Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Worldwide progressive population aging demands consensus development for decision making when treating elderly patients. Age itself might not be a critical determinant for the selection of a therapeutic option. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated, and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, have been demonstrated, leading to evaluation of the activity and toxicity of some of the new molecularly targeted agents. Sorafenib was demonstrated to significantly increase the survival of patients with advanced HCC in two prospective, randomized, placebo-controlled trials. Subsequently, a number of retrospective or prospective studies have indicated that the effectiveness of sorafenib therapy in the treatment of HCC is similar in elderly and non-elderly patients. The aim of this review is to describe the impact of age on the effects of sorafenib-targeted therapy in patients with HCC, and the next treatment options with new targeted agents (everolimus, tivantinib, linifanib, etc.).
Similar content being viewed by others
References
Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
Schwartz M, Roayaie S, Konstadoulakis M. Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol. 2007;4:424–32.
El-Serag HB, Marrero JA, Rudolph L, et al. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 2008;134:1752–63.
Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
Cho SJ, Yoon JH, Hwang SS, et al. Do young hepatocellular carcinoma patients with relatively good liver function have poorer outcomes than elderly patients? J Gastroenterol Hepatol. 2007;22:1226–31.
Chiaramonte M, Stroffolini T, Vian A, et al. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer. 1999;85:2132–7.
Repetto L, Venturino A, Fratino L, et al. Geriatric oncology: a clinical approach to the older patient with cancer. Eur J Cancer. 2003;39:870–80.
Fentiman IS, Tirelli U, Monfardini S, et al. Cancer in the elderly: why so badly treated? Lancet. 1990;335:1020–2.
Hutchins LF, Unger JM, Crowley JJ, et al. Un-derrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341:2061–7.
Unger JM, Coltman CA Jr, Crowley JJ, et al. Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials. Clin Oncol. 2006;24:141–4.
Collier JD, Curless R, Bassendine MF, et al. Clinical features and prognosis of hepatocellular carcinoma in Britain in relation to age. Age Ageing. 1994;23:22–7.
Giannini E, Romagnoli P, Fasoli A, et al. Influence of age on clinical presentation, therapeutic options, and prognosis in anti-HCV positive cirrhotic patients with hepatocellular carcinoma. Age Ageing. 2002;31:457–62.
Dohmen K, Shirahama M, Shigematsu H, et al. Optimal treatment strategy for elderly patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2004;19:859–65.
Poon RT, Fan ST, Lo CM, et al. Hepatocellular carcinoma in the elderly: results of surgical and nonsurgical management. Am J Gastroenterol. 1999;94:2460–6.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology-Hepatobiliary Cancers, Version 1. 2011. http://www.nccn.org/professionals/physician_gls/pdf/.hepatobiliary.pdf. Accessed 3 June 2011.
Di Maio M, De Maio E, Perrone F, et al. Hepatocellular carcinoma: systemic treatments. J Clin Gastroenterol. 2002;35:S109–14.
Huang M, Liu G. The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. Cancer Lett. 1999;135:97–105.
Kato A, Miyazaki M, Ambiru S, et al. Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection. J Surg Oncol. 2001;78:110–5.
Kuo MT, Zhao JY, Teeter LD, et al. Activation of multidrug resistance (Pglycoprotein) mdr3/mdr1a gene during the development of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell Growth Differ. 1992;3:531–40.
Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.
Tomizawa M, Shinozaki F, Sugiyama T, et al. Sorafenib suppresses the cell cycle and induces the apoptosis of hepatocellular carcinoma cell lines in serum-free media. Exp Ther Med. 2010;1(5):863–6.
Llovet JM, Ricci S, Mazzaferro V, SHARP Investigators Study Group, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Cheng A, Kang Y, Chen Z. Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma. J Clin Oncol 2008;26; abstr 4509.
Wong H, Cheung TT, Fong Tang Y, et al. The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC). Oncologist. 2011;16:1721–8.
Kim YJ, Jang BK, Kim ES, et al. Hepatocellular carcinoma in the elderly: clinical characteristics, treatment, survival analysis in Korean patients older than 70 years. J Korean Med Sci. 2012;27:1147–54.
Morimoto M, Numata K, Kondo M, et al. Higher discontinuation and lower survival rates are likely in elderly Japanese patients with advanced hepatocellular carcinoma receiving sorafenib. Hepatol Res. 2011;41:296–302.
Di Costanzo GG, Tortora R, De Luca M, et al. Impact of age on toxicity and efficacy of sorafenib-targeted therapy in cirrhotic patients with hepatocellular carcinoma. Med Oncol. 2013;30(1):446.
Hopfner M, Schuppan D, Scherubl H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer. World J Gastroenterol. 2008;14:1–14.
Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–46.
Messerini L, Novelli L, Comin CE. Microvessel density and clinicopathological characteristics in hepatitis C virus and hepatitis B virus related hepatocellular carcinoma. J Clin Pathol. 2004;57:867–71.
Miura H, Miyazaki T, Kuroda M, et al. Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol. 1997;27:854–61.
Yamaguchi R, Yano H, Iemura A, et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology. 1998;28:68–77.
Yamaguchi R, Yano H, Nakashima Y, et al. Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep. 2000;7:725–72.
Chao Y, Li CP, Chau GY, et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol. 2003;10:355–62.
Jeng KS, Sheen IS, Wang YC, et al. Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study. World J Gastroenterol. 2004;10:643–8.
Poon RT, Ho JW, Tong CS, et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg. 2004;91:1354–60.
Hainsworth JD, Burris HA 3rd, Yardley Da, et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie PearlCancer Research Network phase II trial. J Clin Oncol. 2001;19:3500–3505.
Del Mastro L, Perrone F, Repetto L, et al. Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer). Ann Oncol. 2005;16:253–8.
The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999;91:66–72.
Ricci S, Antonuzzo A, Galli L, et al. Gemcitabine monotherapy in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study. Lung Cancer. 2000;27:75–80.
Gridelli C, Cigolari S, Gallo C, et al. Activity toxicity of gemcitabine and gemcitabine plus vinorelbinen in advanced non-small-cell lung cancer elderly patients: phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial. Lung Cancer. 2001;31:277–84.
Nakamura Y, Sekine I, Furuse K, et al. Retro-spective comparison of toxicity and efficacy in phase II trials of 3-h infusions of paclitaxel for patients 70 years of age or older and patients under 70 years of age. Cancer Chemother Pharmacol. 2000;46:114–8.
Sandler A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for nonsmall-cell lung cancer. N Engl J Med. 2006;355:2542–50.
Ebi N, Semba H, Tokunaga SJ, et al. A phase II of gefitinib monotherapy in chemotherapynaive patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:1166–71.
Jackman DM, Yeap BY, Lindeman NI, et al. Phase II clinical trial of chemotherapy-naive patients <70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007;25:760–6.
Eisen T, Oudard S, Szczylik C, et al. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008;100:1454–63.
Lenfant C, Chobanian AV, Jones DW, et al. Seventh report of the Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure (JNC 7): resetting the hypertension sails. Hypertension. 2003;41:1178–9.
Maitland ML, Kasza KE, Karrison T, et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15:6250–7.
Nichols WW, Nicolini FA, Pepine CJ. Determinants of isolated systolic hypertension in the elderly. J Hypertens Suppl. 1992;10:S73–7.
Franklin SS, Gustin W 4th, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308–15.
Humphreys BD, Atkins MB. Rapid development of hypertension by sorafenib: toxicity or target? Clin Cancer Res. 2009;15:5947–9.
Boehm S, Rothermundt C, Hess D, et al. Antiangiogenic drugs in oncology: a focus on drug safety and the elderly—a mini-review. Gerontology. 2010;56:303–9.
Qi Y, Dy GK, Nelson D, et al. Incidence of bleeding and thrombosis among elderly patients (pts) undergoing systemic chemotherapy in advanced non-small cell lung cancer (NSCLC): an analysis of North Central Cancer Treatment Group (NCCTG) trials. J Clin Oncol. 2010;28(15 suppl):e18093.
Acknowledgments
No funding was received for the preparation of this manuscript.
Dr. B Daniele has received consulting and lecture fees from Bayer, Daiichi Sankyo and Novartis. Drs. E Barletta, L Cannella, D Germano and V Tinessa have no conflict of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Germano, D., Tinessa, V., Barletta, E. et al. Targeted Therapy for Advanced Hepatocellular Cancer in the Elderly: Focus on Sorafenib. Drugs Aging 30, 887–892 (2013). https://doi.org/10.1007/s40266-013-0124-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40266-013-0124-6