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Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

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Abstract

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.

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References

  1. Taketomi A, Fukuhara T, Morita K et al (2010) Improved results of a surgical resection for the recurrence of hepatocellular carcinoma after living donor liver transplantation. Ann Surg Oncol 17:2283–2289

    Article  PubMed  Google Scholar 

  2. Taketomi A, Toshima T, Kitagawa D et al (2010) Predictors of extrahepatic recurrence after curative hepatectomy for hepatocellular carcinoma. Ann Surg Oncol 17:2740–2746

    Article  PubMed  Google Scholar 

  3. Bruix J, Reig M, Sherman M (2016) Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology (in press)

  4. Prieto J, Melero I, Sangro B (2015) Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 12:681–700

    Article  CAS  PubMed  Google Scholar 

  5. Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379:1245–1255

    Article  PubMed  Google Scholar 

  6. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  CAS  PubMed  Google Scholar 

  7. Cheng AL, Kang YK, Chen Z et al (2009) 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

    Article  CAS  PubMed  Google Scholar 

  8. Bruix J, Raoul JL, Sherman M et al (2012) Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 57:821–829

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  10. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer (2012) EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56:908–943

    Article  Google Scholar 

  11. Peng S, Zhao Y, Xu F et al (2014) An updated meta-analysis of randomized controlled trials assessing the effect of sorafenib in advanced hepatocellular carcinoma. PLoS One 9:e112530

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhu AX, Rosmorduc O, Evans TR et al (2015) SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 33:559–566

    Article  CAS  PubMed  Google Scholar 

  13. Bruix J, Takayama T, Mazzaferro V et al (2015) Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 16:1344–1354

    Article  CAS  PubMed  Google Scholar 

  14. Yeung KT, Cohen EE (2015) Lenvatinib in advanced, radioactive iodine-refractory, differentiated thyroid carcinoma. Clin Cancer Res 21:5420–5426

    Article  CAS  PubMed  Google Scholar 

  15. Gu Q, Zhang B, Sun H et al (2015) Genomic characterization of a large panel of patient-derived hepatocellular carcinoma xenograft tumor models for preclinical development. Oncotarget 6:20160–20176

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chuma M, Terashita K, Sakamoto N (2015) New molecularly targeted therapies against advanced hepatocellular carcinoma: from molecular pathogenesis to clinical trials and future directions. Hepatol Res 45:E1–E11

    Article  CAS  PubMed  Google Scholar 

  17. Oikonomopoulos G, Aravind P, Sarker D (2016) Lenvatinib: a potential breakthrough in advanced hepatocellular carcinoma? Future Oncol 12:465–476

  18. Zhu AX, Raymond E (2009) Early development of sunitinib in hepatocellular carcinoma. Expert Rev Anticancer Ther 9:143–150

    Article  CAS  PubMed  Google Scholar 

  19. Zhu AX, Sahani DV, Duda DG et al (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Faivre S, Raymond E, Boucher E et al (2009) Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol 10:794–800

    Article  CAS  PubMed  Google Scholar 

  21. Koeberle D, Montemurro M, Samaras P et al (2010) Continuous sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). Oncologist 15:285–292

  22. Barone C, Basso M, Biolato M et al (2013) A phase II study of sunitinib in advanced hepatocellular carcinoma. Dig Liver Dis 45:692–698

    Article  CAS  PubMed  Google Scholar 

  23. Cheng AL, Kang YK, Lin DY et al (2013) Sunitinib vs sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31:4067–4075

    Article  CAS  PubMed  Google Scholar 

  24. Roy S, Narang BK, Rastogi SK et al (2015) A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib. Anticancer Agents Med Chem 15:37–47

    Article  CAS  PubMed  Google Scholar 

  25. Xiang Q, Chen W, Ren M et al (2014) Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res 20:2959–2970

    Article  CAS  PubMed  Google Scholar 

  26. Verslype C, Cohn AL, Kelley RK et al (2012) Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30:4007

    Google Scholar 

  27. Abou-Alfa GK, Cheng AL, Meyer T et al (2014) Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) vs placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426). J Clin Oncol. 32:TPS4150

    Google Scholar 

  28. Bhide RS, Cai ZW, Zhang YZ et al (2006) Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem 49:2143–2146

  29. Huynh H, Ngo VC, Fargnoli J et al (2008) 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 14:6146–6153

    Article  CAS  PubMed  Google Scholar 

  30. Park JW, Finn RS, Kim JS et al (2011) Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 17:1973–1983

    Article  CAS  PubMed  Google Scholar 

  31. Johnson PJ, Qin S, Park JW et al (2013) Brivanib vs 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

    Article  CAS  PubMed  Google Scholar 

  32. Llovet JM, Decaens T, Raoul JL et al (2013) 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

    Article  CAS  PubMed  Google Scholar 

  33. Zhou J, Goh BC, Albert DH et al (2009) ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. J Hematol Oncol 2:33

    Article  PubMed  PubMed Central  Google Scholar 

  34. Toh HC, Chen PJ, Carr BI et al (2013) Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer 119:380–387

    Article  CAS  PubMed  Google Scholar 

  35. Cainap C, Qin S, Huang WT et al (2015) Linifanib vs Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 33:172–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Spratlin JL, Cohen RB, Eadens M et al (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28:780–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu AX, Finn RS, Mulcahy M et al (2013) A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res 19:6614–6623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhu AX, Park JO, Ryoo BY et al (2015) Ramucirumab vs placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 16:859–870

    Article  CAS  PubMed  Google Scholar 

  39. Pietrantonio F, Orlandi A, Inno A et al (2015) Bevacizumab-based neoadjuvant chemotherapy for colorectal cancer liver metastases: pitfalls and helpful tricks in a review for clinicians. Crit Rev Oncol Hematol 95:272–281

    Article  PubMed  Google Scholar 

  40. Siegel AB, Cohen EI, Ocean A et al (2008) Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 26:2992–2998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu AX, Blaszkowsky LS, Ryan DP et al (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:1898–1903

    Article  CAS  PubMed  Google Scholar 

  42. Sun W, Sohal D, Haller DG et al (2011) Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer 117:3187–3192

    Article  CAS  PubMed  Google Scholar 

  43. Hsu CH, Yang TS, Hsu C et al (2010) Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer 102:981–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

I thank Dr. Yokoo for his help with the preparation of the figure imagess.

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Correspondence to Akinobu Taketomi.

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Taketomi, A. Clinical trials of antiangiogenic therapy for hepatocellular carcinoma. Int J Clin Oncol 21, 213–218 (2016). https://doi.org/10.1007/s10147-016-0966-0

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  • DOI: https://doi.org/10.1007/s10147-016-0966-0

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