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      Combination Therapy of Sorafenib and TACE for Unresectable HCC: A Systematic Review and Meta-Analysis

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          Background and Aim

          A large number of studies have tried to combine sorafenib with TACE for patients with unresectable hepatocellular carcinoma (HCC) and the results were controversial. We conducted this systematic review and meta-analysis to evaluate the safety and efficacy of combination therapy of sorafenib and TACE in the management of unresectable HCC.


          MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Library were searched from January 1990 to October 2013 and these databases were searched for appropriate studies combining TACE and sorafenib in treatment of HCC. Two authors independently reviewed the databases and extracted the data and disagreements were resolved by discussion. Effective value and safety were analyzed. Effective value included disease control rate (DCR), time to progression (TTP) and overall survival (OS).


          17 studies were included in the study. In the 10 noncomparative studies, DCR ranged from 18.4 to 91.2%. Median TTP ranged from 7.1 to 9.0 months, and median OS ranged from 12 to 27 months. In the 7 comparative studies, the hazard ratio (HR) for TTP was found to be 0.76 (95% CI 0.66–0.89; P<0.001) with low heterogeneity among studies (P = 0.243; I 2 = 25.5%). However, the HR for OS was found to be 0.81 (95% CI 0.65–1.01; P = 0.061) with low heterogeneity among studies (P = 0.259; I 2 = 25.4%). The common toxicities included fatigue, diarrhea, nausea, hand foot skin reaction (HFSR), hematological events, hepatotoxicity, alopecia, hepatotoxicity, hypertension and rash/desquamation. AEs are generally manageable with dose reductions.


          Combination therapy may bring benefits for unresectable HCC patients in terms of TTP but not OS. Further well-designed randomized controlled studies are needed to confirm the efficacy of combination therapy.

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          Most cited references 23

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          Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.

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            Rising incidence of hepatocellular carcinoma in the United States.

            Clinical observations have suggested that the number of cases of hepatocellular carcinoma has increased in the United States. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) data base to determine the age-adjusted incidence of hepatocellular carcinoma from 1976 to 1995, data from the U.S. vital-statistics data base to determine age-adjusted mortality rates from 1981 to 1995, and data from the Department of Veterans Affairs to determine age-adjusted rates of hospitalization for the disease from 1983 to 1997. The incidence of histologically proved hepatocellular carcinoma increased from 1.4 per 100,000 population (95 percent confidence interval, 1.3 to 1.4) for the period from 1976 to 1980 to 2.4 per 100,000 (95 percent confidence interval, 2.3 to 2.4) for the period from 1991 to 1995. Among black men, the incidence was 6.1 per 100,000 for the period from 1991 to 1995, and among white men, it was 2.8 per 100,000. There was a 41 percent increase in the mortality rate from primary liver cancer and a 46 percent increase in the proportion of hospitalizations attributable to this disease during the periods studied. The incidence increased significantly among younger persons (40 to 60 years old) during the period from 1991 to 1995 as compared with earlier periods. An increase in the number of cases of hepatocellular carcinoma has occurred in the United States over the past two decades. The age-specific incidence of this cancer has progressively shifted toward younger people.
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              Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.

              Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                20 March 2014
                : 9
                : 3
                [1 ]Department of Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
                [2 ]Department of Gastroenterology, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
                [3 ]Department of Anatomy, Histology and Embryology, K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China
                [4 ]Department of Health Services, School of Military Preventive Medicine, Fourth Military Medical University, Xi'an, China
                Northwestern University Feinberg School of Medicine, United States of America
                Author notes

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

                Conceived and designed the experiments: LL HC GH. Performed the experiments: LL HC MW YZ GC. Analyzed the data: LL HC XQ. Contributed reagents/materials/analysis tools: LL HC XQ. Wrote the paper: LL HC. Critical revision of the manuscript: XQ GH. Study supervision: GH.


                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
                No current funding sources for this study.
                Research Article
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Hepatocellular Carcinoma
                Gastrointestinal Cancers
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Cancer Treatment
                Radiation Therapy
                Physical Sciences
                Statistics (Mathematics)
                Statistical Methods
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Research Design
                Clinical Research Design



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