Background: Transarterial chemoembolization (TACE) is recommended for patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage B. However, because of the heterogeneity of HCC in BCLC stage B; various subclassification systems have been proposed to predict the prognosis of patients. Previously, we proposed the Kinki criteria for precise classification of HCC cases in BCLC stage B. In this study, we compared the time to TACE refractoriness in HCC patients with Kinki criteria substages B1 and B2-HCC. Summary: Between January 2006 and December 2013, 592 HCC patients (substage B1, n = 118; substage B2, n = 170) underwent TACE. Time to progression under TACE treatment was defined as the time to untreatable progression (TTUP). TTUP and changes in liver function were analyzed in patients with substages B1 and B2-HCC. The median TTUP was 25.7 months (95% CI 19.3-37.3) and 16.4 months (95% CI 13.1-20.2) in patients with substage B1-HCC and substage B2-HCC, respectively (p = 0.0050). In patients with substage B2-HCC, median Child-Pugh scores after the first TACE session was significantly different from those after third and fifth TACE sessions (first-third, p = 0.0020; first-fifth, p = 0.0008). Key Message: TACE refractoriness occurred earlier in patients with substage B2-HCC than those with substage B1-HCC; deterioration of liver function with repeated TACE was more obvious in HCC cases with stage-B1 tumor. Shorter TTUP and impaired liver function due to repeated TACE could be responsible for the shorter survival in patients with substage B2-HCC.

1.
Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: globocan 2000. Int J Cancer 2001;94:153-156.
2.
Kim Y, Han KH: Epidemiology and surveillance of hepatocellular carcinoma. Liver Cancer 2012;1:2-14.
3.
El-Serag HB: Hepatocellular carcinoma. N Engl J Med 2011;365:1118-1127.
4.
Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485-1491.
5.
Bruix J, Reig M, Sherman M: Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 2016;150:835-853.
6.
Tsurusaki M, Murakami T: Surgical and locoregional therapy of HCC: TACE. Liver Cancer 2015;4:165-175.
7.
Chow PK, Choo SP, Ng DC, Lo RH, Wang ML, Toh HC, Tai DW, Goh BK, Wong JS, Tay KH, Goh AS, Yan SX, Loke KS, Thang SP, Gogna A, Too CW, Irani FG, Leong S, Lim KH, Thng CH: National cancer centre Singapore consensus guidelines for hepatocellular carcinoma. Liver Cancer 2016;5:97-106.
8.
Kudo M: Locoregional therapy for hepatocellular carcinoma. Liver Cancer 2015;4:163-164.
9.
Kitai S, Kudo M, Nishida N, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M; Liver Cancer Study Group of Japan: Survival benefit of locoregional treatment for hepatocellular carcinoma with advanced liver cirrhosis. Liver Cancer 2016;5:175-189.
10.
Kudo M, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M: Survival analysis over 28 years of 173,378 patients with hepatocellular carcinoma in Japan. Liver Cancer 2016;5:190-197.
11.
Arizumi T, Ueshima K, Minami T, Kono M, Chishina H, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M: Effectiveness of Sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma. Liver Cancer 2015;4:253-262.
12.
Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M: Validation of the criteria of transcatheter arterial chemoembolization failure or refractoriness in patients with advanced hepatocellular carcinoma proposed by the LCSGJ. Oncology 2014;87(suppl 1):32-36.
13.
Raoul JL, Gilabert M, Piana G: How to define transarterial chemoembolization failure or refractoriness: a European perspective. Liver Cancer 2014;3:119-124.
14.
Kudo M, Matsui O, Izumi N, Kadoya M, Okusaka T, Miyayama S, Yamakado K, Tsuchiya K, Ueshima K, Hiraoka A, Ikeda M, Ogasawara S, Yamashita T, Minami T: Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology 2014;87(suppl 1):22-31.
15.
Kudo M: Heterogeneity and subclassification of barcelona clinic liver cancer stage B. Liver Cancer 2016;5:91-96.
16.
Kudo M, Arizumi T, Ueshima K, Sakurai T, Kitano M, Nishida N: Subclassification of BCLC B stage hepatocellular carcinoma and treatment strategies: proposal of modified bolondi's subclassification (Kinki criteria). Dig Dis 2015;33:751-758.
17.
Arizumi T, Ueshima K, Iwanishi M, Minami T, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Ida H, Sakurai T, Kitano M, Nishida N, Kudo M: Validation of Kinki criteria, a modified substaging system, in patients with intermediate stage hepatocellular carcinoma. Dig Dis 2016;34:671-678.
18.
Arizumi T, Ueshima K, Iwanishi M, Minami T, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Ida H, Minami Y, Sakurai T, Kitano M, Nishida N, Kudo M: Validation of a modified substaging system (Kinki criteria) for patients with intermediate-stage hepatocellular carcinoma. Oncology 2015;89(suppl 2):47-52.
19.
Kudo M: Surveillance, diagnosis, treatment, and outcome of liver cancer in Japan. Liver Cancer 2015;4:39-50.
20.
Clinical practice guidelines for hepatocellular carcinoma differ between Japan, United States, and Europe. Liver Cancer 2015;4:85-95.
21.
Teng W, Liu KW, Lin CC, Jeng WJ, Chen WT, Sheen IS, Lin CY, Lin SM: Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation. Liver Cancer 2015;4:26-38.
22.
Kang TW, Rhim H: Recent advances in tumor ablation for hepatocellular carcinoma. Liver Cancer 2015;4:176-187.
23.
Lencioni R, de Baere T, Martin RC, Nutting CW, Narayanan G: Image-guided ablation of malignant liver tumors: recommendations for clinical validation of novel thermal and non-thermal technologies - A Western perspective. Liver Cancer 2015;4:208-214.
24.
Kudo M: Recent trends in the management of hepatocellular carcinoma with special emphasis on treatment with regorafenib and immune checkpoint inhibitors. Dig Dis 2016;34:714-730.
25.
Ramaswami R, Pinato DJ, Kubota K, Ishizuka M, Arizumi T, Kudo M, Jang JW, Kim YW, Pirisi M, Allara E, Sharma R: Prognostic sub-classification of intermediate-stage hepatocellular carcinoma: a multicenter cohort study with propensity score analysis. Med Oncol 2016;33:114.
26.
Yamakado K, Miyayama S, Hirota S, Mizunuma K, Nakamura K, Inaba Y, Yamamoto S, Matsuo K, Nishida N, Aramaki T, Anai H, Kora S, Oikawa S, Watanabe K, Yasumoto T, Furuichi K, Yamaguchi M: Prognosis of patients with intermediate-stage hepatocellular carcinomas based on the Child-Pugh score: subclassifying the intermediate stage (Barcelona Clinic Liver Cancer stage B). Jpn J Radiol 2014;32:644-649.
27.
Hiraoka A, Kumada T, Nouso K, Tsuji K, Itobayashi E, Hirooka M, Kariyama K, Ishikawa T, Tada T, Toyoda H, Kawasaki H, Hiasa Y, Michitaka K: Proposed new sub-grouping for intermediate-stage hepatocellular carcinoma using albumin-bilirubin grade. Oncology 2016;91:153-161.
28.
Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, Raoul JL, Sangro B: Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 2012;32:348-359.
29.
Geschwind JF, Gholam PM, Goldenberg A, Mantry P, Martin RC, Piperdi B, Zigmont E, Imperial J, Babajanyan S, Foreman PK, Cohn A: Use of transarterial chemoembolization (TACE) and sorafenib in patients with unresectable hepatocellular carcinoma: US regional analysis of the GIDEON registry. Liver Cancer 2016;5:37-46.
30.
Zhang B, Finn RS: Personalized clinical trials in hepatocellular carcinoma based on biomarker selection. Liver Cancer 2016;5:221-232.
31.
Kudo M: Regorafenib as second-line systemic therapy may change the treatment strategy and management paradigm for hepatocellular carcinoma. Liver Cancer 2016;5:235-244.
32.
Kudo M: Molecular targeted therapy for hepatocellular carcinoma: where are we now? Liver Cancer 2015;4:I-VII.
33.
Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N, Kaneko S, Tsubouchi H, Suh DJ, Furuse J, Okusaka T, Tanaka K, Matsui O, Wada M, Yamaguchi I, Ohya T, Meinhardt G, Okita K: Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011;47:2117-2127.
34.
Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, Yang J, Lu L, Tak WY, Yu X, Lee JH, Lin SM, Wu C, Tanwandee T, Shao G, Walters IB, Dela Cruz C, Poulart V, Wang JH: Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 2014;60:1697-1707.
35.
Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Guglielmi A, Paik SW, Reig M, Kim Y, Chau GY, Luca A, del Arbol LR, Leberre MA, Niu W, Nicholson K, Meinhardt G, Bruix J: Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol 2016;64:1090-1098.
36.
Kudo M: Immune checkpoint blockade in hepatocellular carcinoma. Liver Cancer 2015;4:201-207.
37.
Yamakado K, Miyayama S, Hirota S, Mizunuma K, Nakamura K, Inaba Y, Maeda A, Matsuo K, Nishida N, Aramaki T, Anai H, Koura S, Oikawa S, Watanabe K, Yasumoto T, Furuichi K, Yamaguchi M: Hepatic arterial embolization for unresectable hepatocellular carcinomas: do technical factors affect prognosis? Jpn J Radiol 2012;30:560-566.
38.
Ogasawara S, Chiba T, Ooka Y, Kanogawa N, Motoyama T, Suzuki E, Tawada A, Kanai F, Yoshikawa M, Yokosuka O: Efficacy of sorafenib in intermediate-stage hepatocellular carcinoma patients refractory to transarterial chemoembolization. Oncology 2014;87:330-341.
39.
Obi S, Sato S, Kawai T: Current status of hepatic arterial infusion chemotherapy. Liver Cancer 2015;4:188-199.
40.
Lin CC, Hung CF, Chen WT, Lin SM: Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein thrombosis: impact of early response to 4 weeks of treatment. Liver Cancer 2015;4:228-240.
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