Medical Systemic Therapies for Hepatocellular Carcinoma: Clinical Perspectives and Safety Profile

Author(s): Antonio Facciorusso, Matteo Antonino, Valentina Del Prete, Annabianca Amoruso, Viviana Neve, Michele Barone

Journal Name: Current Drug Safety

Volume 10 , Issue 3 , 2015

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A multidisciplinary approach based on clinical expertise and knowledge of molecular processes involved in hepatocarcinogenesis is needed for the proper management of hepatocellular carcinoma (HCC) patients. Such information must be considered in the context of pathobiology of the underlying liver disease.

New drugs targeting specific molecular steps in pathways involved in HCC growth and development bear the promise to radically modify the pharmacological therapies currently in use in hepatooncology.

Sorafenib was the first drug approved in the setting of advanced HCC, but although it produces some improvement in survival, the responses are not durable. In addition, there are significant side effects.

Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and after progression following sorafenib failure; among them, tivantinib, an inhibitor of cMET receptor, showed interesting results in a recent phase-II study.

Additional agents currently studied for the treatment of HCC patients are briefly examined in this review.

Aim of this paper is to discuss the state of the art in the management of advanced HCC patients, with a particular interest for the description of their side effects.

Keywords: Angiogenesis, hepatocellular carcinoma, liver cirrhosis, mTOR, sorafenib, tivantinib.

Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002; 31(4): 339-46.
Facciorusso A, Nacchiero MC, Rosania R, et al. Pathways and gene expression profiles in hepatocellular carcinoma. Minerva Gastroenterol Dietol 2012; 58(1): 35-48.
Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14(1): 55-63.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-57.
Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D. Angiogenesis in rheumatoid arthritis. Histol Histopathol 2006; 21: 557-66.
Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006; 32: 437-44.
Uematsu S, Higashi T, Nouso K, et al. Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2005; 20: 583-8.
Montella L, Addeo R, Caraglia M, et al. Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience. Oncol Rep 2008; 20: 385-90.
Poon RT, Ng IO, Lau C, Yu WC, Fan ST, Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001; 182: 298-304.
Hisai H, Kato J, Kobune M, et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clin Cancer Res 2003; 9: 4852-9.
Zhu AX. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? Oncologist 2006; 11: 790-800.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90.
Wilhelm SM, Carter C, Tang L, 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.
Cheng AL, Kang YK, Chen Z, 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.
Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009; 14: 70-6.
Yau T, Chan P, Ng KK, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer 2009; 115: 428-36.
Abou-Alfa GK, Amadori D, Santoro A, et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? [abstract]. J Clin Oncol 2008; 26(15)(Suppl.): 4518.
Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 2008; 13: 1001-11.
Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 2008; 47: 176-86.
Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47: 2117-27.
Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol 2009; 10: 967-74.
Reig M, Torres F, Rodriguez-Lope C, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014; 61(2): 318-24.
Desar IM, Mulder SF, Stillebroer AB, et al. The reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases. Acta Oncol 2009; 48: 927-31.
Schoenleber SJ, Kurtz DM, Talwalkar JA, et al. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and metaanalysis. Br J Cancer 2009; 100(9): 1385-92.
Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010; 304(19): 2154-60.
Faris JE, Michaelson MD. Targeted therapies: sunitinib versus interferon-alpha in metastatic RCC. Nat Rev Clin Oncol 2010; 7(1): 7-8.
Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 2009; 27(18): 3027-35.
Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24(1): 25-35.
Pfizer discontinues phase 3 trial of Sutent in advanced hepatocellular carcinoma [press release]. Business Wire Web site. 2010-10-13. Available from: URL: http;// news/home/20100422006892/en/Pfizer-Discontinues-Phase-3- Trial-Sutent Advanced (accessed December 27, 2012)
Jenab-Wolcott J, Giantonio BJ. Bevacizumab: current indications and future development for management of solid tumors. Expert Opin Biol Ther 2009; 9(4): 507-17.
Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008; 26(18): 2992-8.
Malka D, Dromain C, Farace F. Bevacizumab in patients with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. J Clin Oncol 2007; 25(Suppl. 18): 4570.
Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24(12): 1898-903.
Thomas MB, Morris JS, Chadha R, 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.
Bhide RS, Cai ZW, Zhang YZ, et al. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methyl-pyrrolo[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 2006; 49: 2143-6.
Tille JC, Wood J, Mandriota SJ, et al. Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. J Pharmacol Exp Ther 2001; 299: 1073-85.
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592-603.
Park JW, Finn RS, Kim JS, et al. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2011; 17: 1973-83.
Finn RS, Kang YK, Mulcahy M, 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.
Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006; 43(2)(Suppl. 1): S45-53.
Kaposi-Novak P, Lee JS, Gomez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 2006; 116(6): 1582-95.
You WK, McDonald DM. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep 2008; 41: 833-9.
Zucali P, Santoro A, Rodriguez-Lope C, et al. Final results from ARQ 197-114: A phase Ib safety trial evaluating ARQ 197 in cirrhotic patients (pts) with hepatocellular carcinoma (HCC). J Clin Oncol 2010; 28 suppl: Abstract 4137.
Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a randomized phase II discontinuation study. Proc Am Soc Clin Oncol 2012; 30 (suppl):: abstr 4007.
Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135(6): 1972-83.
Geissler EK, Schlitt HJ, Thomas G. mTOR, cancer and transplantation. Am J Transplant 2008; 8: 2212-8.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-84.
Huynh H. Molecularly targeted therapy in hepatocellular carcinoma. Biochem Pharmacol 2010; 80: 550-60.
Chinnakotla S, Davis GL, Vasani S, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl 2009; 15: 1834-42.
Albert DH, Tapang P, Magoc TJ, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 2006; 5: 995-1006.
Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005; 23(27): 6657-63.
Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007; 110(5): 1059-67.
Cervello M, McCubrey JA, Cusimano A, et al. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget 2012; 3(3): 236-60.
Bekaii-Saab T, Markowitz J, Prescott N, et al. A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 2009; 15(18): 5895-901.
Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009; 64(4): 777-83.
Facciorusso A, Licinio R, Carr BI, Di Leo A, Barone M. MEK 1/2 inhibitors in the treatment of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2015; 27: 1-11.
Facciorusso A, Muscatiello N, Di Leo A, Barone M. Combination therapy with sorafenib and radiofrequency ablation for hepatocellular carcinoma: a glimmer of light after the storm trial? Am J Gastroenterol 2015; 110(5): 770-1.

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Article Details

Year: 2015
Page: [202 - 207]
Pages: 6
DOI: 10.2174/1574886310666150521124222
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