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Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial.

ABSTRACT: Importance:Patients with hepatocellular carcinoma showing macroscopic vascular invasion have a poor prognosis. Sorafenib is the sole treatment option for these patients, with unsatisfactory response and survival benefit. Combined treatment with transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) has shown promising results for these patients in observational studies. Objective:To evaluate the efficacy and safety of TACE plus RT compared with sorafenib for patients with hepatocellular carcinoma and macroscopic vascular invasion. Design, Setting, and Participants:In this randomized, open-label clinical trial conducted at an academic tertiary care center between July 1, 2013, and October 31, 2016, 90 treatment-naive patients with liver-confined hepatocellular carcinoma showing macroscopic vascular invasion were randomly assigned to receive sorafenib (400 mg twice daily; 45 participants [the sorafenib group]) or TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE, maximum 45 Gy with the fraction size of 2.5 to 3 Gy; 45 participants [the TACE-RT group]). Main Outcomes and Measures:The primary end point was the 12-week progression-free survival rate by intention-to-treat analysis. Radiologic response was assessed by independent review according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Treatment crossover was permitted after confirming disease progression. Results:Of the 90 patients (median age, 55 years; range, 33-82 years), 77 were men and 13 were women. All patients had portal vein invasion of hepatocellular carcinoma and Child-Pugh class A liver function. The median maximal tumor diameter was 9.7 cm. Most patients (71 [78.9%]) had multiple lesions. At week 12, the progression-free survival rate was significantly higher in the TACE-RT group than the sorafenib group (86.7% vs 34.3%; P < .001). The TACE-RT group showed a significantly higher radiologic response rate than the sorafenib group at 24 weeks (15 [33.3%] vs 1 [2.2%]; P < .001), a significantly longer median time to progression (31.0 vs 11.7 weeks; P < .001), and significantly longer overall survival (55.0 vs 43.0 weeks; P = .04). Curative surgical resection was conducted for 5 patients (11.1%) in the TACE-RT group owing to downstaging. No patients in the TACE-RT group discontinued treatment owing to hepatic decompensation. Conclusions and Relevance:For patients with advanced hepatocellular carcinoma showing macroscopic vascular invasion, first-line treatment with TACE plus RT was well tolerated and provided an improved progression-free survival, objective response rate, time to progression, and overall survival compared with sorafenib treatment. Trial Registration:clinicaltrials.gov Identifier: NCT01901692.

SUBMITTER: Yoon SM

PROVIDER: S-EPMC5885246 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSeveral 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).MethodsPatients 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.ResultsAt 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.ConclusionsIn 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.

Project description:BackgroundTransarterial chemoembolization (TACE) is the recommended treatment for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage. This updated systemic review and meta-analysis focuses on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration.MethodsPubMed, EMBASE, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017. Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible. The hazard ratio (HR) with 95% confidence intervals (95% CIs) for time to progression (TTP), overall survival (OS), disease control rate (DCR) and aetiology were collected. The data were then analysed through fixed/random effects meta-analysis models with STATA 13.0. The incidence and severity of treatment-related adverse events (AEs) were also evaluated.ResultsTwenty-seven studies were included. Thirteen non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95%). Fourteen comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months). Five comparative studies provided DCR (ranging from 32 to 97.2%). Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95% CI 0.50-0.81, P = 0.002) rather than OS (HR = 0.63, 95% CI 0.55-0.71, P = 0.058), compared to TACE alone. DCR increased significantly in the combination therapy group (OR = 2.93, 95% CI 1.59-5.41, P = 0.005). Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various aetiologies. Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95% CI 0.45-0.79, P = 0.002) in the Asian countries group, and 0.82 (95% CI 0.59-1.05, P = 0.504)) in western countries. The HR for OS was 0.61 (95% CI 0.48-0.75, P = 0.050) in the Asian countries group and was 0.88 (95% CI 0.56-1.20, P = 0.845) in western countries. These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region. The most common AEs included fatigue, hand-foot skin reaction, diarrhoea and hypertension.ConclusionsCombination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR. More well-designed studies are needed to investigate its superiority for OS.

Project description:BackgroundSorafenib has been recommended as the first-line treatment and shown to prolong median overall survival (OS) of patients with advanced unresectable hepatocellular carcinoma (HCC). Recently, a growing amount of research has supported the application of transarterial chemoembolization (TACE) in patients with advanced-stage HCC. The aim of this study was to compare the outcomes of TACE and sorafenib and identify the prognostic factors related to OS for Barcelona Clinic Liver Cancer (BCLC) stage C patients with PS 1 but without vascular invasion or extrahepatic spread.MethodsA total of 323 consecutive patients in BCLC stage C with PS 1 but without vascular invasion or extrahepatic spread were enrolled in this retrospective study. Survival analyses were performed using the Kaplan-Meier analysis, and the statistical differences between the TACE and sorafenib groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS.ResultsBased on the Kaplan-Meier curves, patients treated with TACE showed a better OS than those undergoing sorafenib, with respective OS at 1, 3, and 5 years (67.7%, 41.5%, 23.2% vs. 55.6%, 29.6%, 4.8%; log-rank P=0.002). The univariate analysis indicated that tumor size, tumor number, and treatment method, along with platelet (PLT), white blood cell (WBC), and α-fetoprotein (AFP) count, were associated with OS. The multivariate analysis demonstrated that tumor size, tumor number, and treatment method were significant prognostic factors for OS. According to the subgroups analyses based on the tumor size and tumor number, there were significant differences in OS among overall subsets between TACE and sorafenib therapy.ConclusionsTACE provided better prognostic performance than sorafenib and should be suggested as an alternative treatment modality to sorafenib for BCLC stage C patients with PS 1 but without vascular invasion or extrahepatic spread.

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Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial.

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