Advertisement

Biologic and Systemic Therapies for the Treatment of Hepatocellular Carcinoma

  • Richard S. Finn
Reference work entry

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, yet systemic treatment options for the disease are limited. Only recently, sorafenib, an oral, small-molecule tyrosine kinase inhibitor of several intracellular proteins suspected to be important in HCC progression, including the platelet-derived growth factor receptor-β (PDGFR), “Raf” kinase, and the vascular endothelial growth factor receptors (VEGFR) including VEGFR 1, 2, and 3, was shown to prolong survival in HCC. While the benefit of sorafenib over placebo is modest (the median survival increased from 7.9 to 10.7 months), it was a significant advance, becoming the first systemic agent to prolong survival in this setting, and has spurred an increase in research at all stages of the disease. Currently, there are an unprecedented number of clinical studies of new agents in HCC. In addition to evaluating these agents in combination with sorafenib, they are being compared directly to sorafenib, after progression on sorafenib, and in combination with locally ablative therapies such as transarterial chemoembolization (TACE) and radio-frequency ablation (RFA) and surgical resection. With this robust activity, we are increasing our understanding of HCC and will likely see significant improvements on the initial observations made with sorafenib. As highlighted here, this will take careful study design, patient selection, and a rational selection of new therapeutic targets.

Keywords

Epidermal Growth Factor Receptor Vascular Endothelial Growth Factor Receptor Fibroblast Growth Factor Receptor Disease Control Rate 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.

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMedGoogle Scholar
  2. 2.
    Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. 2005;23:2892–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–38.CrossRefPubMedGoogle Scholar
  4. 4.
    Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.CrossRefPubMedGoogle Scholar
  5. 5.
    Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–14.CrossRefPubMedGoogle Scholar
  6. 6.
    James K, Eisenhauer E, Christian M, Terenziani M, Vena D, Muldal A, Therasse P. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst. 1999;91:523–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.CrossRefPubMedGoogle Scholar
  11. 11.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010;304(19):2154–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Cai ZW, Zhang Y, Borzilleri RM, Qian L, Barbosa S, Wei D, Zheng X, et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem. 2008;51:1976–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Raoul JL, Finn RS, Kang YK, et al. An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol. 2009;27:4577.Google Scholar
  16. 16.
    Finn RS, Kang YK,Mulcahy M, Polite BN, Lim HY, Walters I, Baudelet C, et al. Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18(7):2090–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.CrossRefPubMedGoogle Scholar
  18. 18.
    Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008;14:6146–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004;10:8421–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, Wang X, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation. 2007;83:425–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972–83, 1983 e1971–11.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, Tang ZY. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2008;14:5124–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Huynh H, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, Poon D, et al. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med. 2009;13:1371–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Chen L, Shiah HS, Chen CY, et al. Randomized, phase I, and pharmacokinetic (PK) study of RAD001, and mTOR inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2009;27:4587.Google Scholar
  26. 26.
    Blaszkowsky LS, Abrams TA, Miksad RA, et al. Phase I/II study of everolimus in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2010;28:e14542.CrossRefGoogle Scholar
  27. 27.
    Zhu AX, Finn RS, Mulcahy MF, et al. A phase II study of ramucirumab as first-line monotherapy in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2010;28:4083.CrossRefGoogle Scholar
  28. 28.
    Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, Chen H, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26:2992–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Malka D, Dromain C, Farace F, Horn S, Pignon J, Ducreux M, Boige V. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. J Clin Oncol. 2007;25:4570.Google Scholar
  30. 30.
    Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27(6):843–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006;5:995–1006.CrossRefPubMedGoogle Scholar
  32. 32.
    Toh H, Chen P, Carr BI, et al. A phase II study of ABT-869 in hepatocellular carcinoma (HCC): interim analysis. J Clin Oncol. 2009;27:4581.Google Scholar
  33. 33.
    Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresctable hepatocellular carcinoma. Eur J Cancer. 2011;47(14):2117–27.CrossRefPubMedGoogle Scholar
  34. 34.
    Ahmed M, Monsky WE, Girnun G, Lukyanov A, D’Ippolito G, Kruskal JB, Stuart KE, et al. Radiofrequency thermal ablation sharply increases intratumoral liposomal doxorubicin accumulation and tumor coagulation. Cancer Res. 2003;63:6327–33.PubMedGoogle Scholar
  35. 35.
    Goldberg SN, Kamel IR, Kruskal JB, Reynolds K, Monsky WL, Stuart KE, Ahmed M, et al. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. AJR Am J Roentgenol. 2002;179:93–101.CrossRefPubMedGoogle Scholar
  36. 36.
    Poon RT, Borys N. Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer. Expert Opin Pharmacother. 2009;10:333–43.CrossRefPubMedGoogle Scholar
  37. 37.
    Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, Kondo Y, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;67:315–24.CrossRefPubMedGoogle Scholar
  38. 38.
    Arai Y, Inaba T, Yamamoto T, et al. A randomized Phase II study of TSU-68 in patients (Pts) with hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). J Clin Oncol. 2010;28:4030.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineGeffen School of Medicine at UCLA Ronald Regan Medical Center at UCLALos AngelesUSA

Personalised recommendations