of hepatocellular carcinoma that may require emergency surgery as an alternative to radiological locoregional therapies.Case Presentation: We present a case report of a 78-year-old white man with alcoholic-related cirrhosis and a multifocal hepatocellular carcinoma. An abdominal computed tomography scan showed multiple and bilateral foci of bleeding from broken liver cancer. He was urgently transferred from our radiology unit to our operating room for massive hemoperitoneum. A middle line laparotomy detected a massive hemoperitoneum. His liver was cirrhotic and completely subverted by a tumor; there were two spontaneous bleeding lacerations on segments II and IV, which were uncontrollable with conventional hemostatic techniques. Therefore, it was decided to carry out the coagulation of the multiple vascular afferents of each single mass by means of radiofrequency ablation cycles performed circumferentially on both nodules for a total of 40 minutes. Hemostasis was achieved; the radiofrequency ablation controlled the bleeding from his ruptured hepatocellular carcinoma. He was transferred to our intensive care unit for postoperative monitoring in terms of hemodynamic stability. On postoperative day 2 he was discharged from our intensive care unit.Conclusions: Multifocal bleeding hepatocellular carcinoma still has an extremely high mortality. The angiographic control of multiple bilateral bleeding lesions can be extremely difficult and can be contraindicated by the location of the lesions and by the overall clinical condition of the patient. In this case, treatment with radiofrequency ablation has proven to be effective in the control of multiple and bilateral hepatic lesions. This particular technique allowed us to attack the lesion at the level of the vascular pedicle in order to control the bleeding. [ABSTRACT FROM AUTHOR]

Summary Hepatocellular carcinoma (HCC), in its very early stage, is heterogeneous both in terms of liver function (i.e., presence or absence of portal hypertension, model for end-stage liver disease score, Child-Pugh score 5 or 6, bilirubin level) and tumor characteristics (i.e., location, alpha-fetoprotein values, pathological features such as microvascular invasion, tumor grade and satellitosis). Existing evidence in comparing different curative options for patients with very early HCC is poor due to small sample sizes and lack of solid subgroup analyses. Large observational studies are available, with the potential to identify effective interventions in different subgroup of patients and to discover which treatments work “in a real world setting”. These studies suggest some important treatment selection strategies in very early HCC patients. According to extent of liver resection, and liver function, percutaneous ablation or liver resection are the recommended first line therapies in these patients. Laparoscopic surgery (resection or ablation) is the preferable strategy when the tumor is in the surface of the liver or close to extra-hepatic organs. Due to scarce donor resources and competition with patients at high transplant benefit (HCC patients unsuitable for non-transplant radical therapies and non-HCC patients with decompensated cirrhosis), transplantation is recommended only as second line therapy in patients with very early stage HCC in case of tumor recurrence or liver failure after ablation or liver resection. [ABSTRACT FROM AUTHOR]

Background: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC.Methods and Findings: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score ≤ 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups.Conclusions: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations. [ABSTRACT FROM AUTHOR]

Background & Aims The role of hepatic resection for hepatocellular carcinoma (HCC) in different Barcelona Clinic Liver Cancer (BCLC) stages is controversial. We aimed at measuring the survival benefit of resection vs. non-surgical-therapies in each BCLC stage. Methods Using the ITA.LI.CA database, we identified 2090 BCLC A, B, and C HCC patients observed between 2000 and 2012: 550 underwent resection, 1046 loco-regional therapy (LRT), and 494 best supportive care (BSC). A multivariate log-logistic model was chosen to predict median survival (MS) after resection vs. MS after LRT or BSC. The results were expressed as net survival benefit of resection: (MS resection – MS LRT)/MS BSC. Results After stratifying for BCLC stage, the median net survival benefit of resection over LRT was: BCLC 0 = 62% (40%, 82%), A = 45% (13%, 65%), B = 46% (9%, 76%), C = −16% (−55%, 33%). Model for end-stage liver disease (MELD) score >9, Child B class, and performance status (PST) = 2 were the main risk factors for liver resection. 1181 Child A patients (57%) with MELD ⩽9 and PST <2 had always a large positive net survival benefit of resection over LRT, independently of BCLC stage: BCLC 0 = 64% (44%, 85%), A = 59% (45%, 74%), B = 71% (52%, 90%), C = 56% (36%, 78%). Among the 909 (43%) patients with at least one risk factor (MELD >9 or PST = 2 or Child B class), resection did not prove any survival benefit over LRT. Conclusions Resection could result in survival benefit over LRT for HCC patients regardless of their BCLC stage, provided that liver dysfunction (Child B or MELD >9) and PST >1 are absent. [ABSTRACT FROM AUTHOR]

Background & Aims Significant proportion of Hepatocellular Carcinoma ( HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer ( BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization ( TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients. Methods From 3027 HCC cases recruited from 1986 to 2008 by the Italian Liver Cancer group (2430 with data allowing a correct allocation in the BCLC system), a retrospective analysis was conducted on those diagnosed in BCLC stage B (405 patients, 17%). Statistics were performed with Kaplan-Meier (log rank) method and Cox multivariate analysis. Results Median overall survival in BCLC stage B patients was 25 months (Confidence Interval - C.I. - 22-28 months) with a 5-year survival of 18%. Child-Pugh class, oesophageal varices and Alpha-foetoprotein ( AFP) were the independent predictors of survival. TACE was applied in 40% of cases and did not offer the longest survival in comparison with surgical or percutaneous treatments (median 27 months vs. 37 and 36 months, respectively) ( P < 0.001). BCLC stage B patients undergoing radical treatments were more frequently in Child-Pugh class A and had a significantly lower number of lesions; patients undergoing best supportive care were frequently in Child-Pugh class B and had a multifocal disease. Survival after TACE did not significantly increase over time. Conclusions In clinical practice, TACE cannot be considered the best approach for BCLC stage B patients who represent a heterogeneous population and are often suitable for more aggressive therapies, which lead to a better survival. [ABSTRACT FROM AUTHOR]

Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: a multicentre study. Dear Editor, We read with great interest the article recently published by Wang et al. in the I Journal of Gastrointestinal Surgery i showing that the presence of microvascular invasion may negatively affect the prognosis of patients with Barcelona Clinic Liver Cancer (BCLC) intermediate stage (stage B) hepatocellular carcinoma (HCC) undergoing surgery.[1] The results of this study provide evidence that patients with intermediate stage HCC and microvascular invasion should not receive surgery, as both the 5-year recurrence rates and overall survival of patients with these characteristics are not acceptable.[1] Furthermore, on another note, these results confirm previous findings that some patients with Intermediate stage HCC may be good candidates to surgery. 10.1111/liv.14154Aug 10 Vitale A, Trevisani F, Farinati F, Cillo U. Treatment of hepatocellular carcinoma in the precision medicine era: from treatment stage migration to therapeutic hierarchy. [Extracted from the article]

The aim of this study was to demonstrate the safety and efficacy of laparoscopic ablation for cirrhotic HCC patients. Between January 2004 and December 2009, laparoscopic ablation was applied prospectively in 169 consecutive HCC patients (median age 62 years, 43% hepatitis C positive) considered ineligible for liver resection and/or percutaneous ablation. There was clinically relevant portal hypertension in 72% of cases. A significant proportion of subjects (50%) had multinodular tumors or nodules larger than 25 mm. The main ablation techniques used were radiofrequency in 103 patients (61%), microwave ablation in 8 (5%), and ethanol injection in 58 (34%). The primary endpoint was 3-year survival. There was no perioperative mortality. The overall morbidity rate was 25%. The median postoperative hospital stay was 3 days (range 1–19 days). Patients survived a median 33 months with a 3-year survival rate of 47%. Cox's multivariate analysis identified patient age, presence of diabetes, albumin ≤37 g/l, and alpha-fetoprotein >400 µg/l as significant preoperative predictors of survival, while the chance to undergo liver transplantation and postoperative ascites were the only independent postoperative predictor of survival. Laparoscopic ablation is a safe and effective therapeutic option for selected HCC patients ineligible for liver resection and/or percutaneous ablation. [ABSTRACT FROM AUTHOR]

Summary: Background: Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. Methods: A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient''s 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. Findings: 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B–C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1·530 (95% CI 1·107–2·116) for BCLC A versus BCLC 0, 1·572 (1·350–1·830) for BCLC B–C versus BCLC A, and 1·470 (1·164–1·856) for BCLC D versus BCLC B–C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11·19 months (IQR 10·73–11·67) for BCLC 0, 13·49 months (11·51–15·57) for BCLC A, 17·36 months (15·06–19·28) for BCLC B–C, and 28·46 months (26·38–30·34) for BCLC D. Interpretation: Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B–C), regardless of the nodule number–size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. Funding: None. [Copyright &y& Elsevier]

The article presents information on a study which investigated the efficacy of combination chemotherapy with gemcitabine plus pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma (HCC). Information on the incidence of HCC in the U.S. and East Asia is given. The recruitment of patients with advanced-stage HCC were carried out between November 2003 and May 2008. Findings on clinical efficacy, toxicity and predictive factors are discussed.

Abstract: Background: There are no studies evaluating the survival benefit of liver transplantation over alternative therapies for patients with hepatocellular carcinoma. Methods: The short- to mid-term survival benefit (study group=135 aggressively treated patients with hepatocellular carcinoma, 52% beyond Milan criteria at pathology) was calculated by comparing the mortality rates of liver transplantation vs alternative therapies patients. A Markov prediction model was then created to estimate the long-term survival benefit of liver transplantation (gain in life expectancy) over alternative therapies. The long-term survival rates in the liver transplantation group were calculated using the Metroticket website calculator (http://89.96.76.14/metroticket/calculator/). Results: The short- to mid-term analysis indicated that liver transplantation afforded no significant survival benefit in the group of patients with hepatoma as a whole (hazard ratio=1.229, 95% confidence interval 0.544–2.773, p =.6200). The benefit was concentrated in patients with a poor initial response to alternative therapies (hazard ratio=3.137, 95% confidence interval 1.428–6.891, p =.0044). In the long-term analysis, the gain in life expectancy of liver transplantation vs alternative therapies was 6.115 years (base-case analysis) and the main determinants of gain in life expectancy were the 5-year survival prospects after alternative therapies and the patient''s age. Conclusions: The survival benefit of liver transplantation for patients with hepatocellular carcinoma is strongly related to the patient''s age and the effectiveness of available alternative therapies. [Copyright &y& Elsevier]

Background/Aims: The Barcelona Clinic Liver Cancer (BCLC) classification offers a prognostic stratification of patients with hepatocellular carcinoma (HCC). We recently demonstrated the BCLC''s peculiar prognostic ability in a retrospective cohort of HCC patients. The aim of this study was to evaluate the BCLC system prospectively in a subsequent separate group of HCC patients enrolled at the same surgically oriented liver unit. Methods: One hundred and ninety-five consecutive HCC patients were prospectively enrolled and their liver disease was staged before therapy. Unlike the BCLC treatment protocol, nodule size and number were not used as absolute exclusion criteria for radical treatment. Predictors of survival were identified using the Cox model. Results: The median survival time was 23 months overall, and 53, 16, 7 and 3 months, respectively, for BCLC categories A, B, C, and D. In our cohort, BCLC had the best independent predictive power for survival when compared with the Okuda, CLIP, UNOS-TNM, and JIS prognostic systems (linear trend χ 2=43.01, likelihood χ 2=57.94, AIC 885.98). Moreover, the BCLC classification showed a better prognostic ability than the AJCC-TNM 2002 system in surgical patients. Conclusions: The discriminating power of BCLC staging was prospectively assessed in an Italian cohort of HCC patients treated mainly with radical therapies. [Copyright &y& Elsevier]

Abstract: Background:: The use of orthotopic liver transplantation (OLT) for the treatment of patients with hepatocellular carcinoma (HCC) remains controversial because of the risk of both exclusion from the waiting list due to tumor progression and post OLT HCC recurrence. The aim of the present study was to evaluate the effect of an aggressive HCC treatment during the waiting list time on overall and recurrence-free survival of HCC transplanted patients in a single institutional study. Methods:: Since 1991, 40 HCC patients joined the OLT-waiting list. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. In all, 90% of the study group had HCC treatment while on the waiting list (transarterial chemoembolization, percutaneous therapies, chemotherapy). Results:: Only one patient (2.5%) was removed from the waiting list after developing neoplastic portal thrombosis 3 months after listing, while 33 (82.5%) underwent to OLT after a median waiting list time of 11 months (range 3–16 months). On histological examination, 42% of the group did not meet the “Milan criteria” and 42% were pTNM stages III and IV. The median follow-up was 42 months. The 5-year actuarial survival rate was 64% and recurrence-free survival was 91%. HCC recurred in only two patients (6%). Conclusions:: The use of routine pre-OLT tumor grading and of an aggressive HCC treatment during the waiting list, in our experience, resulted in a very low risk of pre OLT tumor progression leading to exclusion and of post OLT HCC recurrence. [Copyright &y& Elsevier]

Simple Summary: Due to the rapid increase of primary liver cancer incidence and the poor prognosis, it is imperative to identify new modifiable factors such as diet and nutrition for the prevention of liver cancer. Diet high in saturated fatty acids (SFA) has been hypothesized to be associated with increased risk of cancers. However, the associations between dietary fatty acids and liver cancer are not consistent. We aimed to examine the association between dietary total fat, its major components, serum cholesterol, and risk of liver cancer combining current evidence from prospective studies. Our meta-analyses provided new evidence on associations between dietary fats, serum cholesterol, and liver cancer risk. Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and high-density lipoprotein (HDL) were associated with a lower risk of liver cancer with high between-studies variability. Based on our findings, reducing dietary SFA may help to prevent the development of liver cancer. To quantify the associations between dietary fats and their major components, as well as serum levels of cholesterol, and liver cancer risk, we performed a systematic review and meta-analysis of prospective studies. We searched PubMed, Embase, and Web of Science up to October 2020 for prospective studies that reported the risk estimates of dietary fats and serum cholesterol for liver cancer risk. We carried out highest versus lowest intake or level and dose-response analyses. Higher intake of dietary saturated fatty acids (SFA) was associated with a higher liver cancer risk in both category analysis (relative risk [RR]highest vs. lowest intake = 1.34, 95% confidence interval [CI]: 1.06, 1.69) and dose-response analysis (RR1% energy = 1.04, 95%CI: 1.01, 1.07). Higher serum total cholesterol was inversely associated with liver cancer but with large between-studies variability (RR1 mmol/L = 0.72, 95%CI: 0.69, 0.75, I2 = 75.3%). The inverse association was more pronounced for serum high-density lipoprotein (HDL) cholesterol (RR1 mmol/L = 0.42, 95%CI: 0.27, 0.64). Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and HDL were associated with a lower risk of liver cancer with high between-studies variability. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is one of the deadliest cancer. Clinical guidelines for the management of HCC endorse algorithms deriving from clinical variables whose performances to prognosticate HCC is limited. Liquid biopsy is the molecular analysis of tumor by-products released into the bloodstream. It offers minimally-invasive access to circulating analytes like DNA, RNA, exosomes and cells. This technology demonstrated promising results for various applications in cancers, including prognostication. This review aimed to provide a comprehensive overview of the contribution of liquid biopsy in HCC prognostication. The results suggested that liquid biopsy may be a polyvalent and valuable tool to prognosticate HCC. Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses the theme of the issue on patients with hypovascular hepatocellular carcinoma and its treatment using surgical resection (SR), percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA).

Objectives There are no prospective studies of laparoscopic microwave ( MW) ablation in patients with hepatocellular carcinoma ( HCC). The aim of this study was to demonstrate the safety and efficacy of laparoscopic MW ablation. Methods A prospective study group of consecutive HCC patients considered ineligible for liver resection and/or percutaneous ablation was conducted from December 2009 to December 2010. Short-term (3-month) outcomes included a centralized revision of radiological response, mortality and morbidity. Mid-term (24-month) outcomes included time to recurrence in the study group compared with that in a cohort of consecutive patients treated with laparoscopic radiofrequency ( RF) ablation using propensity score analysis. Results A total of 42 patients were enrolled. Their median age was 64 years; 67% were positive for hepatitis C virus; 33% were of Child-Pugh class B status; the median tumour diameter was 2.5 cm, and 48% of patients had multinodular HCC. In 47 of 50 (94%) nodules treated with MW ablation, a complete radiological response was observed at 3 months. There was no perioperative mortality. The overall morbidity rate was 24%. The 2-year survival rate was 79% and the 2-year recurrence rate was 55%. Using propensity score analysis (in 28 MW ablation patients and 28 RF ablation controls), 2-year recurrence rates were 55% in the MW ablation group and 77% in the control group ( P = 0.03). Conclusions Laparoscopic MW ablation is a safe and effective therapeutic option for selected HCC patients who are ineligible for liver resection and/or percutaneous ablation. [ABSTRACT FROM AUTHOR]

Background: Alpha-fetoprotein (AFP) messenger RNA (mRNA) in the blood reflects the presence of circulating hepatocellular carcinoma (HCC) cells and is a sensitive marker of HCC extrahepatic metastases. The specificity of this molecular marker and its correlation with the main HCC clinical–pathological parameters remains controversial, however. Methods: AFPmRNA was determined in 50 HCC patients and in 50 patients with diagnosis of cirrhosis (6), or colon (24) or, pancreatic (20) carcinoma. HCC patients with clinically evident extrahepatic metastasis were excluded. HCC diagnosis was confirmed in all patients by histology on percutaneous biopsies or surgical specimens; pathological grading was assessed at the same time. Results: AFPmRNA was positive in 20 HCC patients (40%) and in 18 patients without HCC (36%). The presence of AFPmRNA in the blood correlated significantly with cholestatic indices (p<0.01), nodule size (p=0.03), vascular invasion (p=0.006) and moderately or poorly differentiated HCC (p<0.0001). Moreover, survival analysis showed a significant impact of AFPmRNA detection on overall (p=0.04) and recurrence-free survival (p=0.0007) after a median follow-up of 17 months. Conclusions: Although AFPmRNA is frequently detected in the blood, even in benign liver diseases or gastroenteric tumors, in HCC patients without clinical evidence of extrahepatic metastases it seemed to identify the biologically more aggressive tumors. [Copyright &y& Elsevier]

Background/Aims: Prognosis assessment in patients with hepatocellular carcinoma (HCC) remains controversial. The most widely used HCC prognostic tool is the Okuda classification, but new staging systems (Cancer of the Liver Italian Program score, Chinese University Prognostic Index, French classification and Barcelona Clinic Liver Cancer, BCLC, staging) have been recently described. We investigated the value of known prognostic systems in the particular setting of a surgically oriented Liver Unit where 187 HCC Italian patients were mainly treated with radical therapies (resection and percutaneous ablation).Methods: A retrospective analysis of 187 HCCs observed at a single Institution from 1990 and 1999 was performed. By using survival time as the only outcome measure (Kaplan–Meier method and Cox regression), the performance of any prognostic system was assessed according the criteria of discriminatory and stratification abilities between different stages, homogeneity of survival within each stage and additional explanatory power respect to the other classifications.Results: In the particular cohort studied, BCLC proved the best HCC prognostic system. This was true for the whole study group and for the 2 subgroups of surgical and non-surgical patients.Conclusions: BCLC staging showed the best interpretation of the survival distribution in an HCC population comprising a large proportion of tumors treated with potentially radical therapies. [Copyright &y& Elsevier]

Background & Aims The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. Methods 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. Results 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs . >2 in the whole population (13.2 ± 1.8% vs . 49.8 ± 8.7%, p <0.001, HR = 4.98), in patients within Milan criteria (12.8 ± 2.0% vs . 32.4 ± 12.1%, p = 0.009, HR = 3.51), beyond Milan criteria (14.9 ± 4.2% vs . 58.9 ± 11.5%, p <0.001, HR = 4.26), HCV patients (14.9 ± 2.5% vs . 67.6 ± 14.7%, p <0.001, HR = 6.56) and HBV patients (11.6 ± 3.4% vs . 34.3 ± 12.5%, p = 0.012, HR = 3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7 ± 2.2% vs . 42.2 ± 8.3% ( p <0.001, HR = 2.14). Conclusions The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. Lay summary Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis. [ABSTRACT FROM AUTHOR]