Objective: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT). Methods: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh ≤7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician. Results: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14–3.57; p = 0.01) as a significant and independent determinant of overall survival. Conclusions: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib.

Keywords:
Hepatocellular carcinoma, Sorafenib, Hepatic arterial infusion chemotherapy, Radiotherapy
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
2.
Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24: 2137–2150.
3.
Okita K: Management of hepatocellular carcinoma in Japan. J Gastroenterol 2006; 41: 100–106.
4.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390.
5.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, 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 Oncol 2009; 10: 25–34.
6.
Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, Sumie S, Yano Y, Okuda K, Sata M: Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 2002; 95: 588–595.
7.
Obi S, Yoshida H, Toune R, Unuma T, Kanda M, Sato S, Tateishi R, Teratani T, Shiina S, Omata M: Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer 2006; 106: 1990–1997.
8.
Uka K, Aikata H, Takaki S, Miki D, Kawaoka T, Jeong SC, Takahashi S, Toyota N, Ito K, Chayama K: Pretreatment predictor of response, time to progression, and survival to intraarterial 5-fluorouracil/interferon combination therapy in patients with advanced hepatocellular carcinoma. J Gastroenterol 2007; 42: 845–853.
9.
Uka K, Aikata H, Takaki S, Miki D, Jeong SC, Hiramatsu A, Kodama H, Shirakawa H, Kawakami Y, Takahashi S, Toyota N, Ito K, Chayama K: Similar effects of recombinant interferon-alpha-2b and natural interferon-alpha when combined with intra-arterial 5-fluorouracil for the treatment of advanced hepatocellular carcinoma. Liver Int 2007; 27: 1209–1216.
10.
Katamura Y, Aikata H, Takaki S, Azakami T, Kawaoka T, Waki K, Hiramatsu A, Kawakami Y, Takahashi S, Kenjo M, Toyota N, Ito K, Chayama K: Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional conformal radiotherapy for portal vein tumor thrombosis. J Gastroenterol 2009; 44: 492–502.
11.
Miyaki D, Aikata H, Honda Y, Naeshiro N, Nakahara T, Tanaka M, Nagaoki Y, Kawaoka T, Takaki S, Waki K, Hiramatsu A, Takahashi S, Ishikawa M, Kakizawa H, Awai K, Chayama K: Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma according to Child-Pugh classification. J Gastroenterol Hepatol 2012; 27: 1850–1857.
12.
Sakon M, Nagano H, Dono K, Nakamori S, Umeshita K, Yamada A, Kawata S, Imai Y, Iijima S, Monden M: Combined intraarterial 5-fluorouracil and subcutaneous interferon-alpha therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer 2002; 94: 435–442.
13.
Ota H, Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, Nakamura M, Damdinsuren B, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Wakasa K, Monden M: Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil: role of type I interferon receptor expression. Br J Cancer 2005; 93: 557–564.
14.
Han KH, Seong J, Kim JK, Ahn SH, Lee DY, Chon CY: Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis. Cancer 2008; 113: 995–1003.
15.
Kawaoka T, Aikata H, Hyogo H, Morio R, Morio K, Hatooka M, Fukuhara T, Kobayashi T, Naeshiro N, Miyaki D, Hiramatsu A, Imamura M, Kawakami Y, Takahashi S, Waki K, Tsuji K, Kohno H, Kohno H, Moriya T, Chayama K: Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma. J Dig Dis 2015; 16: 505–512.
16.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.
17.
Arnold B, Mitchell SA, Lent L, Mendoza TR, Rogak LJ, Barragan NM, Willis G, Medina M, Lechner S, Penedo FJ, Harness JK, Basch EM; PRO-CTCAE Spanish Translation and Linguistic Validation Study Group: Linguistic validation of the Spanish version of the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO- CTCAE). Support Care Cancer 2016; 24: 2843–2851.
18.
Pan CC, Kavanagh BD, Dawson LA, Li XA, Das SK, Miften M, Ten Haken RK: Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010; 76:S94–S100.
19.
Clarke M, Clayton D: The design and interpretation of case-control studies of perinatal mortality. Am J Epidemiol 1981; 113: 636–645.
20.
Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle PR, Santoro A, Beaugrand M, Sangiovanni A, Porta C, Gerken G, Marrero JA, Nadel A, Shan M, Moscovici M, Voliotis D, Llovet JM: Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012; 57: 821–829.
21.
Jeong SW, Jang JY, Shim KY, Lee SH, Kim SG, Cha SW, Kim YS, Cho YD, Kim HS, Kim BS, Kim KH, Kim JH: Practical effect of sorafenib monotherapy on advanced hepatocellular carcinoma and portal vein tumor thrombosis. Gut Liver 2013; 7: 696–703.
22.
Yoshida K, Hirokawa T, Moriyasu F, Liu L, Liu GJ, Yamada M, Imai Y: Arterial-phase contrast-enhanced ultrasonography for evaluating anti-angiogenesis treatment: a pilot study. World J Gastroenterol 2011; 17: 1045–1050.
23.
Hidaka H, Nakazawa T, Kaneko T, Minamino T, Takada J, Tanaka Y, Okuwaki Y, Watanabe M, Shibuya A, Koizumi W: Portal hemodynamic effects of sorafenib in patients with advanced hepatocellular carcinoma: a prospective cohort study. J Gastroenterol 2012; 47: 1030–1035.
24.
Raoul JL, Bruix J, Greten TF, Sherman M, Mazzaferro V, Hilgard P, Scherubl H, Scheulen ME, Germanidis G, Dominguez S, Ricci S, Nadel A, Moscovici M, Voliotis D, Llovet JM: Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol 2012; 56: 1080–1088.
25.
Ando E, Yamashita F, Tanaka M, Tanikawa K: A novel chemotherapy for advanced hepatocellular carcinoma with tumor thrombosis of the main trunk of the portal vein. Cancer 1997; 79: 1890–1896.
26.
Itamoto T, Nakahara H, Tashiro H, Haruta N, Asahara T, Naito A, Ito K: Hepatic arterial infusion of 5-fluorouracil and cisplatin for unresectable or recurrent hepatocellular carcinoma with tumor thrombus of the portal vein. J Surg Oncol 2002; 80: 143–148.
27.
Kim DY, Park W, Lim DH, Lee JH, Yoo BC, Paik SW, Kho KC, Kim TH, Ahn YC, Huh SJ: Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma. Cancer 2005; 103: 2419–2426.
28.
Toya R, Murakami R, Baba Y, Nishimura R, Morishita S, Ikeda O, Kawanaka K, Beppu T, Sugiyama S, Sakamoto T, Yamashita Y, Oya N: Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular carcinoma. Radiother Oncol 2007; 84: 266–271.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.