Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Multimodal approaches to the treatment of hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 6, pages 159–169 (2009)Cite this article

Abstract

The prevalence of hepatocellular carcinoma in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis. Surveillance programs for patients with cirrhosis aim to detect tumors at an early stage, when the greatest therapeutic benefits can be achieved. Curative treatments for early-stage tumors include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib can improve survival for patients with intermediate and advanced tumors, respectively. In clinical practice, combination therapies are often used, despite limited evidence to support this approach from randomized controlled trials. Combination therapy with radiofrequency ablation (RFA) plus percutaneous ethanol injection can, however, improve survival for selected patients compared with RFA alone. Combined treatment with TACE and RFA also improves patients' survival compared with TACE or RFA monotherapy. TACE performed before or after surgical resection, however, is not beneficial. Prevention of tumor progression in patients awaiting liver transplantation requires nonsurgical treatments; however, the real advantages of the available treatment modalities are yet to be defined. The role of sorafenib administration in combination with TACE after the use of potentially curative treatments, for the treatment of intermediate hepatocellular carcinoma, or in selective settings after liver transplantation, requires further study.

Key Points

  • Hepatocellular carcinoma (HCC) is a malignancy that is difficult to treat, and is increasing in prevalence worldwide

  • Curative treatment options for HCC (e.g. liver transplantation, surgical resection, percutaneous ablation) are available if the disease is diagnosed at an early stage

  • Despite the use of aggressive local treatments, tumor recurrence and the development of extrahepatic metastases continue to have a significant effect on the overall survival of patients with HCC

  • Combination treatment with radiofrequency ablation (RFA) plus percutaneous ethanol injection can achieve improved survival compared with the use of RFA alone in selected patients

  • Combined treatment with transarterial chemoembolization and RFA improves survival compared with transarterial chemoembolization or RFA monotherapy

  • Further, well-conducted, randomized controlled trials to examine the effectiveness of different multimodal approaches are urgently needed

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Algorithm for staging and treating patients diagnosed as having hepatocellular carcinoma.

Similar content being viewed by others

References

  1. Parkin DM et al. (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108

    Article  Google Scholar 

  2. El-Serag HB and Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340: 745–750

    Article  CAS  Google Scholar 

  3. El-Serag HB et al. (2003) The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139: 817–823

    Article  Google Scholar 

  4. Chang MH et al. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 336: 1855–1859

    Article  CAS  Google Scholar 

  5. Craxì A et al. (2005) Prevention of hepatocellular carcinoma. Clin Liver Dis 9: 329–346

    Article  Google Scholar 

  6. Bugianesi E et al. (2002) Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123: 134–140

    Article  Google Scholar 

  7. Bugianesi E (2007) Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 11: 191–207

    Article  CAS  Google Scholar 

  8. Sangiovanni A et al. (2004) Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 126: 1005–1014

    Article  Google Scholar 

  9. Bruix J et al. (2005) Management of hepatocellular carcinoma. Hepatology 42: 1208–1236

    Article  Google Scholar 

  10. Llovet JM et al. (2003) Hepatocellular carcinoma. Lancet 362: 1907–1917

    Article  Google Scholar 

  11. Schwartz M et al. (2007) Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol 4: 424–432

    Article  CAS  Google Scholar 

  12. Llovet JM et al. (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19: 329–338

    Article  CAS  Google Scholar 

  13. Cillo U et al. (2006) Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 44: 723–731

    Article  Google Scholar 

  14. Marrero JA et al. (2005) Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 41: 707–716

    Article  Google Scholar 

  15. Cammà C et al. (2008) Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems. Aliment Pharmacol Ther 28: 62–75

    Article  Google Scholar 

  16. Llovet JM et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359: 378–390

    Article  CAS  Google Scholar 

  17. El-Serag HB et al. (2006) Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol 44: 158–166

    Article  Google Scholar 

  18. Kudo M and Okanoue T (2007) Japan Society of Hepatology. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 72 (Suppl 1): 2–15

    Article  Google Scholar 

  19. Adam R and Del Gaudio M (2003) Evolution of liver transplantation for hepatocellular carcinoma. J Hepatol 39: 888–895

    Article  Google Scholar 

  20. Burroughs AK et al. (2004) Hepatocellular carcinoma: systemic therapy and liver transplantation two ends of the spectrum. Lancet Oncology 5: 409–418

    Article  Google Scholar 

  21. Mazzaferro V et al. (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334: 693–699

    Article  CAS  Google Scholar 

  22. Shetty K et al. (2004) Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 10: 911–918

    Article  Google Scholar 

  23. Llovet JM et al. (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25: 181–200

    Article  Google Scholar 

  24. Llovet JM et al. (1999) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30: 1434–1440

    Article  CAS  Google Scholar 

  25. Vauthey JN et al. (2002) Simplified staging for hepatocellular carcinoma. J Clin Oncol 20: 1527–1536

    Article  Google Scholar 

  26. Zhou XD et al. (2001) Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 91: 1479–1486

    Article  CAS  Google Scholar 

  27. Ercolani G et al. (2003) Liver resection for hepatocellular carcinoma on cirrhosis. Ann Surg 237: 536–543

    PubMed  PubMed Central  Google Scholar 

  28. Imamura H et al. (2003) Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 38: 200–207

    Article  Google Scholar 

  29. Sala M et al. (2004) Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 40: 1352–1360

    Article  Google Scholar 

  30. Cammà C et al. (2005) Treatment of hepatocellular carcinoma in compensated cirrhosis with radio-frequency thermal ablation (RFTA): a prospective study. J Hepatol 42: 535–540

    Article  Google Scholar 

  31. Omata M et al. (2004) Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology 127 (Suppl 1): 159–166

    Article  Google Scholar 

  32. Lencioni R et al. (2005) Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 234: 961–967

    Article  Google Scholar 

  33. Lencioni R et al. (2003) Small hepatocellular in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228: 235–240

    Article  Google Scholar 

  34. Lin SM et al. (2004) Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology 127: 1714–1723

    Article  Google Scholar 

  35. Shiina S et al. (2005) A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129: 122–130

    Article  Google Scholar 

  36. Llovet JM and Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37: 429–442

    Article  CAS  Google Scholar 

  37. Llovet JM and Bruix J (2008) Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 48 (Suppl 1): 20–37

    Article  Google Scholar 

  38. Raoul JL et al. (1997) Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 26: 1156–1161

    CAS  PubMed  Google Scholar 

  39. Kulik LM et al. (2006) Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 94: 572–586

    Article  CAS  Google Scholar 

  40. Majno PE et al. (2000) Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology 31: 899–906

    Article  CAS  Google Scholar 

  41. Sala M et al. (2004) High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl 10: 1294–1300

    Article  Google Scholar 

  42. Hakimé A et al. (2007) Combination of radiofrequency ablation with antiangiogenic therapy for tumor ablation efficacy: study in mice. Radiology 244: 464–470

    Article  Google Scholar 

  43. Zhang YJ et al. (2007) Hepatocellular carcinoma treated with radiofrequency ablation with or without ethanol injection: a prospective randomized trial. Radiology 244: 599–607

    Article  Google Scholar 

  44. Veltri A et al. (2006) Radiofrequency thermal ablation (RFA) after transarterial chemoembolization (TACE) as a combined therapy for unresectable non-early hepatocellular carcinoma (HCC). Eur Radiol 16: 661–669

    Article  Google Scholar 

  45. Yamakado K et al. (2004) Combination therapy with radiofrequency ablation and transcatheter chemoembolization for the treatment of hepatocellular carcinoma: short-term recurrences and survival. Oncol Rep 11: 105–109

    PubMed  Google Scholar 

  46. Marelli L et al. (2006) Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies. Cancer Treat Rev 32: 594–606

    Article  CAS  Google Scholar 

  47. Bartolozzi C et al. (1995) Treatment of large HCC: transcatheter arterial chemoembolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 197: 812–818

    Article  CAS  Google Scholar 

  48. Koda M et al. (2001) Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma: a randomized controlled study. Cancer 92: 1516–1524

    Article  CAS  Google Scholar 

  49. Akamatsu M et al. (2004) Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial. Liver Int 24: 625–629

    Article  Google Scholar 

  50. Becker G et al. (2005) Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 11: 6104–6109

    Article  Google Scholar 

  51. Cheng BQ et al. (2008) Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: a randomized controlled trial. JAMA 299: 1669–1677

    Article  CAS  Google Scholar 

  52. Yamasaki S et al. (1996) A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res 87: 206–211

    Article  CAS  Google Scholar 

  53. Wu CC et al. (1995) Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. Br J Surg 82: 122–126

    Article  CAS  Google Scholar 

  54. Li JQ et al. (1995) Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy. J Cancer Res Clin Oncol 121: 364–366

    Article  CAS  Google Scholar 

  55. Izumi R et al. (1994) Postoperative adjuvant hepatic arterial infusion of lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 20: 295–301

    Article  CAS  Google Scholar 

  56. Latteri F et al. (2008) Seeding after radiofrequency ablation of hepatocellular carcinoma in patients with cirrhosis: a prospective study. Dig Liver Dis 40: 684–689

    Article  CAS  Google Scholar 

  57. Roayaie S et al. (2002) Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 235: 533–539

    Article  Google Scholar 

  58. Hayashi PH et al. (2004) Hepatic artery chemoembolization for hepatocellular carcinoma in patients listed for liver transplantation. Am J Transplant 4: 782–787

    Article  Google Scholar 

  59. Maddala YK et al. (2004) Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl 10: 449–455

    Article  Google Scholar 

  60. Liou TC et al. (1995) Pulmonary metastasis of hepatocellular carcinoma associated with transarterial chemoembolization. J Hepatol 23: 563–568

    Article  CAS  Google Scholar 

  61. Troisi R et al. (1998) Multimodal treatment for hepatocellular carcinoma on cirrhosis: the role of chemoembolization and alcoholization before liver transplantation. Clin Transplant 12: 313–319

    CAS  PubMed  Google Scholar 

  62. Llovet JM et al. (2002) Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 50: 123–128

    Article  CAS  Google Scholar 

  63. Llovet JM et al. (2001) Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 33: 1124–1129

    Article  CAS  Google Scholar 

  64. Livraghi T et al. (2003) Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 226: 441–451

    Article  Google Scholar 

  65. Kato T and Reddy KR (2001) Radiofrequency ablation for hepatocellular carcinoma: help or hazard? Hepatology 33: 1336–1337

    Article  CAS  Google Scholar 

  66. Bruix J and Llovet JM (2002) Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 35: 519–524

    Article  Google Scholar 

  67. Majno PE et al. (1997) Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 226: 688–701

    Article  CAS  Google Scholar 

  68. Yao FY et al. (2008) Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 48: 819–827

    Article  Google Scholar 

  69. Oldhafer KJ et al. (1998) Arterial chemoembolization before liver transplantation in patients with hepatocellular carcinoma: marked tumor necrosis, but no survival benefit? J Hepatol 29: 953–959

    Article  CAS  Google Scholar 

  70. Lu DS et al. (2005) Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology 234: 954–960

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Warren Blumberg for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. and Director of the Division of Gastroenterology and Hepatology, Academic Department of Internal Medicine, G Cabibbo and F Latteri are Gastroenterologists at the Unit of Gastroenterology and Hepatology, M Antonucci is a Surgeon at the Unit of General and Oncological Surgery, and A Craxì is Full Professor of Gastroenterology and Internal Medicine, University of Palermo, Palermo, Italy.,

    Giuseppe Cabibbo, Federica Latteri, Michela Antonucci & Antonio Craxì

Authors
  1. Giuseppe Cabibbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica Latteri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michela Antonucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Craxì
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppe Cabibbo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cabibbo, G., Latteri, F., Antonucci, M. et al. Multimodal approaches to the treatment of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 6, 159–169 (2009). https://doi.org/10.1038/ncpgasthep1357

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpgasthep1357

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing