Specific indicators of unsuitability for transarterial chemoembolisation in patients with intermediate-stage hepatocellular carcinoma according to thresholds of tumour burden and liver function as judged by survival benefit over sorafenib.

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When… and Y(90)?

Chemoembolization and Radioembolization for Hepatocellular Carcinoma

Treatment for Hepatocellular Carcinoma in South Asia

Quality Improvement Guidelines for Transhepatic Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic Malignancy

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607–1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466–0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

Focus

Optimal timing of combining sorafenib with trans-arterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis

This study explored liver- and tumour-specific indicators predictive of suboptimal survival outcomes following repeat transarterial chemoembolisation (TACE) in intermediate-stage hepatocellular carcinoma (HCC) patients after an initial TACE. This study included 300 HCC patients who underwent TACE treatment. Based on whether persistent albumin-bilirubin (ALBI) grade deterioration (PABD) occurred after the initial TACE, defining as a shift in ALBI grade to a higher grade from baseline without recovery within 90 days, patients were divided into PABD and non-PABD groups. Overall survival of non-PABD and PABD groups according to subgroups stratified by baseline ALBI grade and tumour burden was compared with that of patients receiving only sorafenib or supportive care during the same period. Repeat TACE provided a survival benefit over systemic therapy or supportive care for patients in all post-TACE non-PABD or most PABD subgroups, regardless of baseline liver condition (ie, modified albumin-bilirubin [mALBI] grade and tumour burden). This benefit was absent in two subgroups among patients who developed PABD after the initial TACE, namely, (1) those with a baseline liver condition of mALBI grade 1 or 2a and tumour burden exceeding the up-to-11 criteria, and (2) those with a baseline liver condition of mALBI grade 2b, regardless of tumour burden. Repeat TACE is not recommended for patients with persistent liver function deterioration after the initial TACE, particularly those exhibiting suboptimal baseline liver function or excessive tumour burden. Understanding the liver condition and tumour burden in HCC patients may assist clinicians in planning optimal treatment strategies, leading to better prognosis.

New Developments in the Treatment of Hepatocellular Carcinoma: The Concept of Adjuvant and Neoadjuvant Chemotherapy

BackgroundHeterogeneity of liver function and tumor burden in intermediate-stage hepatocellular carcinoma (HCC) results in different outcomes after transarterial chemoembolization (TACE). Easy albumin-bilirubin (EZ-ALBI), a simplified albumin-bilirubin (ALBI) score, has recently been proposed as a new prognostic score for HCC. This study aimed to validate the EZ-ALBI score and evaluate the impact of dynamic changes in patients with intermediate-stage HCC undergoing TACE.MethodsAll patients with HCC treated with TACE at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between January 2015 and December 2019 were prospectively enrolled. Intermediate-stage HCC was defined as Barcelona Clinic Liver Cancer (BCLC) stage B or unresectable single HCC with size > 5 cm in BCLC stage A. EZ-ALBI and ALBI scores were calculated and stratified into three different grades. Overall survival (OS) and prognostic factors were assessed using the Kaplan–Meier curve and Cox proportional hazard model. Decision analysis curves were used to evaluate the clinical utility of the predictive scores.ResultsAmong 672 patients with HCC treated with TACE, 166 patients with intermediate-stage HCC who met the eligibility criteria were enrolled. The median OS of all patients in the cohort was 21 months. A good correlation between the EZ-ALBI and ALBI scores was observed (correlation coefficient 1.000, p < 0.001). The baseline EZ-ALBI grades 1, 2, and 3 were 24.5%, 70%, and 5.5%, respectively. EZ-ALBI grade can stratify patients with significantly different prognoses (p = 0.002). Baseline EZ-ALBI grade 2, 3, and serum alpha-fetoprotein > 20 ng/ml were significantly associated with OS [hazard ratio (HR) 2.20 (95% confidence interval [CI] 1.24–3.88, p = 0.007), 3.26 (95% CI 1.24–8.57, p = 0.016), and 1.77 (95% CI 1.10–2.84, p = 0.018), respectively]. Following TACE, 42 (29.6%) patients had a worsening EZ-ALBI grade. However, the EZ-ALBI grade migration was not significantly correlated with OS. EZ-ALBI and ALBI score provided improved discriminatory ability (Harrell’s concordance index 0.599 and 0.602, respectively) and better net benefit compared with Child-Turcotte-Pugh and Model for End-stage Liver Disease scores.ConclusionsThe baseline EZ-ALBI score demonstrated good predictive performance for survival and a strong correlation with conventional ALBI scores. Both the EZ-ALBI and ALBI scores outperformed other prognostic models in patients with intermediate-stage HCC receiving TACE. However, the dynamic change in the EZ-ALBI grade after TACE was not associated with postprocedural survival.

Simple SummaryWe investigated the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) until unacceptable adverse events or progressive disease, followed by transcatheter arterial chemoembolization (TACE) on demand. The overall survival (OS) in patients for whom LEN was re-administered after TACE (TACE-LEN) was significantly longer in comparison to patients who received other therapies, such as only TACE, other drugs after TACE, or other drugs without TACE. TACE-LEN was the most associated with OS in the Cox proportional hazard analysis. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis.The present study clarified the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) followed by transcatheter arterial chemoembolization (TACE) on demand. We retrospectively evaluated 88 intermediate-stage HCC patients who received LEN. The median age was 74 (range: 47–92) years old, 67 patients were male, and 82 were classified as Child-Pugh A. LEN was administered until disease progression or discontinuation due to adverse events (AEs). The mean duration of LEN treatment was 7.0 months. The response and disease control rates were 51.1% and 89.8%, respectively. The median progression-free survival and overall survival (OS) after the initiation of LEN were 6.8 months and 29.9 months, respectively. The OS in patients for whom LEN was re-administered after TACE (TACE-LEN) was better than that in patients who received other therapies (e.g., only TACE, TACE-other therapy, or only other therapy) even with propensity score matching (p = 0.008). A Cox proportional hazard analysis showed that TACE-LEN was most strongly associated with the OS (hazard ratio: 0.083, 95% confidence interval: 0.019–0.362, p = 0.001). LEN was administered for approximately 11.1 months after TACE. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis.

The survival benefit of treatment for unresectable hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE) combined with sorafenib remains uncertain. We compared the survival of patients treated with TACE and sorafenib with that of patients treated with TACE alone. This was a post hoc analysis of the Study in Asia of the Combination of TACE with Sorafenib in Patients with HCC (START) trial. All patients who received TACE and interrupted dosing of sorafenib for early or intermediate-stage HCC in Taiwan from 2009 to 2010 were recruited into the TACE and sorafenib group. They were randomly matched 1:1 by age, sex, Child-Pugh score, tumor size, tumor number, and tumor stage with patients from Taichung Veterans General Hospital in Taiwan who received TACE alone and who fulfilled the selection criteria of the START trial during the same time period (control group). Patient survival [cumulative incidence and hazard ratio (HR)] of the 2 groups were analyzed and compared. The baseline characteristics of the 36 patients in each group were similar. Tumor response rates were significantly better in the TACE and sorafenib group (P < .04). Overall survival of the TACE and sorafenib group was also significantly better than that of the control (TACE alone) group over the 2 years [78%, 95% confidence interval (95% CI) 64-91 vs 49, 95% CI 32-66; P = .012]. In the multivariate regression analysis, TACE and sorafenib was found to be independently associated with a decreased risk of mortality (HR 0.33, 95% CI 0.12-0.89; P = .015). Multivariate stratified analyses verified this association in each patient subgroup (all HR < 1.0). With a high patient tolerance to an interrupted sorafenib dosing schedule, the combination of TACE with sorafenib was associated with improved overall survival in early-intermediate stage HCC when compared with treatment with TACE alone.

Watch a video presentation of this article Watch the interview with the author Hepatocellular carcinoma (HCC) is the most common primary liver malignancy1 and is one of the leading causes of cancer-related death in the United States.2 Prognosis of HCC remains poor, driven by advanced tumor burden at diagnosis in two-thirds of cases. Cancer staging systems are important for prognostication and determination of therapy. HCC has unique characteristics for which it is more difficult to use standard cancer staging strategies. First, there is enormous heterogeneity with regard to patient characteristics and HCC biology. Second, in the Western world, the majority of HCC occurs in patients with significant underlying liver disease, making liver function and functional status important in determining outcome. Lastly, tissue diagnosis is not often required, and radiological diagnosis is often the standard. Various staging systems (Table 1) have been proposed to incorporate these variables, but there is no universal worldwide consensus.3 Two of these staging systems [Barcelona Clinic Liver Cancer (BCLC) and Groupe d'ETUDE et de Traitement du Carcinome Hepatocellulaire (GRETCH)] include performance status, with the BCLC being validated in various geographical settings and with very large data sets.4 As a result, the BCLC staging system is the most accepted system in the United States, having received the endorsement of both the American Association for the Study of Liver Diseases and the European Association for the Study of Liver diseases (Figure 1).5 Its main advantage is the unique way in which it provides therapy guidelines based on staging, making it a very useful clinical tool.6 BCLC staging system. Adapted from Hepatology.5 Copyright 2011. American Association for the Study of Liver Diseases. Although it remains one of the best HCC staging systems, BCLC does have some shortcomings, particularly in regard to intermediate stage (stage B) HCC. In BCLC, transarterial chemoembolization (TACE) is recommended for stage B patients, whereas curative interventions such as surgical resection are recommended only for very early and early disease stage disease (stage 0 or A). Sorafenib and supportive care are recommended for advanced (stage C) and terminal stage (stage D) disease, respectively.5 In practice, these guidelines are not often followed for many reasons.7 One reason is that stage B comprises a highly heterogeneous population with respect to tumor burden, liver function, and cause of underlying liver disease; this latter component is not accounted for in BCLC. Consequently, the prognosis and suitability for treatment are quite variable within this stage. Examples of different stage B patients are listed in Table 2, where all are classified as stage B HCC, but the question remains: Would they benefit from TACE? The cause of the liver disease is also not included in BCLC, yet the presence of comorbid conditions such as diabetes or cardiovascular disease in patients with nonalcoholic steatohepatitis-related HCC will influence treatment options. Thus, recommendations as prescribed by BCLC in this population may not be feasible. In addition to disease etiology, there are also questions whether the classification of performance status within BCLC is optimized.8 Although performance status is clearly an important component of prognosis in HCC, it is not clear that excluding patients with performance status worse than 0 is ideal for patients with stage B HCC.8 In addition to intrinsic difficulties in staging patients, the recommended intervention is also somewhat controversial. For example, surgical intervention is recommended for only early-stage disease, but there is now emerging evidence demonstrating surgical resection may have better long-term outcomes in patients with stage B as compared with TACE,9 prompting the question whether resection should be restricted to stage 0/A disease and not expanded to stage B disease. For patients with more advanced disease, it is also not clear that TACE is not beneficial. Recommendations of TACE for stage B disease were born from analyses of studies showing negative predictors of survival, such as vascular invasion, performance status >0, and BCLC stage C disease. Much of the data were based on conventional TACE, whereas recent advances have made drug-eluting beads TACE and Y90 more commonly available and generally better tolerated. There is continued evidence of individual interdisciplinary decisions resulting in treatment stage migration in the nonsurgical population. Although only approximately 10% to 12% of new HCC diagnoses fall into stage B disease, TACE is easily the most commonly used treatment modality, with almost half the treatments worldwide being used in stage C patients.10 This may be explained by both DEB-TACE and Y90-TACE demonstrating better efficacy as compared with conventional TACE,11 which may expand the reaches of this treatment modality to patients with stage C HCC. As a result of a highly heterogeneous patient population in stage B HCC, patient selection has become crucial to the success of TACE. Within stage B, patients with higher tumor burden and less preserved liver function have poorer responses to TACE.7 In our own study, we found that the best predictor of outcome after TACE was not BCLC but Child-Turcotte-Pugh (CTP) score and tumor burden. Similar findings have been noted by other groups. In an attempt to improve risk stratification and avoid TACE-related harm, multiple groups have been working on creating subclassifications within stage B and scoring systems to better guide therapeutic decision making. This includes Bolondi et al.'s work in developing subclasses with stage B,12 as well as the HAP (Hepatoma Arterial-embolisation Prognostic) and STATE (Selection for TrAnsarterial chemoembolisation TrEatment) scores, which help identify the best patients for initial TACE procedure while limiting procedural harm and lower morbidity and mortality.10 It should be recognized that response to TACE is also an important factor that will not be captured with any pretreatment staging systems. In addition to routine clinical variables to determine risk stratifications, there is growing interest in biomarkers or alternative patient characterization tools that may predict outcome in HCC. Although functional status is clearly an important patient variable, we and others did not find that Eastern Cooperative Oncology Group (ECOG) score was predictive of outcome after TACE.7 This may be reflective of the intrinsic qualitative nature of the scoring system. In an attempt to better characterize the patient population, we have used a novel methodology (analytic morphomics) to assess patient characteristics by using quantitative image analysis of the readily available computed tomography imaging studies.13, 14 Analytic morphomics is an image-processing technique that assesses body composition measures such as body dimensions, visceral fat, and muscle mass, and links them to clinical outcomes.13 This provides a more objective manner of assessing functional status. Our results demonstrated that in comparison with the BCLC staging system, a model that included analytic morphomics provided a highly accurate prognosis in the nonsurgical population. Because all patients with HCC generally have cross-sectional imaging, this method has the potential to provide added information from existing scans that may improve prognostication. Even though BCLC is the most widely accepted HCC staging system in the Western hemisphere and provides very important guidelines for treatment, there are shortcomings. With regard to recommendations for TACE in intermediate-stage HCC, there are concerns around a restrictive prescription of therapy to a highly heterogeneous patient population. Thus, it is important to recognize that BCLC should not be used as a conscripted algorithm. Decisions in practice are likely to be affected by local preferences and availability of resources such as transplantation. It should be noted that HCC therapy is best done with multidisciplinary model input from experts in hepatology, hepatobiliary surgery, and interventional radiology to reduce variability and enhance patient selection. Further research in this area will likely yield better predictors of survival and improve patient selection.

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