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Name of journal: World Journal of Hepatology
ESPS Manuscript NO: 13540
Columns: MINIREVIEWS
Current systemic treatment of hepatocellular carcinoma: A review of the literature
Chen KW et al. Current systemic treatment of hepatocellular carcinoma
Kai-Wen Chen, Tzu-Ming Ou, Chin-Wen Hsu, Chi-Ting Horng, Ching-Chang Lee, Yuh-Yuan Tsai, Chi-Chang Tsai, Yi-Sheng Liou, Chen-Chieh Yang, Chao-Wen Hsueh, Wu-Hsien Kuo
Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
Kai-Wen Chen, Tzu-Ming Ou, Wu-Hsien Kuo, Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11464, Taiwan
Tzu-Ming Ou, Ching-Chang Lee, Yuh-Yuan Tsai, Chi-Chang Tsai, Chao-Wen Hsueh, Wu-Hsien Kuo, Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
Chin-Wen Hsu, Chi-Ting Horng, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
Yi-Sheng Liou, Department of Family Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
Yi-Sheng Liou, Department of Public Health, National Defense Medical Center, Taipei 11490, Taiwan
Chen-Chieh Yang, Division of Gastroenterology, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97059, Taiwan
Author contributions: Kuo WH designed research; Chen KW, Ou TM, Kuo WH performed research; Hsu CW, Horng CT, Lee CC, Tsai YY, Tsai CC, Liou YS, Yang CC, Hsueh CW, Kuo WH analyzed data; Chen KW, Ou TM, Kuo WH wrote the paper.
Conflict-of-interest: The authors declare that they have no competing interests.
Open-Access: This article is an open-accessarticlewhich was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributedinaccordancewith the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: HYPERLINK "http://creativecommons.org/licenses/by-nc/4.0/" http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Wu-Hsien Kuo, MD, PhD, Professor, Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, No.2, Zhongzheng 1st Rd., Lingya District, Kaohsiung 80284, Taiwan. wuhsienku@gmail.com
Telephone: +886-7-7495986
Fax: +886-7-7491056
Received: August 26, 2014
Peer-review started: August 27, 2014
First decision: September 28, 2014
Revised: November 29, 2014
Accepted: March 30, 2015
Article in press:
Published online:
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patients performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently the most used one for patients with HCC. For example, the patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities including resection, transplantation, radiofrequency ablation are taken into consideration. If the patients were in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative trans-arterial chemoembolization (TACE) and even the target medication of sorafenib. In addition, the symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In the review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.
Key words: Hepatocellular carcinoma; Systemic treatment; Trans-arterial chemoembolization; Molecular target therapy; Sorafenib
The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Sorafenib is a multi-targeted tyrosine kinase inhibitor that was the first systemic therapy in the world to improve the survival rate among the patients with advanced hepatocellular carcinoma (HCC) in a phase III trial. However, the overall outcomes are sometimes unsatisfactory, and there is a need for second line therapies in patients with advanced HCC who still progressed after the use of sorafenib. Novel systemic approaches are needed in advanced HCC.
Chen KW, Ou TM, Hsu CW, Horng CT, Lee CC, Tsai YY, Tsai CC, Liou YS, Yang CC, Hsueh CW, Kuo WH. Current systemic treatment of hepatocellular carcinoma: A review of the literature. World J Hepatol 2015; In press
INTRODUCTION
Hepatocellular carcinoma (HCC) is a primary cancer of the liver which owns rate of the occurrence approximate to 90%. In clinical, HCC is the fifth most common form of cancer worldwide and the third most common cause of cancer-related deaths ADDIN EN.CITE Jemal201112212212217Jemal, AhmedinBray, FreddieCenter, Melissa M.Ferlay, JacquesWard, ElizabethForman, DavidGlobal cancer statisticsCA: A Cancer Journal for CliniciansCA Cancer J ClinCA: a cancer journal for clinicians69-906122011Wiley Subscription Services, Inc., A Wiley Company1542-4863http://dx.doi.org/10.3322/caac.2010710.3322/caac.20107[HYPERLINK \l "_ENREF_1" \o "Jemal, 2011 #122"1]. It is usually diagnosed as the advanced stage of the hepatic tumor and the median survival rate is poor (6-20 mo) when they were found ADDIN EN.CITE 199812712712717A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigatorsHepatologyHepatologyHepatologyHepatology751-5283AdultAgedAged, 80 and overCarcinoma, Hepatocellular/*mortality/pathologyFemaleHumansLiver Neoplasms/*mortality/pathologyMaleMiddle AgedPrognosisRetrospective Studiesalpha-Fetoproteins/analysis1998Sep0270-9139 (Print)
0270-9139 (Linking)9731568http://www.ncbi.nlm.nih.gov/pubmed/973156810.1002/hep.510280322[HYPERLINK \l "_ENREF_2" \o ", 1998 #127"2]. The incidence and distribution of HCC varies widely among geographic locations and races in the world. For example, the incidence of HCC is highest in Asia and Africa. Now most of the doctors believed that the potential reasons for the higher incidence rates of HCC are the prevalence of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) which strongly predisposes to the development of chronic liver disease, liver cirrhosis and subsequently HCC ADDIN EN.CITE Venook201012312312317Venook, Alan P.Papandreou, ChristosFuruse, JunjiLadrn de Guevara, LauraThe Incidence and Epidemiology of Hepatocellular Carcinoma: A Global and Regional PerspectiveThe OncologistThe Oncologist5-1315suppl 42010November 1, 2010http://theoncologist.alphamedpress.org/content/15/suppl_4/5.abstract10.1634/theoncologist.2010-S4-05[HYPERLINK \l "_ENREF_3" \o "Venook, 2010 #123"3]. In 1988, One large prospectively HBV study in Taiwan robustly demonstrated that HBV is the primary cause of the high HCC incidence rate in regions of high HBV prevalence ADDIN EN.CITE Beasley198812412412417Beasley, R. PalmerHepatitis B virus. The major etiology of hepatocellular carcinomaCancerCancerCancer1942-195661101988Wiley Subscription Services, Inc., A Wiley Company1097-0142http://dx.doi.org/10.1002/1097-0142(19880515)61:10<1942::AID-CNCR2820611003>3.0.CO;2-J10.1002/1097-0142(19880515)61:10<1942::AID-CNCR2820611003>3.0.CO;2-J[HYPERLINK \l "_ENREF_4" \o "Beasley, 1988 #124"4]. In Taiwan, nearly 5000 patients died from HCC in each year. Although the newer treatment modalities have become more multivariate in recent years, the all survival rates of these patients with advanced HCC still did not have a significant improvement. The one-year survival rate among treated patient with advanced HCC is also around 25% in 1993 and 30% in 2003 ADDIN EN.CITE Altekruse200921221221217Altekruse, Sean F.McGlynn, Katherine A.Reichman, Marsha E.Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005Journal of Clinical OncologyJournal of Clinical Oncology1485-14912792009March 20, 2009http://jco.ascopubs.org/content/27/9/1485.abstract10.1200/jco.2008.20.7753[HYPERLINK \l "_ENREF_86" \o "Altekruse, 2009 #212"5]. Until recently, there is no remarkable and effective medical therapy for patients with advanced HCC. To the knowledge, HCC is a more aggressive tumor and the decision for therapeutic option often depends on the stage of this cancer and the patients hepatic reserve. A number of staging systems are available ADDIN EN.CITE ADDIN EN.CITE.DATA [HYPERLINK \l "_ENREF_2" \o ", 1998 #127"2,6-8] but there is no worldwide consensus on a single system. For instance, the Child-Pugh (C-P) classification system and the model for end-stage liver disease (MELD) score can be used to assess the patients hepatic reserve and liver function. Besides, the performance status (PS) of patients is also needed to be taken into consideration. The Barcelona Clinic Liver Cancer (BCLC) staging and prognostic system accounts for variables related to tumor stage, physical performance, liver functional status, cancer-related symptoms and so on. It may provide the link of diseases and treatment strategies. The curative therapy including various surgeries (ex. hepatic resection and liver transplantation), and locoregional therapies (percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA)) have been proven to get better survival benefits in the very-early and early stage of HCC (such as stage 0-A). However, the intermediate stage (ex. stage B) of HCC comprises a highly heterogeneous patient population and therefore poses challenges for therapeutic management. A sub-classification B1-B4 was recently proposed taking the C-P score, tumor burden (up to seven criteria), PS and portal vein thrombosis into account ADDIN EN.CITE Bolondi201212912912917Bolondi, LuigiBurroughs, AndrewDufour, Jean-FranoisGalle, Peter R.Mazzaferro, VincenzoPiscaglia, FabioRaoul, Jean LucSangro, BrunoHeterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment DecisionsSemin Liver DisSemin Liver Dis348-35932042012//
08.02.20130272-808710.1055/s-0032-1329906En[HYPERLINK \l "_ENREF_8" \o "Bolondi, 2012 #129"9]. Trans-arterial chemoembolization (TACE) and radioembolization (TARE) are the primary options for these patients with preserved liver function (C-P classification A) and PS score 0. Unfortunately, if the HCC had developed into the severely advanced stage, only the systemic medical treatment is indicated and the prognosis and outcome is very poor for the patients. In the articles, we will discuss systemic treatment for patients with HCC for whom liver-directed therapy is not appropriate.
SYSTEMIC CYTOTOXIC CHEMOTHERAPY
HCC is highly refractory to conventional cytotoxic chemotherapy. In the last decade, no effective conventional systemic cytotoxic therapy was available and no single regimen has emerged as superior to any other ADDIN EN.CITE Lopez200620620620617Lopez, P. M.Villanueva, A.Llovet, J. M.Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.Systematic review: evidence-based management of hepatocellular carcinoma--an updated analysis of randomized controlled trialsAliment Pharmacol TherAlimentary pharmacology & therapeuticsAliment Pharmacol TherAlimentary pharmacology & therapeuticsAliment Pharmacol TherAlimentary pharmacology & therapeutics1535-472311Carcinoma, Hepatocellular/*therapy*Evidence-Based MedicineHumansLiver Neoplasms/*therapyPrognosisRandomized Controlled Trials as TopicSurvival Analysis2006Jun 10269-2813 (Print)
0269-2813 (Linking)16696801http://www.ncbi.nlm.nih.gov/pubmed/1669680110.1111/j.1365-2036.2006.02932.x[HYPERLINK \l "_ENREF_9" \o "Lopez, 2006 #206"10]. The substances related to sensitive of chemotherapy include P-glycoprotein ADDIN EN.CITE ADDIN EN.CITE.DATA [HYPERLINK \l "_ENREF_10" \o "Huang, 2012 #210"11-13], glutathione-S-transferase ADDIN EN.CITE Chen201121121121117Chen, Mei-ChuanChen, Chun-HanChuang, Hsiao-ChingKulp, Samuel K.Teng, Che-MingChen, Ching-ShihNovel mechanism by which histone d e a c e t y l a s e i n h i b i t o r s f a c i l i t a t e t o p o i s o m e r a s e I I d e g r a d a t i o n i n h e p a t o c e l l u l a r c a r c i n o m a c e l l s <