Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

M Ikeda, S Shimizu, T Sato, M Morimoto, Y Kojima, Y Inaba, A Hagihara, M Kudo, S Nakamori, S Kaneko, R Sugimoto, T Tahara, T Ohmura, K Yasui, K Sato, H Ishii, J Furuse, T Okusaka, M Ikeda, S Shimizu, T Sato, M Morimoto, Y Kojima, Y Inaba, A Hagihara, M Kudo, S Nakamori, S Kaneko, R Sugimoto, T Tahara, T Ohmura, K Yasui, K Sato, H Ishii, J Furuse, T Okusaka

Abstract

Background: Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC.

Patients and methods: We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5-7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m2, day 1, every 4-6 weeks) or Sor (400 mg bid). The primary end point was overall survival.

Results: A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38-0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated.

Conclusion: SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC.

Clinical trial registration: UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

Keywords: cisplatin; hepatic arterial infusion chemotherapy; hepatocellular carcinoma; randomized phase II trial; sorafenib.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Consort diagram.
Figure 2.
Figure 2.
Kaplan–Meier curves of overall survival (A) and time to progression (B) in the sorafenib arm (blue line) and sorafenib plus hepatic arterial infusion chemotherapy with cisplatin arm (green line). The tick marks indicate censored cases.
Figure 3.
Figure 3.
Forest plots showing subgroup analyses of the overall survival. TACE, transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; HR, hazard ratio; CI, confidence interval.

References

    1. Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol 2013; 14: e283–e288.
    1. Ikeda M, Mitsunaga S, Shimizu S et al. . Current status of hepatocellular carcinoma in Japan. Chin Clin Oncol 2013; 240.
    1. Kudo M. Treatment of advanced hepatocellular carcinoma with emphasis on hepatic arterial infusion chemotherapy and molecular targeted therapy. Liver Cancer 2012; 1: 62–70.
    1. Yoshikawa M, Ono N, Yodono H et al. . Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 2008; 38: 474–483.
    1. Heim M, Scharifi M, Zisowsky J et al. . The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines. Anticancer Drugs 2005; 16: 129–136.
    1. Wei Y, Shen N, Wang Z et al. . Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/beta-catenin signaling. Mol Cell Biochem 2013; 381: 139–144.
    1. Sun W, Powell M, O'Dwyer PJ et al. . Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 2010; 28: 2947–2951.
    1. Paz-Ares LG, Biesma B, Heigener D et al. . Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 2012; 30: 3084–3092.
    1. Xue C, Huang Y, Huang PY et al. . Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 2013; 24: 1055–1061.
    1. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975; 31: 103–115.
    1. Hagihara A, Ikeda M, Ueno H et al. . Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma. Cancer Sci 2014; 105: 354–358.
    1. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52–60.
    1. Sangro B, Gomez-Martin C, de la Mata M et al. . A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59: 81–88.
    1. El-Khoueiry AB, Melero I, Crocenzi TS et al. . Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015;33 (suppl; abstr LBA101).
    1. Ueshima KM, Yokosuka O et al. . Prospective randomized controlled phase III trial comparing the efficacy of sorafenib versus sorafenib in combination with low-dose cisplatin/fluorouracil hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma. J Hepatol 2016; 64: S209–S210 (Abstr LB04).

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner