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Open Access 01-06-2015 | Original Article—Liver, Pancreas, and Biliary Tract

Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial

Authors: Kiwamu Okita, Namiki Izumi, Kenji Ikeda, Yukio Osaki, Kazushi Numata, Masafumi Ikeda, Norihiro Kokudo, Kazuho Imanaka, Shuhei Nishiguchi, Shunsuke Kondo, Yoichi Nishigaki, Susumu Shiomi, Kazuomi Ueshima, Norio Isoda, Yoshiyasu Karino, Masatoshi Kudo, Katsuaki Tanaka, Shuichi Kaneko, Hisataka Moriwaki, Masatoshi Makuuchi, Takuji Okusaka, Norio Hayashi, Yasuo Ohashi, Hiromitsu Kumada, The Peretinoin Study Group

Published in: Journal of Gastroenterology | Issue 6/2015

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Abstract

Background

This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial.

Methods

This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression.

Results

Survey data were collected from all patients (n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day (n = 132), peretinoin 300 mg/day (n = 131), and placebo (n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group (n = 105) was significantly longer than that of the placebo group (n = 108) (hazard ratio 0.575, 95 % CI 0.341–0.967; P = 0.0347).

Conclusions

Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable.
Literature
1.
go back to reference Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: gLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRef Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: gLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRef
2.
go back to reference 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;27:1485–91.PubMedCentralPubMedCrossRef 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;27:1485–91.PubMedCentralPubMedCrossRef
3.
go back to reference Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.PubMedCrossRef Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.PubMedCrossRef
4.
go back to reference El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817–23.PubMedCrossRef El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817–23.PubMedCrossRef
5.
go back to reference Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011;29:339–64.PubMedCrossRef Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011;29:339–64.PubMedCrossRef
6.
go back to reference Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138:299–306.PubMedCrossRef Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138:299–306.PubMedCrossRef
7.
go back to reference Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32:228–32.PubMedCrossRef Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32:228–32.PubMedCrossRef
8.
go back to reference Suou T, Mitsuda A, Koda M, et al. Interferon alpha inhibits intrahepatic recurrence in hepatocellular carcinoma with chronic hepatitis C: a pilot study. Hepatol Res. 2001;20:301–11.PubMedCrossRef Suou T, Mitsuda A, Koda M, et al. Interferon alpha inhibits intrahepatic recurrence in hepatocellular carcinoma with chronic hepatitis C: a pilot study. Hepatol Res. 2001;20:301–11.PubMedCrossRef
9.
go back to reference Kubo S, Nishiguchi S, Hirohashi K, et al. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med. 2001;134:963–7.PubMedCrossRef Kubo S, Nishiguchi S, Hirohashi K, et al. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med. 2001;134:963–7.PubMedCrossRef
10.
go back to reference Breitenstein S, Dimitroulis D, Petrowsky H, et al. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg. 2009;96:975–81.PubMedCrossRef Breitenstein S, Dimitroulis D, Petrowsky H, et al. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg. 2009;96:975–81.PubMedCrossRef
11.
go back to reference Mathurin P, Raynard B, Dharancy S, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247–61.PubMedCrossRef Mathurin P, Raynard B, Dharancy S, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247–61.PubMedCrossRef
12.
go back to reference Samuel M, Chow PK, Chan Shih-Yen E, et al. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst Rev. 2009;1:CD001199.PubMed Samuel M, Chow PK, Chan Shih-Yen E, et al. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst Rev. 2009;1:CD001199.PubMed
13.
go back to reference Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc. 1979;38:2528–34.PubMed Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc. 1979;38:2528–34.PubMed
14.
go back to reference Araki H, Shidoji Y, Yamada Y, et al. Retinoid agonist activities of synthetic geranyl geranoic acid derivatives. Biochem Biophys Res Commun. 1995;209:66–72.PubMedCrossRef Araki H, Shidoji Y, Yamada Y, et al. Retinoid agonist activities of synthetic geranyl geranoic acid derivatives. Biochem Biophys Res Commun. 1995;209:66–72.PubMedCrossRef
15.
go back to reference Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561–7.PubMedCrossRef Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561–7.PubMedCrossRef
16.
go back to reference Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340:1046–7.PubMedCrossRef Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340:1046–7.PubMedCrossRef
17.
go back to reference Okusaka T, Ueno H, Ikeda M, et al. Phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK-333. Hepatol Res. 2011;41:542–52.PubMedCrossRef Okusaka T, Ueno H, Ikeda M, et al. Phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK-333. Hepatol Res. 2011;41:542–52.PubMedCrossRef
18.
go back to reference Okita K, Izumi N, Matsui O, et al. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol. 2014;. doi:10.1007/s00535-014-0956-9. Okita K, Izumi N, Matsui O, et al. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol. 2014;. doi:10.​1007/​s00535-014-0956-9.
19.
go back to reference Llovet JM, Di Bisceglie AM, Bruix J, et al. Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.PubMedCrossRef Llovet JM, Di Bisceglie AM, Bruix J, et al. Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.PubMedCrossRef
20.
go back to reference Nakashima Y, Nakashima O, Tanaka M, et al. Portal vein invasion and intrahepatic micrometastasis in small hepatocellular carcinoma by gross type. Hepatol Res. 2003;26:142–7.PubMedCrossRef Nakashima Y, Nakashima O, Tanaka M, et al. Portal vein invasion and intrahepatic micrometastasis in small hepatocellular carcinoma by gross type. Hepatol Res. 2003;26:142–7.PubMedCrossRef
21.
go back to reference Takai K, Okuno M, Yasuda I, et al. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology. 2005;48:39–45.PubMedCrossRef Takai K, Okuno M, Yasuda I, et al. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology. 2005;48:39–45.PubMedCrossRef
22.
go back to reference Okada H, Honda M, Campbell JS, et al. Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. Cancer Res. 2012;72:4459–71.PubMedCrossRef Okada H, Honda M, Campbell JS, et al. Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. Cancer Res. 2012;72:4459–71.PubMedCrossRef
Metadata
Title
Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial
Authors
Kiwamu Okita
Namiki Izumi
Kenji Ikeda
Yukio Osaki
Kazushi Numata
Masafumi Ikeda
Norihiro Kokudo
Kazuho Imanaka
Shuhei Nishiguchi
Shunsuke Kondo
Yoichi Nishigaki
Susumu Shiomi
Kazuomi Ueshima
Norio Isoda
Yoshiyasu Karino
Masatoshi Kudo
Katsuaki Tanaka
Shuichi Kaneko
Hisataka Moriwaki
Masatoshi Makuuchi
Takuji Okusaka
Norio Hayashi
Yasuo Ohashi
Hiromitsu Kumada
The Peretinoin Study Group
Publication date
01-06-2015
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 6/2015
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-014-0996-1