Neoplastic macrovascular invasion represents an independent risk factor for dismal survival in sorafenib treatment for hepatocellular carcinoma

Abstract

Aim: Sorafenib efficacy and safety in advanced hepatocellular carcinoma (HCC) have been demonstrated in two randomized international clinical trials and in clinical practice studies. Because of poor survival advantage, to identify clinical and biological parameters remains an unmet clinical need.

Methods: Eighty-four patients treated with sorafenib were evaluated for response to therapy and prognostic factors possibly associated with survival.

Results: Median overall survival was 8.5 months. Median duration of therapy was 2.5 months with a median daily dose of 800 mg (IQR 600-800). Dose was adjusted in 52% of patients. Radiological response to therapy showed a significant impact on survival. Child-Pugh score and neoplastic invasion of the portal system were negatively associated with survival. Continuation of sorafenib even at lower dose was positively correlated with survival. The multivariate analysis identified vascular invasion as the only independent variable: median survival of 5.5 months for neoplastic portal vein thrombosis compared to 12 months in the remaining subjects.

Conclusion: A lower sorafenib daily dose is advantageous, even though the reason of this association cannot be explained at present. Neoplastic portal vein thrombosis is strongly associated with dismal survival. Alternative or complementary treatment approaches should be studied in order to improve outcome in this subgroup of patients.

Keywords

Hepatocellular carcinoma / sorafenib / neoplastic portal vein thrombosis

References

[1] Jemal A,Center MM,Ward E.Global cancer statistics..CA Cancer J Clin2011;61:61-9

[2] Ferlay J,Bray F,Mathers C.Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008..Int J Cancer2010;127:2893-917

[3] Schütte K,Malfertheiner P.Hepatocellular carcinoma--epidemiological trends and risk factors..Dig Dis2009;27:80-92

[4] Perz JF,Farrington LA,Bell BP.The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide..J Hepatol2006;45:529-38

[5] Ratziu V,Cortez-Pinto H,Marchesini G.A position statement on NAFLD/NASH based on the EASL 2009 special conference..J Hepatol2010;53:372-84

[6] Loria P,Bellentani S,Grieco A,Gasbarrini A,Lonardo A,Marra F,Prati D,NAFLD Expert Committee of the Associazione Italiana per lo studio del Fegato..Practice guidelines for the diagnosis and management of non-alcoholic fatty liver disease: a decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee..Dig Liver Dis2010;42:272-82

[7] Porepa L,Sanchez-Romeu P.Newly diagnosed diabetes mellitus as a risk factor for serious liver disease..CMAJ2010;182:E526-31 PMCID:PMC2917963

[8] Polesel J,Montella M,Crispo A,Serraino D,Talamini R.The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma..Ann Oncol2009;20:353-7

[9] Balogh J,Asham EH,Boktour M,Li X,Monsour HP, Jr.Hepatocellular carcinoma: a review..J Hepatocell Carcinoma2016;3:41-53 PMCID:PMC5063561

[10] Colagrande S,Aburas S,Nardi C.Challenges of advanced hepatocellular carcinoma..World J Gastroenterol2016;22:7645-59 PMCID:PMC5016365

[11] Kudo M,Kokudo N,Sakamoto M,Kojiro M.Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version..Dig Dis2011;29:339-64

[12] Poon D,Chen LT,Lau WY,Singh H,Ooi LL,Khin MW.Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009..Lancet Oncol2009;10:1111-8

[13] Bruix J.Management of hepatocellular carcinoma: an update..Hepatology2011;53:1020-2 PMCID:PMC3084991

[14] Cheng AL,Chen Z,Qin S,Luo R,Ye S,Xu J,Liang H,Wang J,Pan H,Zou J,Guan Z.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial..Lancet Oncol2009;10:25-34

[15] Mendez-Sanchez N,Zamora-Valdes D.Sorafenib, a systemic therapy for hepatocellular carcinoma..Ann Hepatol2008;7:46-51

[16] Wilhelm SM,Tang L,McNabola A,Chen C,Vincent P,Cao Y,Gawlak S,Rowley B,Adnane L,Auclair D,Gedrich R,Riedl B,Bollag G.Sorafenib (BAY 43-9006, Nexavar) exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis..Cancer Res2004;64:7099-109

[17] Adnane L,Taylor I.Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR tumor vasculature..Methods Enzymol2006;407:597-612

[18] Liu L,Chen C,Mc Nabola A,Wilhelm S,Carter C.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5..Cancer Res2006;66:11851-8

[19] Wilhelm SM,Newell P,Llovet JM.Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling..Mol Cancer Ther2008;7:3129-40

[20] Di Marco V,Koskinas J,Toniutto P.Sorafenib: from literature to clinical practice..Ann Oncol2013;24:ii30-7

[21] Choi GH,Shim JH,Ryoo BY,Kim KM,Lee HC.Prognostic Scoring Models for patients undergoing sorafenib treatment for advanced stage hepatocellular carcinoma in real-life practice..Am J Clin Oncol2017;40:167-74

[22] Kudo M,Arizumi T.Real life clinical practice with sorafenib in advanced hepatocellular carcinoma: a single-centre experience..Dig Dis2012;30:609-16

[23] Trojniak MP,Mazurek M.Sorafenib in hepatocellular carcinoma - a post marketing evaluation..Immunopharmacol Immunotoxicol2012;34:419-22

[24] Chan SL,Chan AW,Chok KS.Management of hepatocellular carcinoma with portal vein tumor thrombosis: review and update at 2016..World J Gastroenterol2016;22:7289-300 PMCID:PMC4997643

[25] Miyahara K,Morimoto Y,Hagihara H,Onishi H,Miyake Y,Shiraha H,Iwadou S,Takaguchi K,Takabatake H,Yamamoto K.Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma..Hepatol Res2014;44:296-301

[26] Nakano M,Kuromatsu R,Tajiri N,Niizeki T,Okamura S,Shimose S,Koga H.Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study..Cancer Med2015;4:1836-43 PMCID:PMC5123720

[27] Raoul JL,Gilabert M.How to assess the efficacy or failure of targeted therapy: deciding when to stop sorafenib in hepatocellular carcinoma..World J Hepatol2016;8:1541-6 PMCID:PMC5165267

[28] Llovet JM,Mazzaferro V,Gane E,de Oliveira AC,Raoul JL,Schwartz M,Zeuzem S,Greten TF,Seitz JF,Häussinger D,Shan M,Voliotis D.Sorafenib in advanced hepatocellular carcinoma..N Engl J Med2008;359:378-90

[29] Iavarone M,Piscaglia F,Grieco A,Cammà C.Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy..Hepatology2011;54:2055-63

[30] D'Angelo S,Zolfino T,Giannitrapani L,Montesarchio V,Buonadonna A,Gasbarrini A,Cillo U,Villa E,Proserpio I,Magini G,Fava G,Calvani N,Di Costanzo F,Poggi G,Cascinu S,Palmieri V,Crocè LS,Tumulo S,Lencioni R.Therapeutic decisions and treatment with Sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy..Recent Prog Med2015;106:217-26

[31] Kim DY,Han KH,Heo J,Um SH,Kweon YO,Yoon JH,Lee BS,Ryoo BY.Real-life experience of sorafenib treatment for hepatocellular carcinoma in Korea: from GIDEON data..Cancer Res Treat2016;48:1243-52 PMCID:PMC5080829