Annals of Surgical Oncology

, Volume 21, Issue 3, pp 971–978 | Cite as

Long-Term Outcomes and Prognostic Factors with Reductive Hepatectomy and Sequential Percutaneous Isolated Hepatic Perfusion for Multiple Bilobar Hepatocellular Carcinoma

  • Takumi Fukumoto
  • Masahiro Tominaga
  • Masahiro Kido
  • Atsushi Takebe
  • Motofumi Tanaka
  • Kaori Kuramitsu
  • Ippei Matsumoto
  • Tetsuo Ajiki
  • Yonson KuEmail author
Hepatobiliary Tumors



Sorafenib is currently recommended as first-line therapy for patients with intermediate or advanced hepatocellular carcinoma (HCC) per Barcelona Clinic Liver Cancer staging. However, the median overall survival (OS) with sorafenib in these patients is 10.7 months with an overall response rate of 2 %. We retrospectively investigated the long-term outcomes and prognostic factors with reductive hepatectomy and sequential percutaneous isolated hepatic perfusion (PIHP) for refractory intermediate or advanced HCC.


A total of 68 patients who had intermediate or advanced stage HCC without extrahepatic metastases were scheduled for reductive hepatectomy plus PIHP. All patients underwent reductive hepatectomy and PIHP with mitomycin C 20–40 mg/m2 and/or doxorubicin 60–120 mg/m2 1–3 months after surgery (mean, 1.51 times/patient).


The objective response rate of PIHP was 70.6 % (complete plus partial response). The median OS of all 68 patients was 25 months, and the 5-year OS rate was 27.6 %. Univariate and multivariate analyses indicated that tumor response to PIHP and normalization of serum des-γ-carboxy prothrombin concentrations after PIHP were independent prognostic factors for OS.


The median OS of the study population treated by reductive hepatectomy and sequential PIHP was 25 months. This treatment strategy can offer a possible curative treatment to patients with refractory intermediate and advanced HCC.


Sorafenib Tace Remnant Liver Extrahepatic Metastasis Barcelona Clinic Liver Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by the new Therapeutic Technology Development Program 2000 from the Japanese Ministry of Education (Y.K.). The authors thank Dr. Kenichi Yoshimura for his valuable advice regarding the statistical analyses.


The authors declare no conflicts of interest.


  1. 1.
    Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology. 2000;31:1019–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–403.PubMedCrossRefGoogle Scholar
  3. 3.
    Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235:373–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Kim WR, Gores GJ, Benson JT, Therneau TM, Melton LJ 3rd. Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology. 2005;129:486–93.PubMedGoogle Scholar
  5. 5.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Shimamura Y, Gunven P, Ishii M, Ono M, Abe K. Debulking surgery and arterial embolization for unresectable liver cancer. Hepatogastroenterology. 1993;40:10–3.PubMedGoogle Scholar
  9. 9.
    Yamamoto M, Iizuka H, Matsuda M, Nagahori K, Miura K, Itakura J. The indications for tumor mass reduction surgery and subsequent multidisciplinary treatments in stage IV hepatocellular carcinoma. Surg Today. 1993;23:675–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Yamamoto K, Takenaka K, Kawahara N, Shimada M, Shirabe K, Itasaka H, et al. Indications for palliative reduction surgery in advanced hepatocellular carcinoma. The use of a remnant tumor index. Arch Surg. 1997;132:120–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Wakabayashi H, Ushiyama T, Ishimura K, Izuishi K, Karasawa Y, Masaki T, et al. Significance of reduction surgery in multidisciplinary treatment of advanced hepatocellular carcinoma with multiple intrahepatic lesions. J Surg Oncol. 2003;82:98–103.PubMedCrossRefGoogle Scholar
  12. 12.
    Inoue K, Nakamura T, Kinoshita T, Konishi M, Nakagohri T, Oda T, et al. Volume reduction surgery for advanced hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:362–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Kobayashi A, Takahashi S, Ishii H, Konishi M, Nakagohri T, Gotohda N, et al. Factors predicting survival in advanced T-staged hepatocellular carcinoma patients treated with reduction hepatectomy followed by transcatheter arterial chemoembolization. Eur J Surg Oncol. 2007;33:1019–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagano H, Miyamoto A, Wada H, Ota H, Marubashi S, Takeda Y, et al. Interferon-alpha and 5-fluorouracil combination therapy after palliative hepatic resection in patients with advanced hepatocellular carcinoma, portal venous tumor thrombus in the major trunk, and multiple nodules. Cancer. 2007;110:2493–501.PubMedCrossRefGoogle Scholar
  15. 15.
    Taniai N, Yoshida H, Mamada Y, Kawano Y, Mizuguchi Y, Akimaru K, et al. Is intraoperative adjuvant therapy effective for satellite lesions in patients undergoing reduction surgery for advanced hepatocellular carcinoma? Hepatogastroenterology. 2006;53:258–61.PubMedGoogle Scholar
  16. 16.
    Konishi M, Ryu M, Kinoshita T, Inoue K. Surgical treatment of hepatocellular carcinoma with direct removal of the tumor thrombus in the main portal vein. Hepatogastroenterology. 2001;48:1421–4.PubMedGoogle Scholar
  17. 17.
    Gotohda N, Kinoshita T, Konishi M, Nakagohri T, Takahashi S, Furuse J, et al. New indication for reduction surgery in patients with advanced hepatocellular carcinoma with major vascular involvement. World J Surg. 2006;30:431–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Bruix J, Llovet JM, Castells A, Montañá X, Brú C, Ayuso MC, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998;27:1578–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Ku Y, Iwasaki T, Tominaga M, Fukumoto T, Takahashi T, Kido M, et al. Reductive surgery plus percutaneous isolated hepatic perfusion for multiple advanced hepatocellular carcinoma. Ann Surg. 2004;239:53–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Ku Y, Saitoh M, Iwasaki T, Tominaga M, Maekawa Y, Shiki H, et al. Intraarterial infusion of high-dose adriamycin for unresectable hepatocellular carcinoma using direct hemoperfusion under hepatic venous isolation. Eur J Surg Oncol. 1993;19:387–92.PubMedGoogle Scholar
  21. 21.
    Ku Y, Fukumoto T, Iwasaki T, Tominaga M, Samizo M, Nishida T, et al. Clinical pilot study on high-dose intraarterial chemotherapy with direct hemoperfusion under hepatic venous isolation in patients with advanced hepatocellular carcinoma. Surgery. 1995;117:510–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Ku Y, Fukumoto T, Tominaga M, Iwasaki T, Maeda I, Kusunoki N, et al. Single catheter technique of hepatic venous isolation and extracorporeal charcoal hemoperfusion for malignant liver tumors. Am J Surg. 1997;173:103–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Ku Y, Iwasaki T, Fukumoto T, Tominaga M, Muramatsu S, Kusunoki N, et al. Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion. Ann Surg. 1998;227:519–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Group d’Etude et de Traitement du Carcinoma Hepatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med. 1995;332:1256–61.CrossRefGoogle Scholar
  25. 25.
    Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. 3rd English ed. Tokyo: Kanehara; 2010.Google Scholar
  26. 26.
    Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. International Union against Cancer. 7th ed. Oxford: Wiley; 2009.Google Scholar
  27. 27.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRefGoogle Scholar
  28. 28.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. 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. 2009;10:25–34.PubMedCrossRefGoogle Scholar
  29. 29.
    Villa E, Moles A, Ferretti I, Buttafoco P, Grottola A, Del Buono M, et al. Natural history of inoperable hepatocellular carcinoma: estrogen receptors’ status in the tumor is the strongest prognostic factor for survival. Hepatology. 2000;32:233–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Friedman MA. Primary hepatocellular cancer—present results and future prospects. Int J Radiat Oncol Biol Phys. 1983;9:1841–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62:479–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29:62–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Fujikawa T, Shiraha H, Ueda N, Takaoka N, Nakanishi Y, Matsuo N, et al. Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. J Biol Chem. 2007;282:8741–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Ikai I, Hatano E, Hasegawa S, Fujii H, Taura K, Uyama N, et al. Prognostic index for patients with hepatocellular carcinoma combined with tumor thrombosis in the major portal vein. J Am Coll Surg. 2006;202:431–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Pawlik TM, Poon RT, Abdalla EK, Ikai I, Nagorney DM, Belghiti J, et al. Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study. Surgery. 2005;137:403–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhou J, Tang ZY, Wu ZQ, Zhou XD, Ma ZC, Tan CJ, et al. Factors influencing survival in hepatocellular carcinoma patients with macroscopic portal vein tumor thrombosis after surgery, with special reference to time dependency: a single-center experience of 381 cases. Hepatogastroenterology. 2006;53:275–80.PubMedGoogle Scholar
  37. 37.
    Minagawa M, Makuuchi M, Takayama T, Ohtomo K. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg. 2001;233:379–84. PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Takumi Fukumoto
    • 1
  • Masahiro Tominaga
    • 1
  • Masahiro Kido
    • 1
  • Atsushi Takebe
    • 1
  • Motofumi Tanaka
    • 1
  • Kaori Kuramitsu
    • 1
  • Ippei Matsumoto
    • 1
  • Tetsuo Ajiki
    • 1
  • Yonson Ku
    • 1
    Email author
  1. 1.Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of MedicineKobe UniversityKobeJapan

Personalised recommendations