Treatment Of Intermediate Hepatocellular Carcinoma Research Articles

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5years, ranging from 34 to 72. The median follow-up time was 12.3months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.

Commentary on 'Liver resection versus transarterial chemoembolisation for the treatment of intermediate hepatocellular carcinoma: a systematic review and meta-analysis'.

Commentary on 'Liver resection versus transarterial chemoembolisation for the treatment of intermediate hepatocellular carcinoma: a systematic review and meta-analysis'.

Liver resection versus transarterial chemoembolisation for the treatment of intermediate hepatocellular carcinoma: a systematic review and meta-analysis.

Transarterial chemoembolisation (TACE) is the primary treatment for intermediate-stage hepatocellular carcinoma (HCC), according to the updated Barcelona Clinic Liver Cancer (BCLC) staging system. Although growing evidence favours liver resection (LR) over TACE for intermediate-stage HCC, the best treatment option remains controversial. This meta-analysis aimed to compare the overall survival (OS) after LR versus TACE for intermediate-stage HCC. A comprehensive literature review of PubMed, Embase, Cochrane Library, and Web of Science was performed. Studies that compared the efficacy of LR and TACE in patients with intermediate (BCLC stage B) HCC were selected. According to the recent updated BCLC classification, intermediate stage of HCC was defined as follows: (a) four or more HCC nodules of any size, or (b) two or three nodules, but if at least one tumour is larger than 3cm. The main outcome was OS, expressed as the hazard ratio. Nine eligible studies of 3355 patients were included in the review. The OS of patients who underwent LR was significantly longer than that of patients who underwent TACE (hazard ratio=0.52; 95% CI: 0.39-0.69; I2=79%). Prolonged survival following LR was confirmed after sensitivity analysis of five studies using propensity score matching (HR=0.45; 95% CI: 0.34-0.59; I2=55%). Patients with intermediate-stage HCC who underwent LR had a longer OS that those who underwent TACE. The role of LR in patients with BCLC stage B should be clarified in future randomised controlled trials.

Safety and Efficacy of Transarterial Chemoembolization in Elderly Patients with Intermediate Hepatocellular Carcinoma.

Simple SummaryTransarterial chemoembolization is the treatment of choice for intermediate hepatocellular carcinoma, which constitutes the second cause of cancer-related death worldwide. Even though the world population is aging, we lack evidence regarding the safety and efficacy of anticancer treatments in these patients. This study including 271 patients shows how elderly patients treated by transarterial chemoembolization have comparable safety profiles, tumor responses, and survival outcomes to younger patients. Transarterial chemoembolization should always be considered in elderly patients with good performance status and a compensated liver function presenting intermediate hepatocellular carcinoma.(1) Introduction: Transarterial chemoembolization (TACE) is the most widely used treatment for intermediate hepatocellular carcinoma (HCC), with limited data available in elderly patients. This study compares the safety and efficacy of TACE for HCC in elderly patients (≥70 years) versus younger patients (<70 years). (2) Materials and Methods: Patients treated by a first TACE for HCC at Grenoble-Alpes University Hospital from January 2012 to March 2017 were included. The primary objective was to compare the safety and predictive factors of serious adverse events between groups using univariate and multivariate analyses. Secondary objectives included tumor response and survival analyses. (3) Results: 271 patients were included: 88 elderly and 183 under 70 years. A total of 20.5% of elderly patients experienced serious adverse events versus 21.3% of patients under 70 (p = 0.87). The predictive factors of serious adverse events were Child–Pugh ≥ B7 (p < 0.0001), ECOG ≥ 1 (p = 0.0019), and MELD ≥ 9 (p = 0.0415). The serious adverse event rate was not increased with age (p = 0.87). The objective tumor response rate was 89.5% in elderly versus 78.7% in younger patients (p = 0.03). (4) Conclusion: This study showed similar safety profiles of the first TACE between elderly and younger patients, with comparable efficacy outcomes, suggesting that advanced age should not constitute a limitation in itself in treatment decision-making.

Treatment Selection for Early to Intermediate Hepatocellular Carcinoma

Many guidelines and standard therapies have been published for the treatment of hepatocellular carcinoma (HCC). Multiple options for the treatment of early to intermediate-stage HCC have resulted in several differences between the guidelines. In addition, more than a few non-standard therapies have been used in a real-world clinical setting. Radiofrequency ablation or chemotherapy, including hepatic arterial infusion chemotherapy and molecular target agents, are sometimes selected for the treatment of intermediate HCC, whereas in many guidelines, the recommended therapy for these patients is transcatheter arterial chemoembolization. The present status of these topics is reviewed and summarized.

Evolution and current status of the subclassification of intermediate hepatocellular carcinoma.

The staging and treatment of intermediate hepatocellular carcinoma (HCC) remains controversial. According to the recommendations of Barcelona Clinic Liver Cancer staging system, patients with intermediate HCC are candidates for transcatheter arterial chemoembolization. However, not all patients with intermediate HCC benefit from transcatheter arterial chemoembolization. Therefore, it is meaningful to propose a novel staging system of intermediate HCC in order to allocate different treatments for different subgroups. Bolondi et al proposed the first subclassification system of intermediate HCC. Subsequently, investigators performed studies to validate the feasibility of Bolondi’ s criteria and proposed several novel staging systems. The present study reviewed the literatures and provided a general overview of the evolution and current status of the subclassification of intermediate HCC. We propose to expand the indication of liver resection and add radical treatments as the first option of the treatment for patients with intermediate HCC.

Epirubicin is More Effective than Miriplatin in Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

Background: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed. Purpose: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE. Methods: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses. Results: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE. Conclusion: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE.

Microwave Ablation in Intermediate Hepatocellular Carcinoma in Cirrhosis: An Italian Multicenter Prospective Study.

Background and Aims: To report long-term results in treatment of intermediate hepatocellular carcinoma (HCC) in cirrhotics using new high-powered microwaves (MWS) ablation alone.Methods: This multicenter study included 215 cirrhotics (age range: 67–84 years; 137 males; 149 Child A, 66 Child B) who underwent percutaneous ultrasound-guided high-powered MWS ablation instead of transarterial chemoembolization. Among the patient population, 109 had a single nodule (Ø 5.3–8 cm) [group A], 70 had 2 nodules (Ø 3–6 cm) [group B] and 36 had 3–5 nodules (Ø 1.5–6.8 cm) [group C]. MWS ablation efficacy was evaluated using enhanced-computed tomography and/or magnetic resonance imaging. Primary end-point was 5-year cumulative overall survival (OS).Results: On enhanced-computed tomography and/or magnetic resonance imaging, complete ablation rates were 100% for 1.5–3.5 cm nodules. In nodules >3.5–5 cm, it was 89% for the first ablation and 100% for the second. For lesions >5–8 cm, ablation was up to 92%. Overall, 1-, 3- and 5-year survival rates were 89, 60, and 21%, respectively. The cumulative OS rate of group A was 89%, 66% and 34% at 1, 3 and 5 years. The cumulative OS rate of group B was 88%, 60% and 11% at 1, 3 and 5 years. The cumulative OS rate of group C was 86%, 55% and 0%. The 5-year survival rate was significantly different among the groups (p <0.001). One patient died from rupture of HCC. Upon multivariate analysis, preablation total bilirubin >1.5 mg/dL was an independent factor for predicting lower survival.Conclusions: Percutaneous MWS ablation of intermediate HCC is safe and effective in inducing large volume of necrosis in intermediate HCC nodules, providing long-term survival rates similar to transarterial chemoembolization. Preablation total bilirubin >1.5 mg/dL as expression of liver function reserve is the main factor predicting a worse outcome.

Effect and safety of sorafenib in patients with intermediate hepatocellular carcinoma who received transarterial chemoembolization: A retrospective comparative study.

AIMTo evaluate the safety and efficacy of sorafenib plus transarterial chemoembolization (TACE) treatment for intermediate hepatocellular carcinoma (HCC).METHODSSixty-seven patients with intermediate-stage [Barcelona Clinic liver cancer stage B (BCLC-B)] HCC who were treated with sorafenib plus TACE or TACE alone between 2009 and 2011 were included in the study. Follow-up was until 2014 or patient death. Two groups were defined in the experiment: The experimental group, treated with sorafenib plus TACE, and the control group, treated with standard TACE alone.RESULTSThe Kaplan-Meier survival analysis showed that the median overall survival (mOS) of the experimental group was 35.2 mo, while that of the control group was 22.0 mo (P < 0.05). Sorafenib plus TACE showed higher incidence rates of rash, hand-foot syndrome (HFS), and hypertension (P < 0.05) than TACE treatment alone.CONCLUSIONSorafenib plus TACE treatment for BCLC-B HCC significantly prolonged the mOS of patients compared to TACE treatment alone. The most common toxicities with sorafenib were rash (31.6%), HFS (39.5%) and hypertension (31.6%), but there were no intolerable adverse events. The Cox multivariate analysis showed that the survival of patients with BCLC-B HCC depended on the Child-Pugh classification, tumor diameter, and treatment with sorafenib plus TACE compared to TACE alone.

Multipronged ethanol ablation combined with TACE for intermediate hepatocellular carcinoma

Purpose: To retrospectively investigate the efficacy of multipronged ethanol ablation with or without transarterial chemoembolization (TACE) in the treatment of intermediate hepatocellular carcinoma (HCC) (3.1-5.0 cm in diameter) at high-risk locations .Material and methods: From March 2009 to April 2014, 25 consecutive patients with intermediate HCC who underwent multipronged ethanol ablation combined with TACE were included in the combination treatment group, while 50 patients who underwent multipronged ethanol ablation alone were included in the control group.Results: Primary technique effectiveness was achieved in 70 patients (25/25, 100% in the combination treatment group; 45/50, 90% in the control group; p = .162). The local tumor progression (LTP) rates at 1, 3, 5, and 7 years were 8.0%, 24.0%, 24.0%, and 24.0% in the combination treatment group, respectively, which were significantly lower than those in the control group (24.4%, 44.1%, 66.5% and 66.5%, respectively; p = .043). However, no significant differences of overall survival and disease-free survival were found between the two groups (p = .996 and .974, respectively).Conclusion: Multipronged ethanol ablation combined with TACE could improve local tumor control for patients with intermediate HCC at high-risk locations when compared with multipronged ethanol ablation alone, although the survival outcomes were comparable.

Prognostic Factors for Survival in Patients with Hepatocellular Carcinoma Treated By Transarterial Chemoembolization Using Drug-Eluting Beads

Objective: Transarterial chemoembolization (TACE) is the most widely used therapeutic option in the treatment of intermediate hepatocellular carcinoma (HCC). Due to the heterogeneity of the intermediate stage patient population, survival rates are variable. The purpose of this retrospective study was to investigate prognostic factors in predicting overall survival in patients with HCC treated by transarterial chemoembolization using drug-eluting beads loaded with doxorubicin (DEBDOX TACE). Methods: 119 patients with intermediate stage HCC who had undergone DEBDOX TACE between February 2010 and January 2017 were studied. All procedures were performed under Cone Beam Computed Tomography (CBCT) control. Survival was calculated from the date of the first procedure. The survival rates and curves were calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test.Results: Overall, 362 procedures were performed (mean: 3.04 per patient). After a mean follow up of 24.5 ± 1.3 months, 83 patients had died and 36 survived. The average survival was 30.7 months ± 2.3 months (95% CI: 26.3-35.2 months). Median survival was 24.7 months. One-year, two-year and five-year survival rates were 84%, 47% and 3%, respectively. Independent survival prognostic factors were Child-Pugh class ,B (p=0.009), ascites (p=0.019), portal hypertension (p=0.024), bilirubin increase after procedure (p=0.002) and number of procedures (p=0.022).Conclusion: The presence of ascites, portal hypertension, Child-Pugh class B, Child-Pugh score, a higher increase in bilirubin levels after the procedure and a lower number of DEBDOX TACE procedures are significant prognostic factors in overall survival.

Transarterial chemoembolization with or without microwave ablation in the treatment of intermediate (BCLC B) hepatocellular carcinoma.

e15635 Background: Transarterial chemoembolization (TACE) is currently the first-line treatment for patients with intermediate (BCLC stage B) hepatocellular carcinoma (HCC). However, the prognosis of patients with intermediate HCC remains unsatisfactory, because TACE was limited by its lack of ability to achieve complete tumor necrosis. In this study, we retrospectively compare the outcome of TACE with or without microwave ablation (MWA) in the treatment of intermediate HCC. Methods: Included in this study were 140 patients with intermediate stage HCC who underwent initial TACE and were potentially amendable for MWA (the sum of the size of the largest tumor in centimeters and the number of tumors should be no more than nine; and a total tumor diameter ≤11 cm) between January 2005 and February 2015. 75 patients were treated with following MWA (TACE-MWA), and the remaining 65 patients were treated with TACE alone. Cumulative overall survival (OS) and progression-free survival (PFS) rates were compared. Results: The respective 1-, 3-, and 5-year OS rates were 80%, 30%, and 20% in the TACE group; and 96%, 69%, and 48% in the TACE-MWA group (Fig. 2). The OS was statistically significantly better in the TACE-MWA group compared with the TACE group (P &lt; 0.001). The respective 1-, 3-, and 5-year PFS rates were 53%, 13%, and 0% in the TACE group; and 59%, 27%, and 17% in the TACE-MWA group (Fig. 3B). PFS rates between the two groups did not differ significantly (P = 0.069). Conclusions: MWA following initial TACE prolongs OS and PFS of patients with potentially amendable intermediate HCC.

CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro.

Transarterial chemoembolization (TACE) is the standard of care for treatment of intermediate hepatocellular carcinoma (HCC), however, key molecules involved in HCC cell survival and tumor metastasis post-TACE remain unclear. CD147 is a member of the immunoglobulin superfamily that is overexpressed on the surface of HCC cells and is associated with malignant potential and poor prognosis in HCC patients. In this study, using an Earle's Balanced Salt Solution medium culture model that mimics nutrient deprivation induced by TACE, we investigated the regulation of CD147 expression on HCC cells under starvation conditions and its functional effects on HCC cell death. During early stages of starvation, the expression of CD147 was considerably upregulated in SMMC7721, HepG2 and HCC9204 hepatoma cell lines at the protein levels. Downregulation of CD147 by specific small interfering RNA (siRNA) significantly promoted starvation-induced cell death. In addition, CD147 siRNA-transfected SMMC7721 cells demonstrated significantly increased levels of both apoptosis and autophagy as compared to cells transfected with control siRNA under starvation conditions, whereas no difference was observed between the two treatment groups under normal culture conditions. Furthermore, silencing of CD147 resulted in a remarkable downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in starved SMMC7721 cells. Finally, the combined treatment of starvation and anti-CD147 monoclonal antibody exhibited a synergistic HCC cell killing effect. Our study suggests that upregulation of CD147 under starvation may reduce hepatoma cell death by modulating both apoptosis and autophagy through mTOR signaling, and that CD147 may be a novel potential molecular target to improve the efficacy of TACE.

Systematic review of guidelines for management of intermediate hepatocellular carcinoma using the Appraisal of Guidelines Research and Evaluation II instrument

BackgroundHepatocellular carcinoma is the second leading cause of cancer-related mortality worldwide. Multiple guidelines have been developed to assist clinicians in its management. We aimed to explore methodological quality of these guidelines focusing on treatment of intermediate hepatocellular carcinoma by transarterial chemoembolization. MethodsA systematic search was performed for Clinical Practice Guidelines and Consensus statements for hepatocellular carcinoma management. Guideline quality was appraised using the Appraisal of Guidelines Research and Evaluation II instrument, which rates guideline development processes across 6 domains: ‘Scope and purpose’, ‘Stakeholder involvement’, ‘Rigour of development’, ‘Clarity of presentation’, ‘Applicability’ and ‘Editorial independence’. Thematic analysis of guidelines was performed to map differences in recommendations. ResultsQuality of 21 included guidelines varied widely, but was overall poor with only one guideline passing the 50% mark on all domains. Key recommendations as (contra)indications and technical aspects were inconsistent between guidelines. Aspects on side effects and health economics were mainly neglected. ConclusionsMethodological quality of guidelines on transarterial chemoembolization in hepatocellular carcinoma management is poor. This results in important discrepancies between guideline recommendations, creating confusion in clinical practice. Incorporation of the Appraisal of Guidelines Research and Evaluation II instrument in guideline development may improve quality of future guidelines by increasing focus on methodological aspects.

Mo2028 Comparison Between Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Chemoembolization Combined With Percutaneous Radiofrequency Ablation (TACE-RFA) for Treatment of Intermediate Hepatocellular Carcinoma

Background/Aims: Hepatolithiasis is a well known risk factor of cholangiocarcinoma. Despite advances in diagnostic modalities, diagnosing cholangiocarcinoma in patients with hepatolithiasis still challenging and there are not enough reports on the incidence of cholangiocarcinoma in patient with hepatolithiasis after treatment. We aimed to evaluate the incidence and clinical characteristics of cholangiocarcinoma in patients with hepatolithiasis who underwent liver resection or non-resection. Methods: Among a total of 257 patients who received treatment for hepatolithiasis from 2002 to 2011 at Korea University Anam and Guro Hospital, 236 patients were eligible for analysis; 92 patients underwent liver resection (resection group) and 144 patients did not (non-resection group). The data were retrospectively collected and analyzed. Results: The incidence of cholangiocarcinoma was 6.8% (16/236) during follow-up period (mean 41±41 months). The median tumor occurrence time was 28 (13-111) months. Cholangiocarcinoma occurred 6.5% (6/92) and 6.9% (10/144) in resection and non-resection group respectively (P=0.425). In resection group, cholangiocarcinoma occurred in 3.6% (2/56) of patients with complete stone removal, and in 13.3% (4/ 30) of patients with incomplete stone removal (p=0.591). In non-resection group, cholangiocarcinoma occurred in 5.7% (3/53) of patients with complete stone removal, and in 8.9% (7/79) of patient with incomplete stone removal (p=0.738). When analyzed according to completeness of stone removal regardless of treatment modality, cholangiocarcinoma occurred in 4.6% (5/109) of patients with complete stone removal, and in 10.1% (11/109) of patients with incomplete stone removal (p=0.429). Although the site of stone and tumor occurrence concurred in 10/16 patients (3/6 patients in the resection group, 7/10 patient in the non-resection group), it did not match in 6 patients. On univariate analysis, none of the factors (age, gender, abdominal pain, bile duct stenosis, bile duct dilatation, liver atrophy, residual stone, stone recurrence and liver resection) showed relationship with the incidence of cholangiocarcinoma. Conclusion: There was no difference in the incidence of cholangiocarcinoma according to the treatment modality or completeness of stone removal. Therefore, patients with hepatolithiasis should carefully be followed-up to detect cholangiocarcinoma even after treatment.

Multimodal approaches to the treatment of hepatocellular carcinoma

The prevalence of hepatocellular carcinoma in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis. Surveillance programs for patients with cirrhosis aim to detect tumors at an early stage, when the greatest therapeutic benefits can be achieved. Curative treatments for early-stage tumors include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib can improve survival for patients with intermediate and advanced tumors, respectively. In clinical practice, combination therapies are often used, despite limited evidence to support this approach from randomized controlled trials. Combination therapy with radiofrequency ablation (RFA) plus percutaneous ethanol injection can, however, improve survival for selected patients compared with RFA alone. Combined treatment with TACE and RFA also improves patients' survival compared with TACE or RFA monotherapy. TACE performed before or after surgical resection, however, is not beneficial. Prevention of tumor progression in patients awaiting liver transplantation requires nonsurgical treatments; however, the real advantages of the available treatment modalities are yet to be defined. The role of sorafenib administration in combination with TACE after the use of potentially curative treatments, for the treatment of intermediate hepatocellular carcinoma, or in selective settings after liver transplantation, requires further study.