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      Transarterial Chemoembolization (TACE) plus Sorafenib Versus TACE for Intermediate or Advanced Stage Hepatocellular Carcinoma: A Meta-Analysis

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      PLoS ONE

      Public Library of Science

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          Abstract

          Background

          Sorafenib is used in patients with intermediate or advanced stage hepatocellular carcinoma (HCC) before or after of transarterial chemoembolization (TACE). However, the survival outcomes of TACE combined with sorafenib versus TACE alone remain controversial. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC.

          Methods

          Pubmed and Embase databases were systematically reviewed for studies published up to November 2013, that compared TACE alone or in combination with sorafenib. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), time to progression (TTP), objective response rate (ORR), and progression free survival (PFS) using random-effects or fixed-effects model, depending on the heterogeneity between the included studies.

          Results

          Six studies published from 2011 to 2013, with a total of 1254 patients, were included in this meta-analysis. The pooled results showed that TACE combined with sorafenib significantly improved OS (HR = 0.65; 95% CI: 0.47–0.89, P = 0.007), TTP (HR = 0.68; 95% CI: 0.52–0.87, P = 0.003), ORR (HR = 1.06; 95% CI: 1.01–1.12, P = 0.021), but did not affect PFS (HR = 0.84; 95% CI: 0.62–1.14, P = 0.267). The incidence of grade III/IV adverse reaction was higher in the TACE plus sorafenib group than in the TACE group.

          Conclusions

          The meta-analysis confirmed that the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC, can improve the OS, TTP, and ORR. This combination therapy was also associated with a significantly increased risk of adverse reactions.

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          Most cited references 14

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          Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma.

          In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and ≥25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials.

             R Kunz,  A D Oxman (1998)
            To summarise comparisons of randomised clinical trials and non-randomised clinical trials, trials with adequately concealed random allocation versus inadequately concealed random allocation, and high quality trials versus low quality trials where the effect of randomisation could not be separated from the effects of other methodological manoeuvres. Systematic review. Cohorts or meta-analyses of clinical trials that included an empirical assessment of the relation between randomisation and estimates of effect. Cochrane Review Methodology Database, Medline, SciSearch, bibliographies, hand searching of journals, personal communication with methodologists, and the reference lists of relevant articles. Relation between randomisation and estimates of effect. Eleven studies that compared randomised controlled trials with non-randomised controlled trials (eight for evaluations of the same intervention and three across different interventions), two studies that compared trials with adequately concealed random allocation and inadequately concealed random allocation, and five studies that assessed the relation between quality scores and estimates of treatment effects, were identified. Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more, relative decreases of up to 90%, inversion of the estimated effect and, in some cases, no difference. On average, failure to use randomisation or adequate concealment of allocation resulted in larger estimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups. Failure to use adequately concealed random allocation can distort the apparent effects of care in either direction, causing the effects to seem either larger or smaller than they really are. The size of these distortions can be as large as or larger than the size of the effects that are to be detected.
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              Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness.

              Although transcatheter arterial chemoembolization (TACE) is effective in hepatocellular carcinoma (HCC), it is not considered a curative procedure. Among the factors potentially interfering with its effectiveness is a hypothetical neoangiogenic reaction due to ischemia. In our study, we evaluated the changes in the levels of two angiogenic factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [b-FGF]) and one parameter of invasiveness (urokinase-type plasminogen activator [uPA]) in patients treated with TACE. Three blood samples were provided from 71 HCC patients undergoing TACE: before TACE (t0), after 3 days (t1), and after 4 wk, when they had spiral computed tomography (sCT) scanning (t2). The referring radiologists blindly evaluated tumor burden and vascularization at t0 and residual activity at t2. The choice of TACE as treatment was based on the American Association for the Study of Liver Diseases (AASLD) guidelines. Complete response at sCT was recorded in 27% of patients; mean survival was 35 months (confidence interval [CI] 31-40) and the 4-yr survival was 57%. VEGF levels were significantly correlated with the number of nodes and were higher in nonresponders at t2 (P = 0.01); below-median VEGF levels predicted a longer survival (P = 0.008). b-FGF correlated with VEGF, tumor size, vascularization, and residual activity, showing a borderline correlation with survival. uPA correlated with tumor size and VEGF. VEGF was singled out in the Cox multivariate analysis as an independent predictor of survival. When TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF following treatment; this affects patient survival. VEGF emerges as the most reliable prognostic parameter, so it could be measured for judging TACE efficacy. Finally, antiangiogenic drugs may be indicated in TACE-treated HCC.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                19 June 2014
                : 9
                : 6
                Affiliations
                Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqin, People’s Republic of China
                Xiangya Hospital of Central South University, China
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PB. Performed the experiments: LDZ PH XC PB. Analyzed the data: LDZ PH PB. Contributed reagents/materials/analysis tools: LDZ PH XC PB. Wrote the paper: LDZ PH XC PB.

                Article
                PONE-D-14-03740
                10.1371/journal.pone.0100305
                4063775
                24945380

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 8
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Alcoholic Liver Disease
                Cirrhosis
                Oncology
                Cancers and Neoplasms
                Cancer Treatment
                Oncology Agents

                Uncategorized

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