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Original article
Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial
  1. Masatoshi Kudo1,
  2. Kazuomi Ueshima1,
  3. Masafumi Ikeda2,
  4. Takuji Torimura3,
  5. Nobukazu Tanabe4,
  6. Hiroshi Aikata5,
  7. Namiki Izumi6,
  8. Takahiro Yamasaki7,
  9. Shunsuke Nojiri8,
  10. Keisuke Hino9,
  11. Hidetaka Tsumura10,
  12. Teiji Kuzuya11,
  13. Norio Isoda12,
  14. Kohichiroh Yasui13,
  15. Hajime Aino14,
  16. Akio Ido15,
  17. Naoto Kawabe16,
  18. Kazuhiko Nakao17,
  19. Yoshiyuki Wada18,
  20. Osamu Yokosuka19,
  21. Kenichi Yoshimura20,
  22. Takuji Okusaka21,
  23. Junji Furuse22,
  24. Norihiro Kokudo23,
  25. Kiwamu Okita24,
  26. Philip James Johnson25,
  27. Yasuaki Arai26
  28. on behalf of the TACTICS study group
    1. 1 Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
    2. 2 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
    3. 3 Department of Gastroenterology and Hepatology, Kurume University School of Medicine, Kurume, Japan
    4. 4 Department of Gastroenterology, National Hospital Organisation Sendai Medical Center, Sendai, Japan
    5. 5 Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
    6. 6 Department of Gastroenterology, Musashino Red Cross Hospital, Tokyo, Japan
    7. 7 Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube-Yamaguchi, Japan
    8. 8 Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
    9. 9 Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
    10. 10 Department of Gastroenterology and Hepatology, Hyogo Cancer Center, Akashi, Japan
    11. 11 Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
    12. 12 Department of Medicine, Division of Gastroenterology, Jichi Medical University, Shimotsuke, Japan
    13. 13 Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
    14. 14 Division of Gastroenterology, Department of Medicine, Social Insurance Tagawa Hospital, Tagawa, Japan
    15. 15 Department of Gastroenterology and Hepatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
    16. 16 Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University School of Medicine, Aichi, Japan
    17. 17 Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
    18. 18 Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
    19. 19 Department of Gastroenterology, School of Medicine, Chiba University, Chiba, Japan
    20. 20 Center for Integrated Medical Research, Hiroshima University, Hiroshima, Japan
    21. 21 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
    22. 22 Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
    23. 23 Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
    24. 24 Deapartment of Medicine, Shunan Memorial Hospital, Kudamatsu, Yamaguchi, Japan
    25. 25 Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
    26. 26 Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan
    1. Correspondence to Dr Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; m-kudo{at}med.kindai.ac.jp

    Abstract

    Objective This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE.

    Design Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing.

    Results Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities.

    Conclusion TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials.

    Trial registration number NCT01217034.

    • transarterial chemoembolization
    • sorafenib
    • hepatocellular carcinoma
    • combination therapy with transarterial chemoembolisation and sorafenib
    • progression-free survival

    This is an open access article distributed in accordance with 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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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    Footnotes

    • MK and KU contributed equally.

    • Collaborators The following members are the TACTICS trial group: Masatosi Kudo, Kazuomi Ueshima, Takuji Torimura, Masafumi Ikeda, Nobukazu Tanabe, Hiroshi Aikata, Namiki Izumi, Takahiro Yamasaki, Shunsuke Nojiri, Keisuke Hino, Hidetaka Tsumura, Teiji Kuzuya, Norio Isoda, Kohichiroh Yasui, Hajime Aino, Akio Ido, Naoto Kawabe, Kazuhiko Nakao, Yohiyuki Wada, Osamu Yokosuka, Kenichi Yoshimura, Takashi Okusaka, Junji Furuse, Norihiro Kokudo, Kiwamu Okita, Philip James Johnson, Yasuaki Arai, Masao Fujimoto, Masahiko Koda, Eiichi Tomita, Yukio Osaki, Hisashi Hidaka, Hiroshi Ogawa, Takayuki Kogure, Atsuhiro Nakatsuka, Nobuyuki Enomoto, Katsuaki Tanaka, Masataka Seike, Toru ishikawa, Tetsuro Inokuma, Manabu Morimoto.

    • Contributors Masatoshi Kudo and Kazuomi Ueshima contributed to the study design, data collection, study analysis, manuscript writing, critical review of the manuscript and final approval of the manuscript submission. Masafumi Ikeda, Takuji Torimura, Nobukazu Tanabe, Hiroshi Aikata, Namiki Izumi, Takahiro Yamasaki, Shunsuke Nojiri, Keisuke Hino, Hidetaka Tsumura, Teiji Kuzuya, Norio Isoda, Kohichiroh Yasui, Hajime Aino, Akio Ido, Naoto Kawabe, Kazuhiko Nakao, Yoshiyuki Wada, Osamu Yokosuka, Takuji Okusaka, Junji Furuse, Norihiro Kokudo, Kiwamu Okita and Yasuaki Arai contributed to data collection, critical review of the manuscript and final approval of the manuscript submission. Philip Johnson contributed to interpretation of the data, critical review of the manuscript and final approval of the manuscript submission. Ken-ichi Yoshimura did the statistical analysis, critical review of the manuscript and final approval of the manuscript.

    • Funding This study was supported by the Japan Liver Oncology Group with funding from Bayer Yakuhin, Ltd., Japan, under a research contract.

    • Competing interests KM: Honoraria from Bayer, Eisai, MSD, Ajinomoto. Consulting or advisory role for Kowa, MSD, BMS, Bayer, Chugai, Taiho. Research funding from Chugai, Otuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie. IM: Honoraria from Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Taiho Pharmaceutical, Eli Lilly Japan, Daiichi-Sankyo, Yakult, Otsuka Pharmaceutical, Nobelpharma, EA Pharma, Teijin Pharma. Consulting or advisory role for Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD, Bristol Myers Sqiibb, Eli Lilly Japan, Sumitomo Dainippon, Daiichi-Sankyo, Teijin Pharma, Takara Bio. Research funding from Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Chugai, Bristol Myers Sqiibb, Merck Serono, Kowa, Nano Carrier, ASLAN, Daiichi-Sankyo., Sumitomo Dainippon, Novartis Pharma, Baxalta, Boehringer Ingelheim, Takara Bio. Board membership: ASLAN, Chugai. IN: Honoraria from Bayer, Gilead, Abbvie, Otuka. IN: Research funding from Abbvie GK. HK: Honoraria from MSD, Abbvie, Bristrol-Myers Squibb, Dainippon Sumitomo and Otsuka, Research funding from Gilead, Bristrol-Myers Squibb, MSD. IA: Honoraria from AbbVie GK, Bristol Myers Squibb, Gilead, Eisai. Research funding from AbbVie GK, Otsuka, MSD, Chugai, Eisai, Astellas, Takeda. KN: Research funding from Abbvie GK.Nakao K: Honoraria from Gilead. YO: Research funding from AstraZeneca, Asteras, Ajinomoto, AsahiKasei-Kurare Medical, Bayer Yakuhin, Bristol Myers Sqiibb, Chugai, Daiichi-Sankyo, Eisai, Kyowa Hakko Kirin, Kowa, Nihon Kayaku, MSD, Otsuka, Ono, Taiho, Tanabe-Mitsubishi, Takeda, Torii, Tsumura, Zeria. YK: Honoraria from Chugai, Eli Lilly, Taiho, Nippon Shinyaku. OT: Honoraria from Novartis, Taiho, Eli Lilly, Dainippon Sumitomo, Bayer, Yakult, FUJIFILM, AstraZeneca, Ono Pharmaceutical, EA Pharma, Nippon Chemiphar, Celgene, Chugai, Bristol Myers, Eisai, Pfizer, Teijin, Daiichi Sankyo, MSD, Shire, AbbVie, Takeda. Consulting or advisory role for Eli Lilly, Dainippon Sumitomo, Taiho, Zeria Pharmaceutical, Daiichi Sankyo, Bristol Myers. Research Funding from Eli Lilly, Eisai, Novartis, Yakult Honsha, Taiho, Kowa, Kyowa Hakko Kirin, Merck Serono, Ono Pharmaceutical, Bayer, Pfizer Japan, AstraZeneca, Dainippon Sumitomo, Chugai, Bristol Myers, Zeria Pharmaceutical. KN: Honoraria from Eisai. AY: Royalties from Sumitomo Bakelite. Research funding from Canon Medical Systems, Taiho Pharmaceutical, Eisai. Honoraria from Merit Medical Systems., Fuji Pharma, Terumo International Systems, Nippon Kayaku, Canon Medical Systems, Bristol Meyer Squibb, Sumitomo Bakelite, Bayer Pharmaceuticals, Boston Scientific Japan, Taiho Pharmaceutical, Guerbet Japan, Guerbet Asia Pacific.

    • Patient consent for publication Not required.

    • Ethics approval The study conformed to the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating institution.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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