Pathways and targets in hepatocellular carcinoma

Expert Review of Anticancer Therapy

Volumn 12, Issue 10, 2012, Pages 1347-1357

  Psyrri, Amanda ^a   Arkadopoulos, Nikolaos ^a   Vassilakopoulou, Maria ^b   Smyrniotis, Vassilios ^a   Dimitriadis, George ^a  

^a NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS   (Greece)

^b YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

HCC; Molecular targeted agents; Signaling pathways

Indexed keywords

AVE 1642; BEVACIZUMAB; BRIVANIB; CABOZANTINIB; CAPECITABINE; CETUXIMAB; CIXUTUMUMAB; DOVITINIB; DOXORUBICIN; ERLOTINIB; EVEROLIMUS; GEFITINIB; GEMCITABINE; LAPATINIB; LINIFANIB; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; NINTEDANIB; ORANTINIB; OXALIPLATIN; PANITUMUMAB; PLACEBO; RAPAMYCIN; SELUMETINIB; SORAFENIB; SUNITINIB; TEMSIROLIMUS; TIVANTINIB; VORINOSTAT; ANTINEOPLASTIC AGENT; CARBANILAMIDE DERIVATIVE; DRUG DERIVATIVE; NICOTINAMIDE;

ANGIOGENESIS; ANOREXIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ASTHENIA; BLEEDING; CANCER INCIDENCE; CANCER MORTALITY; CANCER PALLIATIVE THERAPY; CANCER PROGNOSIS; CANCER STAGING; CANCER SURVIVAL; CELL PROLIFERATION; COMORBIDITY; CONTROLLED STUDY; DIARRHEA; DRUG DOSE REDUCTION; DRUG RESPONSE; ENZYME PHOSPHORYLATION; EPITHELIAL MESENCHYMAL TRANSITION; FATIGUE; GASTROINTESTINAL HEMORRHAGE; GASTROINTESTINAL TOXICITY; HAND FOOT SYNDROME; HEMATOLOGIC DISEASE; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPERTRANSAMINASEMIA; LIGAND BINDING; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LOSS OF APPETITE; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PROGRESSION FREE SURVIVAL; PROTEIN TARGETING; RANDOMIZED CONTROLLED TRIAL; REVIEW; SIGNAL TRANSDUCTION; SKIN DISEASE; SKIN TOXICITY; SYSTEMATIC REVIEW; THROMBOCYTOPENIA; THROMBOSIS; TUMOR VOLUME; ANIMAL; CLINICAL TRIAL (TOPIC); DRUG EFFECT; LIVER TUMOR; METABOLISM; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA, HEPATOCELLULAR; CLINICAL TRIALS AS TOPIC; HUMANS; LIVER NEOPLASMS; NIACINAMIDE; PHENYLUREA COMPOUNDS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SIGNAL TRANSDUCTION;

EID: 84876794946     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/era.12.113     Document Type: Review

References (97)

1. El-Serag HB. Hepatocellular carcinoma. N. Engl. J. Med. 365(12), 1118-1127 (2011).
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA. Cancer J. Clin. 62(1), 10-29 (2012).
3. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127(5 Suppl. 1), S27-S34 (2004).
4. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N. Engl. J. Med. 340(10), 745-750 (1999).
5. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 353(9160), 1253-1257 (1999).
6. Howlader. SEER Cancer Statistics Review. National Cancer Institute, Bethesda MD, USA, 1975-2008.
7. Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br. J. Cancer 96(7), 1127-1134 (2007).
8. Franceschi S, Raza SA. Epidemiology and prevention of hepatocellular carcinoma. Cancer Lett. 286(1), 5-8 (2009).
9. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N. Engl. J. Med. 348(17), 1625-1638 (2003).
10. Wolk A, Gridley G, Svensson M et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 12(1), 13-21 (2001).
11. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin. Gastroenterol. Hepatol. 4(3), 369-380 (2006).
12. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126(2), 460-468 (2004).
13. Donato F, Tagger A, Gelatti U et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am. J. Epidemiol. 155(4), 323-331 (2002).
14. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134(6), 1752-1763 (2008).
15. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 130(7), 417-422 (2004).
16. Chen JG, Parkin DM, Chen QG et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J. Med. Screen. 10(4), 204-209 (2003).
17. Villanueva A, Minguez B, Forner A, Reig M, Llovet JM. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Annu. Rev. Med. 61, 317-328 (2010).
18. Davila JA, Morgan RO, Richardson PA, Du XL, McGlynn KA, El-Serag HB. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 52(1), 132-141 (2010).
19. Huang M, Liu G. The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. Cancer Lett. 135(1), 97-105 (1999).
20. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin. Liver Dis. 30(1), 61-74 (2010).
21. Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ. Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br. J. Cancer 100(9), 1385-1392 (2009).
22. Llovet JM, Ricci S, Mazzaferro V et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359(4), 378-390 (2008).
23. 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, placebocontrolled trial. Lancet Oncol. 10(1), 25-34 (2009).
24. Frenette C, Gish R. Targeted systemic therapies for hepatocellular carcinoma: clinical perspectives, challenges and implications. World J. Gastroenterol. 18(6), 498-506 (2012).
25. Finn RS Jr, Manekas D, Baudelet C, Walters IB. Optimal assessment of treatment benefit with targeted agents for hepatocellular carcinoma (HCC): an analysis of brivanib Phase II data. J. Clin. Oncol. 28(Suppl.), Abstract 4096, 15 (2010).
26. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat. Rev. Cancer 3(5), 321-329 (2003).
27. Mínguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr. Opin. Gastroenterol. 25(3), 186-194 (2009).
28. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin. Liver Dis. 27(1), 55-76 (2007).
29. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene 25(27), 3778-3786 (2006).
30. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48(4), 1312-1327 (2008).
31. Höpfner M, Schuppan D, Scherübl H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer. World J. Gastroenterol. 14(1), 1-14 (2008).
32. Kudo M. Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma. Dig. Dis. 29(3), 289-302 (2011).
33. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22), 3291-3310 (2007).
34. Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 236(1), 54-58 (1997).
35. Huynh H, Nguyen TT, Chow KH, Tan PH, Soo KC, Tran E. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 3, 19 (2003).
36. Feo F, Pascale RM, Simile MM, De Miglio MR, Muroni MR, Calvisi D. Genetic alterations in liver carcinogenesis: implications for new preventive and therapeutic strategies. Crit. Rev. Oncog. 11(1), 19-62 (2000).
37. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 49(17), 4682-4689 (1989).
38. Tannapfel A, Sommerer F, Benicke M et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52(5), 706-712 (2003).
39. Jenke HS, Deml E, Oesterle D. C-raf expression in early rat liver tumorigenesis after promotion with polychlorinated biphenyls or phenobarbital. Xenobiotica. 24(6), 569-580 (1994).
40. Huang S, Sinicrope FA. Sorafenib inhibits STAT3 activation to enhance TRAILmediated apoptosis in human pancreatic cancer cells. Mol. Cancer Ther. 9(3), 742-750 (2010).
41. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J. Hepatol. 50(3), 604-620 (2009).
42. 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. 26(18), 2992-2998 (2008).
43. Finn RS. Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin. Cancer Res. 16(2), 390-397 (2010).
44. 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. 24(12), 1898-1903 (2006).
45. Sun W, Sohal D, Haller DG et al. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer 117(14), 3187-3192 (2011).
46. Hsu CH, Yang TS, Hsu C et al. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br. J. Cancer 102(6), 981-986 (2010).
47. Faivre S, Raymond E, Boucher E et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, Phase II study. Lancet Oncol. 10(8), 794-800 (2009).
48. 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. 27(18), 3027-3035 (2009).
49. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr. Rev. 18(1), 4-25 (1997).
50. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8(8), 592-603 (2008).
51. Allen EWI, Rivera IC, Hanahan D. Anti-angiogenic therapy using brivanib, a combined VEGF and FGF pathway inhibitor, in a mouse model of pancreatic neuroendocrine cancer (PNET), results in sustained vascular blockade, without evidence for evasive/acquired resistance in a form of VEGF-independent revascularization, in contrast to other VEGF inhibitors. Mol. Cancer Ther. 8(12 Suppl.), B16 (2009).
52. Huynh H, Ngo VC, Fargnoli J 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. 14(19), 6146-6153 (2008).
53. 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. 17(7), 1973-1983 (2011).
54. 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. 18(7), 2090-2098 (2012).
55. Kanai F, Yoshida H, Tateishi R et al. A Phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother. Pharmacol. 67(2), 315-324 (2011).
56. Albert DH, Tapang P, Magoc TJ et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther. 5(4), 995-1006 (2006).
57. Jasinghe VJ, Xie Z, Zhou J et al. ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft. J. Hepatol. 49(6), 985-997 (2008).
58. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 358(11), 1160-1174 (2008).
59. Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am. J. Clin. Pathol. 129(2), 245-251 (2008).
60. Schiffer E, Housset C, Cacheux W et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41(2), 307-314 (2005).
61. Nakopoulou L, Stefanaki K, Boletis J et al. Immunohistochemical study of epidermal growth factor receptor (EGFR) in various types of renal injury. Nephrol. Dial. Transplant. 9(7), 764-769 (1994).
62. Huether A, Höpfner M, Sutter AP, Schuppan D, Scherübl H. Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. J. Hepatol. 43(4), 661-669 (2005).
63. Matsuo M, Sakurai H, Saiki I. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. Mol. Cancer Ther. 2(6), 557-561 (2003).
64. Ueda S, Basaki Y, Yoshie M et al. PTEN/ Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. Cancer Res. 66(10), 5346-5353 (2006).
65. Okano J, Matsumoto K, Nagahara T, Murawaki Y. Gefitinib and the modulation of the signaling pathways downstream of epidermal growth factor receptor in human liver cancer cells. J. Gastroenterol. 41(2), 166-176 (2006).
66. Philip PA, Mahoney MR, Allmer C et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J. Clin. Oncol. 23(27), 6657-6663 (2005).
67. Thomas MB, Chadha R, Glover K et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 110(5), 1059-1067 (2007).
68. O’Dwyer BJG, Levy DE, Kauh JS, Fitzgerald DB, Benson AB, Abstract: Gefitinib in advanced unresectable hepatocellular carcinoma: Results from the Eastern Cooperative Oncology Group’s Study E1203. Presented at: ASCO Annual Meeting. Atlanta, GA, USA, 2-6 June 2006.
69. Zhu AX, Stuart K, Blaszkowsky LS et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110(3), 581-589 (2007).
70. Gruenwald VLW, Gebel M, Greten TF et al. A Phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: Final results. J. Clin. Oncol. Abstract 18S (2007).
71. 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. 15(18), 5895-5901 (2009).
72. 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. 64(4), 777-783 (2009).
73. Bunney TD, Katan M. Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat. Rev. Cancer 10(5), 342-352 (2010).
74. Zhou L, Huang Y, Li J, Wang Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med. Oncol. 27(2), 255-261 (2010).
75. Chen JS, Wang Q, Fu XH et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol. Res. 39(2), 177-186 (2009).
76. Villanueva A, Chiang DY, Newell P et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135(6), 1972-83, 1983.e1 (2008).
77. Rizell M, Andersson M, Cahlin C, Hafström L, Olausson M, Lindnér P. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int. J. Clin. Oncol. 13(1), 66-70 (2008).
78. Knox Jennifer JRQ, Strosberg JR, Andreas K, El-Khoueiry AB, Bekaii-Saab TB, Erlichman C. A Phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol. 30(Suppl.), Abstract 4092 (2012).
79. Tan S, Li R, Ding K, Lobie PE, Zhu T. miR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. FEBS Lett. 585(14), 2229-2234 (2011).
80. Zucali PSA, Rodriguez-Lope C, Simonelli M et al. Final results from ARQ 197-114: a Phase Ib safety trial evaluating ARQ197 in cirrhotic patients (pts) with hepatocellular carcinoma. J. Clin. Oncol. Abstract 4137 (2010).
81. Rimassa Lorenza CP, Borbath I, Daniele B et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized controlled Phase II trial (RCT). J. Clin. Oncol. 30, Abstract 4006 (2012)
82. Verslype Chris ALC, Kelley RK, Yang TS et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a Phase II randomized discontinuation trial (RDT). J. Clin. Oncol. 30(Suppl.), Abstract 4007 (2012).
83. Yang JM, Chen WS, Liu ZP, Luo YH, Liu WW. Effects of insulin-like growth factors-IR and-IIR antisense gene transfection on the biological behaviors of SMMC-7721 human hepatoma cells. J. Gastroenterol. Hepatol. 18(3), 296-301 (2003).
84. Höpfner M, Huether A, Sutter AP, Baradari V, Schuppan D, Scherübl H. Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem. Pharmacol. 71(10), 1435-1448 (2006).
85. Carlisi D, Lauricella M, D’Anneo A et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAILDISC activation. Eur. J. Cancer 45(13), 2425-2438 (2009).
86. Doi T, Hamaguchi T, Shirao K et al. Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a Phase I clinical trial. Int. J. Clin. Oncol. doi:10.1007/s10147-011-0348-6 (2012) (Epub ahead of print).
87. Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 24(26), 4293-4300 (2006).
88. Meza-Junco J, Chu QS, Christensen O et al. UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib. Cancer Chemother. Pharmacol. 65(1), 1-4 (2009).
89. Abou-Alfa GK, Amadori D, Santoro A et al. Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest. Cancer Res. 4(2), 40-44 (2011).
90. Miller AA, Murry DJ, Owzar K et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J. Clin. Oncol. 27(11), 1800-1805 (2009).
91. Chung Y, Kim B, Chen C et al. Study in Asia of the combination of transcatheter arterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma (HCC) trial (START): Second interim safety and efficacy analysis. J. Clin. Oncol. 28, Abstract 4026 (2010).
92. Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J. Clin. Oncol. 29(30), 3960-3967 (2011).
93. 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 304(19), 2154-2160 (2010).
94. Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 47(2), 176-186 (2008).
95. Lee JH, Chung YH, Kim JA et al. Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma. Cancer doi:10.1002/cncr.27705 (2012) (Epub ahead of print).
96. 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. 10(10), 967-974 (2009).
97. Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J; SHARP Investigators Study Group. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 18(8), 2290-2300 (2012).