Medical Oncology

, 30:381 | Cite as

New progress of non-surgical treatments for hepatocellular carcinoma

  • Ji-Wen Cheng
  • Yi LvEmail author
Review Article


Many non-surgical treatments of hepatocellular carcinoma (HCC) have significantly improved in the last few decades and have shown survival benefits for selected patients with HCC. Today ablation can improve survival in individuals diagnosed in early HCC and even offer a curative treatment in selected candidates. Patients with intermediate-stage HCC benefit from transarterial chemoembolization (TACE). Drug-eluting bead transarterial chemoembolization (DEB-TACE) has shown a better combined ischemic and cytotoxic effect locally and less system toxicity when compared with conventional TACE. Those diagnosed at advanced stage benefit from sorafenib. In addition to TACE and sorafenib which could improve survival for selected patients, three-dimensional conformal radiotherapy treatment (3-DCRT), selection internal radiation therapy and systemic chemotherapy have also shown anti-tumor activity in the treatment of advanced HCC, but their survival benefit have not been proven. The limited effects of single therapy suggested that the combination would enhance the overall treatment effect. Other potential non-surgical therapies like gene therapy and immunotherapy are still in testing phases, except for some small-scale clinical trials which have been reported to show some beneficial effect. Here, we review the current non-surgical treatments in HCC and the new advances in this field.


Hepatocellular carcinoma Non-surgical treatment Transarterial chemoembolization Three-dimensional conformal radiotherapy treatment (3-DCRT) Selection internal radiation therapy (SIRT) Systemic chemotherapy 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.PubMedCrossRefGoogle Scholar
  2. 2.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.PubMedCrossRefGoogle Scholar
  3. 3.
    Malagari K, Pomoni M, Kelekis A, Pomoni A, Dourakis S, Spyridopoulos T, Moschouris H, Emmanouil E, Rizos S, Kelekis D. Prospective randomized comparison of chemoembolization with doxorubicin eluting beads and bland embolization with Beadblock for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010;33(3):541–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Nicolini A, Martinetti L, Crespi S, Maggioni M, Sangiovanni A. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(3):327–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Malagari K. Drug-eluting particles in the treatment of_HCC: chemoembolization with doxorubicin-loaded DC Bead. Expert Rev Anticancer Ther. 2008;8(10):1643–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, Pitton M, Sergent G, Pfammatter T, Terraz S, et al. Prospective randomised study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Vogl TJ, Lammer J, Lencioni R, Malagari K, Watkinson A, Pilleul F, Denys A, Lee C. Liver, gastrointestinal, and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: results from the PRECISION V randomized trial. AJR Am J Roentgenol. 2011;197(4):W562–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Muros-Ortega M, Díaz-Carrasco MS, Vila-Clérigues N, Mendoza-Otero F, de la Rubia A, Capel Alemán A. Experience using doxorubicin-loaded DC Beads during hepatic chemoembolisation. Farm Hosp. 2011;35(4):172–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis. 2010;30(1):61–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. 2010;52(2):762–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104(2):514–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgrò G, Burroughs AK. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocellular carcinoma: a meta-analysis. J Hepatol. 2010;52(3):380–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Choi D, Lim HK, Rhim H, Kim YS, Lee WJ, Paik SW, Koh KC, Lee JH, Choi MS, Yoo BC. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series. Eur Radiol. 2007;17(3):684–92.PubMedCrossRefGoogle Scholar
  14. 14.
    Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47(1):82–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Sala M, Llovet JM, Vilana R, Bianchi L, Solé M, Ayuso C, Brú C, Bruix J. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology. 2004;40(6):1352–60.PubMedCrossRefGoogle Scholar
  16. 16.
    Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, Ishikawa T, Koike Y, Yoshida H, Kawabe T, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129(1):122–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Yoshida H, Kawabe T, Omata M. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer. 2005;103(6):1201–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Brunello F, Veltri A, Carucci P, Pagano E, Ciccone G, Moretto P, Sacchetto P, Gandini G, Rizzetto M. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled trial. Scand J Gastroenterol. 2008;43(6):727–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Feng K, Yan J, Li X, Xia F, Ma K, Wang S, Bie P, Dong J. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012;57(4):794–802.PubMedCrossRefGoogle Scholar
  20. 20.
    Hasegawa K, Makuuchi M, Takayama T, Kokudo N, Arii S, Okazaki M, Okita K, Omata M, Kudo M, Kojiro M, et al. Surgical resection vs. percutaneous ablation for hepatocellular carcinoma; a preliminary report of the Japanese nationwide survey. J Hepatol. 2008;49(4):589–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim H, Rhim H, Choi D, Lim HK, Kim YS, Lee WJ, Joh JW. Recurrence and treatment pattern in long-term survivors with hepatocellular carcinoma: a comparison between radiofrequency ablation and surgery as a first-line treatment. World J Surg. 2010;34(8):1881–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Song I, Rhim H, Lim HK, Kim YS, Choi D. Percutaneous radiofrequency ablation of hepatocellular carcinoma abutting the diaphragm and gastrointestinal tracts with the use of artificial ascites: safety and technical efficacy in 143 patients. Eur Radiol. 2009;19(11):2630–40.PubMedCrossRefGoogle Scholar
  23. 23.
    Rhim H, Lim HK, Kim YS, Choi D. Percutaneous radiofrequency ablation with artificial ascites for hepatocellular carcinoma in the hepatic dome: initial experience. AJR Am J Roentgenol. 2008;190(1):91–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Uehara T, Hirooka M, Ishida K, Hiraoka A, Kumagi T, Kisaka Y, Hiasa Y, Onji M. Percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinoma with artificially induced pleural effusion and ascites. J Gastroenterol. 2007;42(4):306–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Nishimura M, Nouso K, Kariyama K, Wakuta A, Kishida M, Wada N, Higashi T, Yamamoto K. Safety and efficacy of radiofrequency ablation with artificial ascites for hepatocellular carcinoma. Acta Med Okayama. 2012;66(3):279–84.PubMedGoogle Scholar
  26. 26.
    Zhang YJ, Liang HH, Chen MS, Guo RP, Li JQ, Zheng Y, Zhang YQ, Lau WY. Hepatocellular carcinoma treated with radiofrequency ablation with or without ethanol injection: a prospective randomized trial. Radiology. 2007;244(2):599–607.PubMedCrossRefGoogle Scholar
  27. 27.
    Yamakado K, Nakatsuka A, Takaki H, Yokoi H, Usui M, Sakurai H, Isaji S, Shiraki K, Fuke H, Uemoto S, et al. Early-stage hepatocellular carcinoma: radiofrequency ablation combined with chemoembolization versus hepatectomy. Radiology. 2008;247(1):260–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamagiwa K, Shiraki K, Yamakado K, Mizuno S, Hori T, Yagi S, Hamada T, Iida T, Nakamura I, Fujii K, et al. Survival rates according to the cancer of liver Italian Program scores of 345 hepatocellular carcinoma patients after multimodality treatments during a 10-year period in a retrospective study. J Gastroenterol Hepatol. 2008;23(3):482–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Solazzo SA, Ahmed M, Schor-Bardach R, Yang W, Girnun GD, Rahmanuddin S, Levchenko T, Signoretti S, Spitz DR, Torchilin V, et al. Liposomal doxorubicin increases radiofrequency ablation-induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways. Radiology. 2010;255(1):62–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Goldberg SN, Kamel IR, Kruskal JB, Reynolds K, Monsky WL, Stuart KE, Ahmed M, Raptopoulos V. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. AJR Am J Roentgenol. 2002;179(1):93–101.PubMedCrossRefGoogle Scholar
  31. 31.
    Olivo M, Valenza F, Buccellato A, Scala L, Virdone R, Sciarrino E, Di Piazza S, Marrone C, Orlando A, Fusco G, et al. Transcatheter arterial chemoembolisation for hepatocellular carcinoma in cirrhosis: survival rate and prognostic factors. Dig Liver Dis. 2010;42(7):515–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Takayasu K, Arii S, Ikai I, Kudo M, Matsuyama Y, Kojiro M, Makuuchi M. Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis. AJR Am J Roentgenol. 2010;194(3):830–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Bruix J, Llovet JM, Castells A, Montañá X, Brú C, Ayuso MC, Vilana R, Rodés J. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998;27(6):1578–83.PubMedCrossRefGoogle Scholar
  35. 35.
    Pelletier G, Ducreux M, Gay F, Luboinski M, Hagège H, Dao T, Van Steenbergen W, Buffet C, Rougier P, Adler M, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol. 1998;29(1):129–34.CrossRefGoogle Scholar
  36. 36.
    Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37(2):429–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Cammà C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, Andreone P, Craxì A, Cottone M. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002;224(1):47–54.PubMedCrossRefGoogle Scholar
  38. 38.
    Malagari K, Chatzimichael K, Alexopoulou E, Kelekis A, Hall B, Dourakis S, Delis S, Gouliamos A, Kelekis D. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol. 2008;31(2):269–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Grosso M, Vignali C, Quaretti P, Nicolini A, Melchiorre F, Gallarato G, Bargellini I, Petruzzi P, Massa Saluzzo C, Crespi S, et al. Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multi-centre study. Cardiovasc Intervent Radiol. 2008;31(6):1141–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Reyes DK, Vossen JA, Kamel IR, Azad NS, Wahlin TA, Torbenson MS, Choti MA, Geschwind JF. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J. 2009;15(6):526–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Seki A, Hori S, Kobayashi K, Narumiya S. Transcatheter arterial chemoembolization with epirubicin-loaded superabsorbent polymer microspheres for 135 hepatocellular carcinoma patients: single-center experience. Cardiovasc Intervent Radiol. 2011;34(3):557–65.PubMedCrossRefGoogle Scholar
  42. 42.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.PubMedCrossRefGoogle Scholar
  43. 43.
    Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology. 2010;51(4):1274–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhu AX. Systemic treatment of hepatocellular carcinoma: dawn of a new era? Ann Surg Oncol. 2010;17(5):1247–56.PubMedCrossRefGoogle Scholar
  46. 46.
    Tanaka S, Arii S. Current status of molecularly targeted therapy for hepatocellular carcinoma: basic science. Int J Clin Oncol. 2010;15(3):235–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheng A, Kang Y, Lin D, Park J, Kudo M, Qin S, Omata M, Pitman Lowenthal S W, Lanzalone S, Yang L, et al. Phase III trial of sunitinib (Su) versus sorafenib (So) in advanced hepatocellular carcinoma (HCC). J Clin Oncol 2011; 29 (suppl) : 4000 (abstr). Available at:
  48. 48.
    Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, Hirte HW, Eder JP, Lenz HJ, Schwartz B. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. 2007;12(4):426–37.PubMedCrossRefGoogle Scholar
  49. 49.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Hampton T. Cancer drug trials show modest benefit: drugs target liver, gastric, head and neck cancers. JAMA. 2007;298(3):273–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Flaherty KT. Sorafenib: delivering a targeted drug to the right targets. Expert Rev Anticancer Ther. 2007;7(5):617–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Di Costanzo GG, Tortora R, Iodice L, Lanza AG, Lampasi F, Tartaglione MT, Picciotto FP, Mattera S, De Luca M. Safety and effectiveness of sorafenib in patients with hepatocellular carcinoma in clinical practice. Dig Liver Dis. 2012;44(9):788–92.PubMedCrossRefGoogle Scholar
  53. 53.
    Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle PR, Santoro A, Beaugrand M, Sangiovanni A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: sub analyses of a phase III trial. J Hepatol. 2012;57(4):821–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, 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(1):25–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang T, Ding X, Wei D, Cheng P, Su X, Liu H, Wang D, Gao H. Sorafenib improves the survival of patients with advanced hepatocellular carcinoma: a meta-analysis of randomized trials. Anticancer Drugs. 2010;21(3):326–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140(5):1410–26.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhu AX. Beyond sorafenib: novel targeted therapies for advanced hepatocellular carcinoma. Expert Opin Investig Drugs. 2010;19(5):663–72.PubMedCrossRefGoogle Scholar
  58. 58.
    Rimassa L, Santoro A. The present and the future landscape of treatment of advanced hepatocellular carcinoma. Dig Liver Dis. 2010;42(Suppl 3):S273–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Wörns MA, Schuchmann M, Düber C, Otto G, Galle PR, Weinmann A. Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment. Oncology. 2010;79(1–2):85–92.PubMedCrossRefGoogle Scholar
  60. 60.
    Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat Oncol. 2001;11(3):240–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Liu MT, Li SH, Chu TC, Hsieh CY, Wang AY, Chang TH, Pi CP, Huang CC, Lin JP. Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization. Jpn J Clin Oncol. 2004;34(9):532–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Kim TH, Kim DY, Park JW, Kim YI, Kim SH, Park HS, Lee WJ, Park SJ, Hong EK, Kim CM. Three-dimensional conformal radiotherapy of unresectable hepatocellular carcinoma patients for whom transcatheter arterial chemoembolization was ineffective or unsuitable. Am J Clin Oncol. 2006;29(6):568–75.PubMedCrossRefGoogle Scholar
  63. 63.
    Ohto M, Yoshikawa M, Saisho H, Ebara M, Sugiura N. Nonsurgical treatment of hepatocellular carcinoma in cirrhotic patients. World J Surg. 1995;19(1):42–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Shirai S, Sato M, Suwa K, Kishi K, Shimono C, Kawai N, Tanihata H, Minamiguchi H, Nakai M. Single photon emission computed tomography-based three-dimensional conformal radiotherapy for three-dimensional conformal radiotherapy for hepatocellular carcinoma with portal vein tumor thrombus. Int J Radiat Oncol Biol Phys. 2009;73(3):824–31.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhao JD, Xu ZY, Zhu J, Qiu JJ, Hu WG, Cheng LF, Zhang XJ, Jiang GL. Application of active breathing control in 3-dimensional conformal radiation therapy for hepatocellular carcinoma: the feasibility and benefit. Radiother Oncol. 2008;87(3):439–44.PubMedCrossRefGoogle Scholar
  66. 66.
    Hilgard P, Hamami M, Fouly AE, Scherag A, Müller S, Ertle J, Heusner T, Cicinnati VR, Paul A, Bockisch A, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology. 2010;52(5):1741–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138(1):52–64.PubMedCrossRefGoogle Scholar
  68. 68.
    Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology. 2011;54(3):868–78.PubMedCrossRefGoogle Scholar
  69. 69.
    Han KH, Seong J, Kim JK, Ahn SH. Lee do Y, Chon CY. Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis. Cancer. 2008;113(5):995–1003.PubMedCrossRefGoogle Scholar
  70. 70.
    Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, Sato KT, Gupta R, Nikolaidis P, Miller FH, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011; 140(2):497–507.Google Scholar
  71. 71.
    Iñarrairaegui M, Thurston KG, Bilbao JI, D’Avola D, Rodriguez M, Arbizu J, Martinez-Cuesta A, Sangro B. Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol. 2010;21(8):1205–12.PubMedCrossRefGoogle Scholar
  72. 72.
    Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi C, Maccauro M, Marchianò A, Bongini M, Lanocita R, et al. Yttrium(90) radioembolization for intermediate-advanced hepatocarcinoma: a phase II study. Hepatology. 2012;. doi: 10.1002/hep.26014.Google Scholar
  73. 73.
    Palmer DH, Hussain SA, Johnson PJ. Systemic therapies for hepatocellular carcinoma. Expert Opin Investig Drugs. 2004;13(12):1555–68.PubMedCrossRefGoogle Scholar
  74. 74.
    Ang MK, Poon D, Foo KF, Chung YF, Chow P, Wan WK, Thng CH, Ooi L. A new chemoimmunotherapy regimen (OXAFI) for advanced hepatocellular carcinoma. Hematol Oncol Stem Cell Ther. 2008;1(3):159–65.PubMedGoogle Scholar
  75. 75.
    Uhm JE, Park JO, Lee J, Park YS, Park SH, Yoo BC, Paik SW, Koh KC, Kang WK, Lim HY. A phase II study of oxaliplatin in combination with doxorubicin as first-line systemic chemotherapy in patients with inoperable hepatocellular carcinoma. Cancer Chemother Pharmacol. 2009;63(5):929–35.PubMedCrossRefGoogle Scholar
  76. 76.
    Zaanan A, Williet N, Hebbar M, Dabakuyo TS, Fartoux L, Mansourbakht T, Dubreuil O, Rosmorduc O, Cattan S, Bonnetain F, et al. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol. 2012. doi: 10.1016/j.jhep.2012.09.006.
  77. 77.
    Qin S, Bai Y, Ye S, Fan J, Lim H, Cho JY, Thongprasert S, Chao Y, Rau K, Sun Y. Phase III study of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin as palliative systemic chemotherapy in advanced HCC in Asian patients. J Clin Oncol 28:15 s, 2010 (suppl; abstr 4008). Available at:
  78. 78.
    Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C, Oliveri F, Bartolozzi C, Ricci S. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2012;69(3):773–80.PubMedCrossRefGoogle Scholar
  79. 79.
    Strebel BM, Dufour JF. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease. Expert Rev Anticancer Ther. 2008;8(11):1743–9.PubMedCrossRefGoogle Scholar
  80. 80.
    ClinicalTrials. Chemoembolization with or without sorafenib tosylate in treating patients with liver cancer that cannot be removed by surgery. Last Updated on Sept 12, 2012. Available at:
  81. 81.
    Meyer T, Fox R, Bird D, Watkinson A, Hacking N, Stocken D, Johnson PJ, Palmer DH. TACE 2: a randomized placebo-controlled, double blinded, phase III trial evaluating sorafenib in combination with transarterial chemoembolisation(TACE) in patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 30, 2012 (suppl; abstr TPS4150). Available at:
  82. 82.
    Lencioni R, Zou J, Leberre M, Meinhardt G, Voliotis D, Bruix J, Llovet JM. Sorafenib (SOR) or placebo (PL) in combination with transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (SPACE).J Clin Oncol 28:15s, 2010 (suppl; abstr TPS178^). Available at:
  83. 83.
    Gadaleta CD, Ranieri G. Trans-arterial chemoembolization as a therapy for liver tumours: new clinical developments and suggestions for combination with angiogenesis inhibitors. Crit Rev Oncol Hematol. 2011;80(1):40–53.PubMedCrossRefGoogle Scholar
  84. 84.
    Park JW, Koh YH, Kim HB, Kim HY, An S, Choi JI, Woo SM, Nam BH. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol. 2012;56(6):1336–42.PubMedCrossRefGoogle Scholar
  85. 85.
    Merle P, Mornex F, Trepo C. Innovative therapy for hepatocellular carcinoma: three-dimensional high-dose photon radiotherapy. Cancer Lett. 2009;286(1):129–33.PubMedCrossRefGoogle Scholar
  86. 86.
    Reiser M, Neumann I, Schmiegel W, Wu PC, Lau JY. Induction of cell proliferation arrest and apoptosis in hepatoma cells through adenoviral-mediated transfer of p53 gene. J Hepatol. 2000;32(5):771–82.PubMedCrossRefGoogle Scholar
  87. 87.
    Guan YS, La Z, Yang L, He Q, Li P. p53 gene in treatment of hepatic carcinoma: status quo. World J Gastroenterol. 2007;13(7):985–92.PubMedGoogle Scholar
  88. 88.
    Martinet O, Ermekova V, Qiao JQ, Sauter B, Mandeli J, Chen L, Chen SH. Immunomodulatory gene therapy with interleukin 12 and 4–1BB ligand: long- term remission of liver metastases in a mouse model. J Natl Cancer Inst. 2000;92(11):931–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Yang W, Guo C, Liu QG, Pan C. Experimental study of specific immunotherapy induced by H22 autologous tumor as whole tumor cell vaccine. Biomed Pharmacother. 2009;63(6):404–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Los M, Panigrahi S, Rashedi I, Mandal S, Stetefeld J, Essmann F, Schulze-Osthoff K. Apoptin, a tumor-selective killer. Biochim Biophys Acta. 2009;1793(8):1335–42.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang KJ, Qian J, Wang SB, Yang Y. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma. J Biomed Sci. 2012;19:20.PubMedCrossRefGoogle Scholar
  92. 92.
    Bertelli R, Neri F, Tsivian M, Ruhrman N, Cavallari G, Beltempo P, Puviani L, DeVinci C, Pizza G, Nardo B. Endolymphatic immunotherapy in inoperable hepatocellular carcinoma. Transplant Proc. 2008;40(6):1913–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, et al. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006;132(7):458–65.PubMedCrossRefGoogle Scholar
  94. 94.
    Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007;245(6):831–42.PubMedCrossRefGoogle Scholar
  95. 95.
    Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44(6):1543–54.PubMedCrossRefGoogle Scholar
  96. 96.
    Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Kerr DJ, Young LS, Adams DH. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49(1):124–32.PubMedCrossRefGoogle Scholar
  97. 97.
    Shimoda M, Tomimaru Y, Charpentier KP, Safran H, Carlson RI, Wands J. Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma. J Hepatol. 2012;56(5):1129–35.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Hepatobiliary Surgery, First Affiliated Hospital, School of MedicineXi’an Jiaotong UniversityXi’anPeople’s Republic of China

Personalised recommendations