Effect of vitamin K2 on the recurrence of hepatocellular... : Hepatology (original) (raw)

Hepatobiliary Malginances

Yoshida, Haruhiko1; Shiratori, Yasushi2; Kudo, Masatoshi3; Shiina, Shuichiro1; Mizuta, Toshihiko4; Kojiro, Masamichi5; Yamamoto, Kyosuke6; Koike, Yukihiro7; Saito, Kenichi8; Koyanagi, Nozomu8; Kawabe, Takao1; Kawazoe, Seiji9; Kobashi, Haruhiko2; Kasugai, Hiroshi10; Osaki, Yukio11; Araki, Yasuyuki12; Izumi, Namiki13; Oka, Hiroko14; Tsuji, Kunihiko15; Toyota, Joji16; Seki, Toshihito17; Osawa, Toshiya18; Masaki, Naohiko19; Ichinose, Masao20; Seike, Masataka21; Ishikawa, Akihisa22; Ueno, Yoshiyuki23; Tagawa, Kazumi24; Kuromatsu, Ryoko25; Sakisaka, Shotaro26; Ikeda, Hiroshi27; Kuroda, Hidekatsu28; Kokuryu, Hiroyuki29; Yamashita, Tatsuya30; Sakaida, Isao31; Katamoto, Tetsuo32; Kikuchi, Kentaro33; Nomoto, Minoru34; Omata, Masao1

1_Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan_

2_Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan_

3_Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan_

4_Department of Internal Medicine, Saga University, Saga, Japan_

5_First Department of Pathology, Kurume University, Fukuoka, Japan_

6_Takagi Hospital, Fukuoka, Japan_

7_Department of Gastroenterology and Hepatology, Kanto Central Hospital, Tokyo, Japan_

8_Clinical Research Center, Eisai Co., Ltd., Tokyo, Japan_

9_Department of Internal Medicine, Saga Prefectural Hospital Koseikan, Saga, Japan_

10_Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan_

11_Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan_

12_Department of Medicine, Hiroshima City Hospital, Hiroshima, Japan_

13_Department of Gastroenterology and Hepatology, Musashino Red-Cross Hospital, Tokyo, Japan_

14_Department of Gastroenterology, Osaka City General Hospital, Osaka, Japan_

15_Center for Gastroenterology, Teine Keijinkai Hospital, Hokkaido, Japan_

16_Department of Gastroenterology, Sapporo Kosei General Hospital, Hokkaido, Japan_

17_Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan_

18_Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan_

19_Department of Gastroenterology, International Medical Center of Japan, Tokyo, Japan_

20_Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan_

21_Department of Gastroenterology, Oita University Faculty of Medicine, Oita, Japan_

22_Department of Internal Medicine, Hitachi General Hospital, Ibaraki, Japan_

23_Department of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi, Japan_

24_Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan_

25_Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan_

26_Department of Gastroenterology, Fukuoka University School of Medicine, Fukuoka, Japan_

27_Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan_

28_Department of Gastroenterology and Hepatology, Iwate Medical University, Iwate, Japan_

29_Department of Gastroenterology, Shizuoka General Hospital, Shizuoka, Japan_

30_Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Ishikawa, Japan_

31_Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan_

32_Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan_

33_The Fourth Department of Internal Medicine, Teikyo University School of Medicine, Kanagawa, Japan_

34_Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan_

Address reprint requests to: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail:[email protected]

Abstract

Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P = 0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007.

Conclusion:

Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study. (Hepatology 2011;)