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A multi-institutional phase II trial of hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombosis

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Abstract

Purpose

The objective of this study was to evaluate the response rate, survival, and adverse effects of hepatic arterial infusion chemotherapy (HAIC) using cisplatin in patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT).

Methods

Twenty-five patients of advanced HCC with PVTT in the main or first branch, having no prior history of chemotherapy, measurable lesions, adequate liver and renal function, and adequate bone marrow reserve, were enrolled. Cisplatin was administered at the dose of 65 mg/m2 via the proper hepatic artery. Treatment was repeated every 4–6 weeks for a maximum of six courses until the appearance of evidence of tumor progression or unacceptable toxicity.

Results

The median number of treatments was 3 (range 1–6). Among the 25 enrolled patients, complete response was achieved in 1 (4 %) patient and partial response in 6 (24 %), corresponding to a response rate of 28 % (95 % CI 12–49 %). The median progression-free and overall survival times and the 1-, 2-, and 3-year survival rates in the enrolled patients were 3.6 and 7.6 months and 40.3, 36.0, 20 %, respectively. Four of the seven patients who showed complete or partial response survived for more than 3 years. The main grade 3/4 non-hematological adverse events of this treatment were elevation of the serum aspartate aminotransferase (44 %) and alanine aminotransferase (24 %).

Conclusion

HAIC with cisplatin exerts moderate activity with mild toxicity in advanced HCC patients with PVTT. Especially, markedly prolonged survival can be expected in patients who respond to this treatment.

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Abbreviations

HCC:

Hepatocellular carcinoma

PVTT:

Portal vein tumor thrombosis

HAIC:

Hepatic arterial infusion chemotherapy

AFP:

Alpha-fetoprotein

PIVKA II:

Protein induced by vitamin K absence or antagonist-II

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

References

  1. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127

    Article  PubMed  CAS  Google Scholar 

  2. Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379:1245–1255

    Article  PubMed  Google Scholar 

  3. Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, Kojiro M, Makuuchi M (2011) Management of hepatocellular carcinoma in Japan: consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 29:339–364

    Article  PubMed  Google Scholar 

  4. Yamashita T, Kaneko S (2012) Treatment strategies for hepatocellular carcinoma in Japan. Hepatol Res. doi:10.1111/j.1872-034X.2012.01029.x

    Google Scholar 

  5. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  6. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34

    Article  PubMed  CAS  Google Scholar 

  7. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle PR, Santoro A, Beaugrand M, Sangiovanni A, Porta C, Gerken G, Marrero JA, Nadel A, Shan M, Moscovici M, Voliotis D, Llovet JM (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 57:821–829

    Article  PubMed  CAS  Google Scholar 

  8. Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 48:1452–1465

    Article  PubMed  CAS  Google Scholar 

  9. Ensminger WD, Gyves JW (1983) Regional chemotherapy of neoplastic diseases. Pharmacol Ther 21:277–293

    Article  PubMed  CAS  Google Scholar 

  10. Tzoracoleftherakis EE, Spiliotis JD, Kyriakopoulou T, Kakkos SK (1999) Intra-arterial versus systemic chemotherapy for non-operable hepatocellular carcinoma. Hepatogastroenterology 46:1122–1125

    PubMed  CAS  Google Scholar 

  11. Kondo M, Morimoto M, Numata K, Nozaki A, Tanaka K (2011) Hepatic arterial infusion therapy with a fine powder formulation of cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Jpn J Clin Oncol 41:69–75

    Article  PubMed  Google Scholar 

  12. Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, Sumie S, Yano Y, Okuda K, Sata M (2002) Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 95:588–595

    Article  PubMed  Google Scholar 

  13. Lai YC, Shih CY, Jeng CM, Yang SS, Hu JT, Sung YC, Liu HT, Hou SM, Wu CH, Chen TK (2003) Hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol 9:2666–2670

    PubMed  CAS  Google Scholar 

  14. Cheong JY, Lee KM, Cho SW, Won JH, Kim JK, Wang HJ, Hahm KB, Kim JH (2005) Survival benefits of intra-arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Hepatol Res 32:127–133

    Article  PubMed  CAS  Google Scholar 

  15. Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, Kitai S, Ishikawa E, Yada N, Inoue T, Hagiwara S, Minami Y, Chung H (2010) Hepatic arterial infusion chemotherapy using low-dose 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma. Oncology 78(Suppl 1):148–153

    Article  PubMed  CAS  Google Scholar 

  16. Ota H, Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, Nakamura M, Damdinsuren B, Wada H, Marubashi S, Miyamoto A, Dono K, Umeshita K, Nakamori S, Wakasa K, Monden M (2005) Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-alpha and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression. Br J Cancer 93:557–564

    Article  PubMed  CAS  Google Scholar 

  17. Obi S, Yoshida H, Toune R, Unuma T, Kanda M, Sato S, Tateishi R, Teratani T, Shiina S, Omata M (2006) Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer 106:1990–1997

    Article  PubMed  CAS  Google Scholar 

  18. Uka K, Aikata H, Takaki S, Miki D, Kawaoka T, Jeong SC, Takahashi S, Toyota N, Ito K, Chayama K (2007) Pretreatment predictor of response, time to progression, and survival to intraarterial 5-fluorouracil/interferon combination therapy in patients with advanced hepatocellular carcinoma. J Gastroenterol 42:845–853

    Article  PubMed  CAS  Google Scholar 

  19. Nagano H, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Tomimaru Y, Osuga K, Umeshita K, Doki Y, Mori M (2011) Long-term outcome of combined interferon-α and 5-fluorouracil treatment for advanced hepatocellular carcinoma with major portal vein thrombosis. Oncology 80:63–69

    Article  PubMed  CAS  Google Scholar 

  20. Yamashita T, Arai K, Sunagozaka H, Ueda T, Terashima T, Yamashita T, Mizukoshi E, Sakai A, Nakamoto Y, Honda M, Kaneko S (2011) Randomized, phase II study comparing interferon combined with hepatic arterial infusion of fluorouracil plus cisplatin and fluorouracil alone in patients with advanced hepatocellular carcinoma. Oncology 81:281–290

    Article  PubMed  CAS  Google Scholar 

  21. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (1995) A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 332:1294–1296

    Article  Google Scholar 

  22. Pelletier G, Ducreux M, Gay F, Luboinski M, Hagège H, Dao T, Van Steenbergen W, Buffet C, Rougier P, Adler M, Pignon JP, Roche A (1998) Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. J Hepatol 29:129–134

    Article  PubMed  CAS  Google Scholar 

  23. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171

    Article  PubMed  CAS  Google Scholar 

  24. Yoshikawa M, Ono N, Yodono H, Ichida T, Nakamura H (2008) Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 38:474–483

    Article  PubMed  CAS  Google Scholar 

  25. World Health Organization (1979) WHO handbook for reporting results of cancer treatment, vol 48. World Health Organization, Geneva

    Google Scholar 

  26. Simon R (1987) How large should a phase II trial of a new drug be? Cancer Treat Rep 71:1079–1085

    PubMed  CAS  Google Scholar 

  27. Monden M, Sakon M, Sakata Y, Ueda Y, Hashimura E, FAIT Research Group (2012) 5-fluorouracil arterial infusion + interferon therapy for highly advanced hepatocellular carcinoma: a multicenter, randomized, phase II study. Hepatol Res 42:150–165

    Article  PubMed  CAS  Google Scholar 

  28. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH, Sato KT, Wang E, Gupta R, Benson AB, Newman SB, Omary RA, Abecassis M, Kulik L (2010) Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138:52–64

    Article  PubMed  CAS  Google Scholar 

  29. Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, Ettorre GM, Salvatori R, Giampalma E, Geatti O, Wilhelm K, Hoffmann RT, Izzo F, Iñarrairaegui M, Maini CL, Urigo C, Cappelli A, Vit A, Ahmadzadehfar H, Jakobs TF, Lastoria S, European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY) (2011) Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 54:868–878

    Article  PubMed  Google Scholar 

  30. Kang YK, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Burock K, Zou J, Voliotis D, Cheng AL (2008) Sorafenib is effective in patients from the Asia-Pacific region with hepatocellular carcinoma (HCC): subgroup analysis of effect of macroscopic vascular invasion, extrahepatic spread, and ECOG performance status on outcome. Hepatology 48(suppl 1):976A (abstr 1505)

    Google Scholar 

  31. Chen FS, Cui YZ, Luo RC, Wu J, Zhang H (2008) Coadministration of sorafenib and cisplatin inhibits proliferation of hepatocellular carcinoma HepG2 cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao 28:1684–1687

    PubMed  CAS  Google Scholar 

  32. Eicher C, Dewerth A, Thomale J, Ellerkamp V, Hildenbrand S, Warmann SW, Fuchs J, Armeanu-Ebinger S (2013) Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts. Br J Cancer 108:334–341

    Article  PubMed  CAS  Google Scholar 

  33. Sun W, Powell M, O’Dwyer PJ, Catalano P, Ansari RH, Benson AB 3rd (2010) 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 28:2947–2951

    Article  PubMed  CAS  Google Scholar 

  34. Xue C, Huang Y, Huang PY, Yu QT, Pan JJ, Liu LZ, Song XQ, Lin SJ, Wu JX, Zhang JW, Zhao HY, Xu F, Liu JL, Hu ZH, Zhao LP, Zhao YY, Wu X, Zhang J, Ma YX, Zhang L (2013) Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 24:1055–1061

    Article  PubMed  CAS  Google Scholar 

  35. Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A, NSCLC [non-small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group (2012) 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 30:3084–3092

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by Grants-in-Aid for Cancer Research and for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour, and Welfare of Japan and National Cancer Center Research and Development Fund (23-A-22).

Conflict of interest

None.

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Authors and Affiliations

  1. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Masafumi Ikeda, Takuji Okusaka & Hideki Ueno

  2. Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Masafumi Ikeda, Junji Furuse & Shuichi Mitsunaga

  3. Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan

    Junji Furuse

  4. Department of Interventional and Diagnostic Radiology, Aichi Cancer Center, Nagoya, Japan

    Hidekazu Yamaura & Yoshitaka Inaba

  5. Division of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan

    Yoshito Takeuchi & Yasuaki Arai

  6. Division of Diagnostic Radiology, National Cancer Center Hospital East, Kashiwa, Japan

    Mitsuo Satake

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  1. Masafumi Ikeda
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  2. Takuji Okusaka
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Correspondence to Masafumi Ikeda.

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Ikeda, M., Okusaka, T., Furuse, J. et al. A multi-institutional phase II trial of hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol 72, 463–470 (2013). https://doi.org/10.1007/s00280-013-2222-x

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  • DOI: https://doi.org/10.1007/s00280-013-2222-x

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