Intermediate Hepatocellular Carcinoma Research Articles

Mathematical modeling of cancer cells and vasculature dynamics with serological and imaging biomarkers suggests synergistic effects of TACE and TKIs in HCC patients

Background and Aims: Transarterial-chemoembolization (TACE) and tyrosine-kinase inhibitors (TKI) represent first-line treatments in intermediate and advanced hepatocellular carcinoma (HCC). Deepening TKI and TACE response mechanisms may provide insights to optimize their combination. We developed a physic-mathematical model to analyze cancer cells and tumor vasculature dynamics in HCC patients (pts) using serum biomarkers combined with tumor digital imaging before and after TACE or TKI treatment.

Transarterial radioembolization of hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Since the first version of the S3guideline for the diagnosis and treatment of hepatocellular carcinoma (HCC) in 2013, alarge number of studies have consolidated the data on transarterial radioembolization (TARE) and created abroad evidence base. As aresult, TARE was incorporated into the current 2021 S3guideline with anumber of specific recommendations, whereas it was previously only offered under study conditions. TARE is now offered with the other minimally invasive procedures for bridging and downstaging before liver transplantation, but also as an alternative to transarterial chemotherapy (TACE) in intermediate HCC and in locally limited intrahepatic cholangiocarcinoma in second-line therapy for selected patients-albeit with different levels of evidence. Based on the study situation, however, TARE is not recommended for advanced HCC; here, systemic therapy with immunotherapeutic agents is preferred based on current data.

Doxorubicin-Loaded UiO-66/Bi2S3 Nanocomposite-Enhanced Synergistic Transarterial Chemoembolization and Photothermal Therapy against Hepatocellular Carcinoma

Transcatheter arterial chemoembolization (TACE) is the first choice for patients with intermediate hepatocellular carcinoma (HCC), but clinical applications still face some problems, such as the difficulties in clearing all cancer cells and lack of targeting, which would damage normal liver cells. Recently, photothermal therapy (PTT) and nanodelivery systems have been used to improve the efficacy of TACE. However, most of these strategies achieve only a single function, and the synthesis process is complicated. Here, a simple one-step solvothermal method was used to develop multifunctional nanoparticles (UiO-66/Bi2S3@DOX), which can simultaneously achieve photothermal effects and low pH-triggered DOX release. UiO-66/Bi2S3 exhibited a pH-responsive release behavior and an excellent photothermal effect in a series of in vitro and in vivo studies. Biocompatibility was confirmed by cytotoxicity and hemocompatibility evaluations. The rat N1S1 liver tumor model was established to investigate the therapeutic effect and biosafety of the nanoplatforms using TACE. The results revealed that the combination of TACE and PTT resulted in remarkable tumor growth inhibition, and the histopathological assay further revealed extensive necrosis, downregulated angiogenesis, increased apoptosis, and proliferation in the tumor response. These results demonstrated that this nanosystem platform was a promising therapeutic agent for enhancing TACE therapy for HCC treatment.

Efficacy and safety of anlotinib combined with TACE among patients with intermediate and advanced-stage hepatocellular carcinoma (HCC).

454 Background: Given that the onset of hepatocellular carcinoma (HCC) remained insidious, HCC was usually diagnosed of intermediate and advaned stage and surgical resection was not available. Currently, TACE was considered as the standard of care for patients with intermediate and advaned stage HCC, which yielded a complete tumor necrosis rate of 10%̃20% and a median overall survival of 16-20 months. Interestingly, studies had demonstrated that TACE could result in up-regulation of VEGF expression and tumor angiogenesis, thus contributing to tumor recurrence or distant metastasis to some extent. As a novel oral multi-target antiangiogenic TKI, anlotinib could inhibit both tumor angiogenesis and tumor cell proliferation simultaneously. Therefore, anlotinib combined with TACE might play a synergistic action for patients with HCC. Consequently,this retrospective study aimed to investigate the efficacy and safety of anlotinib combined with TACE for patients with intermediate and advaned stage HCC. Methods: This single-center retrospective study involved 75 HCC patients with intermediate and advaned stage BCLC staging B or C and ECOG PS ≤ 2. Enrolled pts was treated with TACE plus anlotinib (12 mg, qd, 2 weeks on 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS), while the secondary outcomes included safety, objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) and safety. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: By the cutoff date of August, 2021, the median PFS of the 75 pts was 8.0 months (95%CI, 6.3-9.7). The median OS was not yet reached and the 6-month OS rate was 97.3%. In best overall response assessment, there were 13.3% CR (10/75), 45.3% PR (34/75), 34.7% SD (26/75) and 6.7% PD (5/75). Confirmed ORR and DCR was 58.7% (95% CI: 46.7%-69.9%) and 93.3% (95% CI: 85.1%-97.8%) respectively according to mRECIST. Only 5.3% (4/75) of pts had grade 3 treatment-related adverse events (TRAEs). No grade ≥ 4 TRAEs were observed. And the most common TRAEs were hypertension (20%), hand-foot skin reaction (8%), anorexia (6.7%) and diarrhea (6.6%). Conclusions: It was indicated that anlotinib combined with TACE for patients with intermediate and advaned stage HCC demonstrated promising anti-tumor efficacy and a favorable safety profile. The conclusion should be validated in prospective clinical trials subsequently.

ABC-HCC: A phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma.

TPS498 Background: Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. In the intermediate stage the current standard of care is locoregional treatment with transarterial chemoembolization (TACE). The IMbrave150 phase 3 study has demonstrated that the combination of atezolizumab, an anti-PD-L1 antibody, and bevacizumab, an anti-VEGF antibody (atezo/bev), extends survival in comparison to sorafenib in the first-line setting in advanced HCC[1] which has led to its approval for patients with unresectable HCC. However, it is unknown whether atezo/bev is more efficacious than TACE for the treatment of intermediate HCC. ABC-HCC (NCT04803994) is a phase 3b, randomized, multicenter, open-label, investigator-initiated trial of atezo/bev versus TACE in intermediate stage HCC with high tumor burden exceeding the Milan criteria. Methods: The ABC-HCC study is recruiting patients ≥18 years of age who have a confirmed diagnosis of HCC in the intermediate stage (multifocal, exceeding the Milan criteria, no extrahepatic spread, no macrovascular invasion) and no curative treatment option. In addition, patients must have an ECOG performance status of 0, preserved liver function (Child-Pugh A), and ≥2 untreated lesions with a diameter > 10 mm and arterial hyperenhancement on cross-sectional imaging. Those who have previously received locoregional or systemic treatment are excluded. 434 patients will be randomly assigned 1:1 to systemic treatment (atezo at 1200 mg IV plus bev at 15 mg/kg IV) once every three weeks or to TACE. Both conventional and DEB-TACE are allowed. Region, AFP level (< 200 ng/mL vs. ≥200 ng/mL), and ALBI (1 vs. 2) will be used for stratification. Cross-sectional imaging (CT/MRI) will be performed every 8 weeks to determine the time to failure of treatment strategy, a novel primary endpoint. Failure of strategy is reached in case of progressive disease and any of the following: loss of clinical benefit, unacceptable toxicity, liver function deterioration, and therapy not further applicable for other reasons. Secondary endpoints are overall survival (OS), OS rate at 24 months, objective response rate, time to progression, time to loss of systemic treatment options, progression-free survival, duration of treatment, duration of response, time to deterioration of liver function, safety, and quality of life (EORTC QLQ-C30 and HCC18). Patients will be followed for survival, quality of life and subsequent anti-cancer therapy every 12 weeks after the end of study treatment. Recruitment for this study began in July 2021. FF, RK, JB and PRG contributed equally.

LEAP-012 trial in progress: Transarterial chemoembolization (TACE) with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma (HCC)

TPS494 Background: Limited treatment options are available for patients with intermediate HCC. Lenvatinib, a potent multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, are approved first- and second-line therapies for advanced HCC, respectively. The LEAP-012 study (NCT04246177) is investigating lenvatinib plus pembrolizumab in combination with TACE versus placebo plus TACE in patients with intermediate-stage HCC. Methods: LEAP-012 is a randomized, double-blind, phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥1 measurable lesion per RECIST v1.1, Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to receive lenvatinib 8 mg (body weight < 60 kg) or 12 mg (body weight ≥60 kg) orally once daily plus pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) plus TACE or placebo orally once daily plus placebo IV Q6W plus TACE. Response will be assessed by imaging every 9 weeks; safety will be assessed throughout the study and up to 90 days after the end of treatment. Dual primary end points are overall survival and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified RECIST by BICR; ORR, DCR, DOR, and TTP per RECIST v1.1 by BICR; and safety. Exploratory end points are PFS, ORR, DCR, DOR, TTP, and time from randomization to second/subsequent disease progression after initiation of new anticancer therapy or death from any cause, whichever occurs first, per RECIST v1.1 by investigator review, identification of molecular biomarkers, and health-related quality of life. Recruitment began in April 2020, and the planned sample size is 950 patients. The results of the LEAP-012 study will show the clinical benefit of adding lenvatinib plus pembrolizumab to the current standard of care TACE for patients with intermediate-stage HCC not amenable to curative treatment. Clinical trial information: NCT04246177.

Sintilimab plus lenvatinib as conversion therapy in patients with unresectable locally intermediate to advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase 2 study.

449 Background: Most patients (pts) with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combining a PD-1 inhibitor with tyrosine kinase inhibitors (TKIs)has achieved a high response rate for advanced HCC in first- and second-line settings. This study aimed to explore the efficacy and safety of conversion therapy with sintilimab (PD-1 inhibitor) plus Lenvatinib (TKI) in pts with unresectable locally intermediate advanced HCC. Methods: This was a phase 2, single-arm study (NCT04042805). Eligible pts were adults who were newly diagnosed with HCC, not amenable to curative resection, no extrahepatic metastasis, with an ECOG PS 0-1 and Child-Pugh class A/B. Pts received 12mg or 8mg oral Lenvatinib daily plus 200mg intravenous sintilimab every 3 weeks until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was tumor objective response rate (ORR) RECIST version 1.1. Secondary endpoints included conversion resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between August 1, 2019, and September 1, 2021, 26 pts were enrolled with a median age of 60 years (range, 30-78). The study population was predominantly male (92%), and 92% were HBV-positive. Patients were classified as BCLC stage B (46%) and stage C (54%). Twenty-six pts were evaluable for response, with an ORR of 35% (95%CI, 0.15-0.54) and a DCR of 92% (95%CI, 0.81-0.99). Seven (27%) pts received hepatectomy, and 1 (4%) patient received radical ablation and stereotactic radiotherapy. With a median follow-up of 9 months (range, 2-24), the median PFS and OS were not reached. All pts were evaluable for toxicity, and 20 (77%) pts had at least one treatment-related AE (TRAE). TRAEs occurring in ≥20% of pts were hypothyroidism (38%), proteinuria (31%), and hypertension (23%). Five pts had grade 3 TRAEs. Conclusions: In view of the encouraging response rate observed and the acceptable safety profile, the lenvatinib plus sintilimab regimen may achieve a favorable conversion rate and be a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. Clinical trial information: NCT04042805.

Efficacy of Radiofrequency Ablation Following Transarterial Chemoembolization Combined with Sorafenib for Intermediate Stage Recurrent Hepatocellular Carcinoma

Efficacy of Radiofrequency Ablation Following Transarterial Chemoembolization Combined with Sorafenib for Intermediate Stage Recurrent Hepatocellular Carcinoma

Nomograms including the controlling nutritional status score in patients with hepatocellular carcinoma undergoing transarterial chemoembolisation for prediction survival: a retrospective analysis.

This retrospective study investigated the predictive value of the Controlling Nutritional Status (CONUT) score in patients with intermediate-stage hepatocellular carcinoma (HCC) who received transarterial chemoembolization (TACE). Nomograms were developed to predict progression-free and overall survival (PFS, OS). The medical data of 228 patients with HCC and treated with TACE were collected. The patients were apportioned to 2 groups according to CONUT score: low or high (<4, ≥4). Univariate and multivariate analyses were performed using Cox regression for OS and PFS. OS and PFS were estimated by the Kaplan-Meier curve and compared with the log-rank test. Nomograms were constructed to predict patient OS and PFS. The nomograms were evaluated for accuracy, discrimination, and efficiency. The cut-off value of CONUT score was 4. The higher the CONUT score, the worse the survival; Kaplan-Meier curves showed significant differences in OS and PFS between the low and high CONUT score groups (P = 0·033, 0·047). The nomograms including CONUT, based on the prognostic factors determined by the univariate and multivariate analyses, to predict survival in HCC after TACE were generated. The CONUT score is an important prognostic factor for both OS and PFS for patients with intermediate HCC who underwent TACE. The cut-off value of the CONUT score was 4. A high CONUT score suggests poor survival outcomes. Nomograms generated based on the CONUT score were good models to predict patient OS and PFS.

Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC-B stage patients classified as beyond up to seven criteria - Multicenter analysis.

Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76years, males 73, Child-Pugh 5:6=68:27, TNM stage II:III=17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0months (median observation period: 6.0months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.

Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress

ABSTRACT Introduction Unfortunately, some hepatocellular carcinoma (HCC) patients do not qualify for curative-intent treatments such as surgical resection or transplantation. Hence, locoregional treatments such as transarterial chemoembolization (TACE) remain instrumental in the treatment of HCC. Systemic therapy has improved over the past decade with the introduction of combination atezolizumab and bevacizumab as the new standard of care for advanced disease. These new therapies are currently under investigation in combination with TACE. Area covered Combination therapies with TACE including systemic therapies, locoregional therapies, and immunotherapies are reviewed. Expert opinion There has been limited progress in the management of advanced and intermediate HCC. Recent advances in the management of advanced disease with systemic therapy could be beneficial in combination with TACE for the treatment of intermediate stage disease. Immune based therapies are potentially beneficial in combination with TACE because TACE may produce increased antigen release and immune recognition.

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review.

BACKGROUNDDespite the use of current standard therapy, the prognosis of patients with unresectable hepatocellular carcinoma (HCC) is poor, with median survival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer [BCLC] stage B) and 6–8 mo for advanced HCC (BCLC stage C). Although patients with early-stage HCC are usually suitable for therapies with curative intention, up to 70% of patients experience relapse within 5 years. In the past decade, the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC, the most common type of liver cancer among adults. Nevertheless, no treatment is useful in the adjuvant setting. Since 2007, the multi-kinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC. However, in 2020, the IMbrave150 trial demonstrated that combination therapy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment.AIMTo conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies, which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease. METHODSA comprehensive literature review was conducted using the PubMed, Scopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis.RESULTSIn the atezolizumab/bevacizumab group, an improvement in overall tumor response, reduction of disease progression, and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab. Hypertension and proteinuria were the most common adverse events, and the rates of adverse events were comparable to those with the monotherapy. Of the studies, there were two completed trials and two ongoing trials analyzed using high quality and low bias. A more thorough analysis was only performed on the completed trials.CONCLUSIONTreatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.

Visualization and Evaluation of Chemoembolization on a 3D Decellularized Organ Scaffold.

Transarterial chemoembolization (TACE) has emerged as the mainstay treatment for patients suffering from unresectable intermediate hepatocellular carcinoma and also holds the potential to treat other types of hypervascular cancers such as renal cell carcinoma. However, an in vitro model for evaluating both embolic performance and drug-release kinetics of the TACE embolic agents is still lacking since the current models greatly simplified the in vivo vascular systems as well as the extracellular matrices (ECM) in the organs. Here, we developed a decellularized organ model with preserved ECM and vasculatures as well as a translucent appearance to investigate chemoembolization performances of a clinically widely used embolic agent, i.e., a doxorubicin-loaded ethiodised oil (EO)-based emulsion. We, for the first time, utilized an ex vivo model to evaluate the liquid-based embolic agent in two organs, i.e., liver and kidneys. We found that the EO-based emulsion with enhanced stability by incorporating an emulsifier, i.e., hydrogenated castor oil-40 (HCO), showed an enhanced occlusion level and presented sustained drug release in the ex vivo liver model, suggesting an advantageous therapeutic effect for TACE treatment of hepatocellular carcinoma. In contrast, we observed that drug-release burst happened when applying the same therapy in the kidney model even with the HCO emulsifier, which may be explained by the presence of the specific renal vasculature and calyceal systems, indicating an unfavorable effect in the renal tumor treatment. Such an ex vivo model presents a promising template for chemoembolization evaluation before in vivo experiments for the development of novel embolic agents.

Optimizing outcomes in HCC: Comment on “optimal timing of combining sorafenib with trans-arterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis” by Jiang et al.

Recent years have witnessed notable advances in the management of intermediate and advanced hepatocellular carcinoma (HCC). However, several questions remain unanswered, including the timely transition from locoregional to systemic therapies and the lack of data on sequencing. In this Commentary, we critically discuss the results of the interesting meta-analysis conducted by Jiang and colleagues on the role of the combination therapy of trans-arterial chemoembolization (TACE) and sorafenib in this setting.

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

BackgroundThe combination therapy of trans-arterial chemoembolization (TACE) and sorafenib were proved to be one of the effective methods for intermediate and advanced hepatocellular carcinoma (HCC). Although it has been confirmed that the combination therapy can prolong survival for advanced HCC effectively, the therapeutic efficacy and safety are still controversial and the clinical value has not been determined. This meta-analysis aims to evaluate the efficacy and safety of combination therapy and discuss the optimal timing of combination for better clinical benefits. Data sourcesPubMed, EMBASE, the Cochrane Library, MEDLINE, and Web of Science were systematically reviewed to search for relevant studies published before May 15, 2021. Studies comparing the efficacy and safety of TACE + sorafenib with TACE + placebo / alone were adopted. Two reviewers independently extracted study outcomes. The data were analyzed through fixed/random-effect meta-analysis models with Review Manager (Version 5. 3) software. Results7 randomized controlled trials (RCTs) were included with 1464 patients with unresectable HCC (734 in TACE + sorafenib group and 730 in TACE + placebo or alone group). Meta-analysis showed that objective response rate (ORR) and disease control rate (DCR) were slightly improved in TACE + sorafenib group (ORR: risk ratio = 1.24; 95% confidence interval: 1.08–1.42; P = 0.002; DCR: risk ratio = 1.09; 95% confidence interval: 1.01–1.18; P = 0.02). The combination therapy obviously improved time to progression (TTP) (hazard ratio: 0.73; 95% confidence interval: 0.55–0.96; P = 0.03) and progression-free survival (PFS) (hazard ratio 0.62; 95% confidence interval: 0.52–0.73, P < 0.00001) but not overall survival (OS) (hazard ratio: 0.93; 95% confidence interval: 0.59–1.46; P = 0.75) or time to untreatable progression (TTUP) (hazard ratio: 0.76; 95% confidence interval: 0.31–1.89; P = 0.56). In addition, the incidence of adverse reactions (AEs) in combination group were higher than TACE + placebo / alone group. Furthermore, the subgroup analysis showed that the heterogeneity of TTP was notably decreased (pre-TACE: P = 0.12, I2 = 48%; post-TACE: P = 0.58, I2 = 0%), and the hazard ratio was 0.59 (95% confidence interval: 0.51–0.68; P < 0.00001) in pre-TACE subgroup which indicated that combination before TACE significantly prolonged TTP but not in combination after TACE (hazard ratio: 0.88; 95% confidence interval: 0.62–1.24; P = 0.46). In term of AEs, sensitivity analysis indicated that the risk ratio for hand-foot skin reaction, diarrhea, rash/desquamation, and hypertension was 7.41, 2.58, 2.14, 1.55 in pre-TACE subgroup respectively and was 11.34, 3.26, 3.61, 4.11 in post-TACE subgroup respectively (All P < 0.05). ConclusionThe combination of TACE and sorafenib significantly can improve TTP and PFS, and reduce the level of risk of adverse reactions of unresectable HCC, especially in the combination before TACE.

Lobar Radioembolization for Intermediate and Advanced Hepatocellular Carcinoma: Retrospective and Prospective Data.

Historically, outcomes reporting for radioembolization with yttrium-90 ( 90 Y) of hepatocellular carcinoma has included patients across the range of Barcelona Clinic Liver Cancer (BCLC) stages. With the potential for curative radiation segmentectomy for BCLC 0/A patients and evolution of systemic therapy for BCLC C patients, focused review by group is of increasing interest. In this review, we report on efficacy of 90 Y in patients with intermediate (BCLC B) and advanced (BCLC C) hepatocellular carcinoma as well as expected toxicities. Additionally, we review existing trials comparing 90 Y to transarterial chemoembolization and systemic treatments in these patient groups and outline future studies.

Efficacy and safety of raltitrexed-based transcatheter arterial chemoembolization for intermediate and advanced hepatocellular carcinoma: A multicenter real-world study.

This study aimed to evaluate efficacy and safety of raltitrexed-based transcatheter arterial chemoembolization (TACE) for intermediate and advanced hepatocellular carcinoma (HCC) using real-world evidence. All eligible HCC cases were collected from multiple centers in Chongqing, China, from January 2013 to December 2018 and divided into the raltitrexed group (raltitrexed+lobaplatin+pirarubicin) and control group (lobaplatin+pirarubicin). Propensity score matching (PSM) with a 1:1 ratio was used to eliminate the imbalance of potential confounding factors between groups. The primary end-point was overall survival (OS) and the secondary end-points were progression-free survival (PFS) and disease control rate. The median follow-up period for patients in the raltitrexed and control groups was 8.7 and 5.9months, respectively. After PSM, median OS was 10.0months in the raltitrexed group and 7.0months in the control group (p=0.002). The 6-month, 1-year, and 2-year OS rates of the raltitrexed group were significantly higher than those of the control group (78.2% vs. 60.9%, p=0.010; 43.5% vs. 22.8%, p=0.030; and 17.4% vs. 2.2% p=0.001, respectively). Multivariate analysis of these propensity score-matched HCC patients revealed treatment, age, tumor size, lipiodol accumulation, and the number of TACE cycles as independent predictors of OS (all p<0.05). The disease control rate of the raltitrexed and control groups was 87.4% and 65.8%, respectively (p<0.001). Raltitrexed-based TACE can prolong the OS of patients with intermediate and advanced HCC in a real-world clinical setting, and is safe and tolerable.

Combination of ablation and embolization for intermediate-sized liver metastases from colorectal cancer: what can we learn from treating primary liver cancer?

Colorectal cancer liver metastases (CRLMs) are common. Treating CRLMs with thermal ablation can prolong survival, but compared to lesions smaller than 3 cm, local control rates and overall survival are relatively worse with larger, intermediate (3-5 cm) lesions. Local recurrence rates range between 1.7%-20.2% and 6.7%-68.9% for CRLMs less than 3 cm and greater than 3 cm, respectively. Worse outcomes are also present when ablating intermediate size hepatocellular carcinoma (HCC) and there are some pathological similarities with CRLMs, namely the presence of micrometastatic disease. Combining ablation with transarterial chemoembolization is more effective in treating intermediate-size HCC than ablation alone. A meta-analysis of robust randomized controlled trials demonstrated long-term improved survival with combination therapy compared to ablation alone (odds ratio at 1, 3 and 5 years of 2.74, 2.77 and 5.23, respectively). There is, however, minimal evidence for combination therapy in CRLMs, limited to a handful of studies that are predominantly retrospective and have heterogeneous inclusion criteria. Given the difficulty in successfully treating intermediate CRLMs, the strong evidence for combination therapy in intermediate HCC and potential pathological similarities, formal evaluation of combination treatment in CRLM is merited. This review highlights existing evidence for treatment of intermediate-size liver lesions and highlights where trials in CRLMs should focus.

Medical therapy of HCC

Medical therapy of HCC

Multimolecular-Targeted Agents for Intermediate-Stage Hepatocellular Carcinoma Influence Time to Stage Progression and Overall Survival

Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. Methods: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Results: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01). Conclusion: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.