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      Treatment Strategies for Hepatocellular Carcinoma—A Multidisciplinary Approach

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          Abstract

          Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections—even in patients with underlying chronic liver disease—are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient’s general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients.

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          The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level : Results From the Global Burden of Disease Study 2015

          Importance Liver cancer is among the leading causes of cancer deaths globally. The most common causes for liver cancer include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and alcohol use. Objective To report results of the Global Burden of Disease (GBD) 2015 study on primary liver cancer incidence, mortality, and disability-adjusted life-years (DALYs) for 195 countries or territories from 1990 to 2015, and present global, regional, and national estimates on the burden of liver cancer attributable to HBV, HCV, alcohol, and an “other” group that encompasses residual causes. Design, Settings, and Participants Mortality was estimated using vital registration and cancer registry data in an ensemble modeling approach. Single-cause mortality estimates were adjusted for all-cause mortality. Incidence was derived from mortality estimates and the mortality-to-incidence ratio. Through a systematic literature review, data on the proportions of liver cancer due to HBV, HCV, alcohol, and other causes were identified. Years of life lost were calculated by multiplying each death by a standard life expectancy. Prevalence was estimated using mortality-to-incidence ratio as surrogate for survival. Total prevalence was divided into 4 sequelae that were multiplied by disability weights to derive years lived with disability (YLDs). DALYs were the sum of years of life lost and YLDs. Main Outcomes and Measures Liver cancer mortality, incidence, YLDs, years of life lost, DALYs by etiology, age, sex, country, and year. Results There were 854 000 incident cases of liver cancer and 810 000 deaths globally in 2015, contributing to 20 578 000 DALYs. Cases of incident liver cancer increased by 75% between 1990 and 2015, of which 47% can be explained by changing population age structures, 35% by population growth, and −8% to changing age-specific incidence rates. The male-to-female ratio for age-standardized liver cancer mortality was 2.8. Globally, HBV accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), HCV for 167 000 (21%), and other causes for 133 000 (16%) deaths, with substantial variation between countries in the underlying etiologies. Conclusions and Relevance Liver cancer is among the leading causes of cancer deaths in many countries. Causes of liver cancer differ widely among populations. Our results show that most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use. In line with the Sustainable Development Goals, the identification and elimination of risk factors for liver cancer will be required to achieve a sustained reduction in liver cancer burden. The GBD study can be used to guide these prevention efforts. This data analysis of the Global Burden of Disease 2015 study on primary liver cancer reports incidence, mortality, and disability-adjusted life-years for 195 countries or territories from 1990 to 2015, and presents global, regional, and national estimates on the burden of liver cancer. Question What is the burden of liver cancer globally, what are the major risk factors for liver cancer across countries, regions, and at the global level and how did these change between 1990 and 2015? Findings There were 854 000 incident liver cancer cases and 810 000 deaths globally in 2015, contributing to 20 578 000 disability-adjusted life-years. Hepatitis B virus infection accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), hepatitis C virus infection for 167 000 (21%), and other causes for 133 000 (16%) deaths. Meaning Most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use.
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            Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.

            The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P =.87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P =.0001). An alpha-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > or = 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P =.0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT.
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              Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

              There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 March 2019
                March 2019
                : 20
                : 6
                : 1465
                Affiliations
                [1 ]Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; ibarth@ 123456ukaachen.de (I.L.); zczigany@ 123456ukaachen.de (Z.C.); jbednarsch@ 123456ukaachen.de (J.B.); uneumann@ 123456ukaachen.de (U.P.N.)
                [2 ]Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; croderburg@ 123456ukaachen.de
                [3 ]Department of Gastroenterology/Hepatology, Campus Virchow Klinikum and Charité Mitte, Charité University Medicine Berlin, 13353 Berlin, Germany
                [4 ]Department for Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, 52074 Aachen, Germany; isfort@ 123456ukaachen.de
                [5 ]Department of Surgery, Maastricht University Medical Centre (MUMC), 6229 ET Maastricht, The Netherlands
                Author notes
                [* ]Correspondence: glurje@ 123456ukaachen.de
                [†]

                Both authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-4006-7707
                https://orcid.org/0000-0003-0373-3210
                https://orcid.org/0000-0001-9674-0756
                Article
                ijms-20-01465
                10.3390/ijms20061465
                6470895
                30909504
                4bb2ceb9-5838-445d-9f01-29abc76d48c6
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 March 2019
                : 21 March 2019
                Categories
                Review

                Molecular biology
                hepatocellular carcinoma,liver cirrhosis,liver transplantation,liver resection,multimodal treatment

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