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.

  • Opinion
  • Published:

HCC therapies—lessons learned

Nature Reviews Gastroenterology & Hepatology volume 11, pages 447–452 (2014)Cite this article

Subjects

Abstract

The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure of subsequent randomized controlled phase III trials underscores the urgent need to identify the driver targets and to develop matched active agents with manageable toxicities in specific phase I studies in patients with cirrhosis. Refinement of phase II–III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC.

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

Similar content being viewed by others

References

  1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    PubMed  Google Scholar 

  2. Worns, M. A., Weinmann, A., Schuchmann, M. & Galle, P. R. Systemic therapies in hepatocellular carcinoma. Dig. Dis. 27, 175–188 (2009).

    Article  PubMed  Google Scholar 

  3. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Cheng, A. L. 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. 10, 25–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Bruix, J. & Sherman, M. Management of hepatocellular carcinoma: an update. Hepatology 53, 1020–1022 (2011).

    Article  PubMed  Google Scholar 

  6. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012).

  7. Worns, M. A. & Galle, P. R. Novel inhibitors in development for hepatocellular carcinoma. Expert Opin. Investig. Drugs 19, 615–629 (2010).

    Article  PubMed  Google Scholar 

  8. Llovet, J. M. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst. 100, 698–711 (2008).

    Article  PubMed  Google Scholar 

  9. Worns, M. A. Systemic therapy and synergies by combination. Dig. Dis. 31, 104–111 (2013).

    Article  PubMed  Google Scholar 

  10. Cheng, A. L. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J. Clin. Oncol. 31, 4067–4075 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Cainap, C. et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) [abstract]. J. Clin. Oncol. 30 (Suppl. 34), 249 (2013).

    Article  Google Scholar 

  12. Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J. Clin. Oncol. 31, 3517–3524 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Lencioni, R. & Llovet, J. M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Zhu, A. X. et al. SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma (HCC) [abstract]. Eur. J. Cancer 48 (Suppl.) 2 (2012).

    Google Scholar 

  15. Qin, S. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J. Clin. Oncol. 31, 3501–3508 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Llovet, J. M. et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J. Clin. Oncol. 31, 3509–3516 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Novartis study of Afinitor® in advanced liver cancer does not meet primary endpoint of overall survival. Novartis [online], (2013).

  18. Worns, M. A. & Galle, P. R. Future perspectives in hepatocellular carcinoma. Dig. Liver Dis. 42 (Suppl. 3), S302–S309 (2010).

    Article  PubMed  Google Scholar 

  19. Villanueva, A. & Llovet, J. M. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib. Clin. Cancer Res. 18, 1824–1826 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Villanueva, A. Rethinking future development of molecular therapies in hepatocellular carcinoma: a bottom-up approach. J. Hepatol. 59, 392–395 (2013).

    Article  PubMed  Google Scholar 

  21. Kelley, R. K. & Venook, A. P. Novel therapeutics in hepatocellular carcinoma. Am. Soc. Clin. Oncol. Educ. Book 2013, 137–142 (2013).

    Article  Google Scholar 

  22. Llovet, J. M., Bru, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

    Article  PubMed  Google Scholar 

  24. Villanueva, A., Newell, P., Chiang, D. Y., Friedman, S. L. & Llovet, J. M. Genomics and signaling pathways in hepatocellular carcinoma. Semin. Liver Dis. 27, 55–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Weinstein, I. B. & Joe, A. Oncogene addiction. Cancer Res. 68, 3077–3080 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marquardt, J. U. & Andersen, J. B. Next-generation sequencing: application in liver cancer—past, present and future? Biology (Basel) 1, 383–394 (2012).

    Google Scholar 

  29. Schirmacher, P. et al. Fighting the bushfire in HCC trials. J. Hepatol. 55, 276–277 (2011).

    Article  PubMed  Google Scholar 

  30. Villanueva, A. & Llovet, J. M. Impact of intra-individual molecular heterogeneity in personalized treatment of hepatocellular carcinoma. Hepatology 56, 2416–2419 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Pantel, K. & Alix-Panabieres, C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 73, 6384–6388 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Santoro, A. et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 14, 55–63 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  34. Schmieder, R. et al. Allosteric MEK1/2 inhibitor refametinib (BAY 86–9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia 15, 1161–1171 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhu, A. X. et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 19, 920–928 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Catalogue of Somatic Mutations in Cancer [online].

  37. Assenat, E. et al. Sorafenib alone versus sorafenib combined with gemcitabine and oxaliplatin (GEMOX) in the first-line treatment of advanced hepatocellular carcinoma: final results of the randomized phase II GoNext trial (a UNICANCER/FFCD/PRODIGE 10 study) [abstract]. Eur. J. Cancer 49 (Suppl. 2), 2467 (2013).

    Google Scholar 

  38. US National Library of Medicine ClinicalTrials.gov [online], (2013).

  39. Llovet, J. M., Burroughs, A. & Bruix, J. Hepatocellular carcinoma. Lancet 362, 1907–1917 (2003).

    Article  PubMed  Google Scholar 

  40. ArQule Announces Third Quarter Fiscal 2013 Results. Arqule [online], (2013).

  41. Reig, M. et al. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second line trial design. Hepatology 58, 2023–2031 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Kelley, R. K. Brivanib and FOLFOX in hepatocellular carcinoma: finding the common themes among negative trials. J. Clin. Oncol. 31, 3483–3486 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Shao, Y. Y. et al. Prognosis of patients with advanced hepatocellular carcinoma who failed first-line systemic therapy. J. Hepatol. 60, 313–318 (2014).

    Article  PubMed  Google Scholar 

  44. He, A. R. & Goldenberg, A. S. Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations. Therap. Adv. Gastroenterol. 6, 447–458 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  46. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  47. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  48. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  49. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz, 55131, Germany

    Marcus-Alexander Wörns & Peter Robert Galle

Authors
  1. Marcus-Alexander Wörns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Robert Galle
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.-A.W. contributed to researching data, discussing the content and writing the manuscript. P.R.G. contributed to researching data, discussing the content, and reviewing/editing the manuscript.

Corresponding author

Correspondence to Marcus-Alexander Wörns.

Ethics declarations

Competing interests

M.-A. Wörns and P. R. Galle have received consulting and lecture fees from Bayer HealthCare and Bristol-Myers Squibb.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wörns, MA., Galle, P. HCC therapies—lessons learned. Nat Rev Gastroenterol Hepatol 11, 447–452 (2014). https://doi.org/10.1038/nrgastro.2014.10

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2014.10

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