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An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma
Infectious Agents and Cancer volume 10, Article number: 9 (2015)
Hepatocellular carcinoma is a highly aggressive malignancy and is the third leading cause of cancer-related deaths worldwide. Although surgery is currently considered the most effective curative treatment for this type of cancer, it is note that most of patients have a poor prognosis due to chemioresistence and tumor recurrence. Loco-regional therapies, including radiofrequency ablation, surgical resection and transcatheter arterial chemoembolization play a major role in the clinical management of hepatocellular carcinoma. In order to improve the treatment outcome of patients diagnosed with this disease, several in vivo studies by using different techniques on cancer mouse models have been performed. This review will focus on the latest papers on the efficacy of loco-regional therapy and combined treatments in patients and mouse models of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a worldwide malignancy and the third leading causes of cancer-related deaths [1,2]. The incidence of primary liver cancer is increasing in several developed countries and the increase will likely continue for some decades as a result of viral infection of hepatitis C [3,4]. Liver transplant and surgery are considered the potential effective curative treatment for HCC, although most patients have a poor prognosis due to unresectable disease at presentation, multidrug resistance (MDR)  and tumor recurrence. In most cases, this pathology develops in patients with chronic liver disease (70-90% of all patients) . In order to bypass these problems, several regional cancer therapy and multimodality treatments, have been developed [7,8]. Additionally, to improve the treatment outcome of patients diagnosed with HCC, several in vivo studies by using different techniques on HCC mouse models have been performed. This review will focus on the latest papers on the efficacy of loco-regional therapy and combined treatments in patients and mouse models of hepatocellular carcinoma.
Loco-regional treatments in patients with hepatocellular carcinoma
Loco-regional therapies, including image-guided tumor ablation, percutaneous ethanol injection (PEI), transcatheterial chemoembolization (TACE) and transarterial radioembolization (TARE) are commonly used as a nonsurgical approach for HCC patients [9-11]. For patients with early-stage unresectable HCC, image-guided tumor ablation (chemical or thermal) is recommended. Chemical ablation is used for treatment of nodular-type HCC and it is based on PEI which leads to tumor necrosis. One limit of PEI is represented by tumor recurrence in HCC patients as well as needs of multiple sessions [12,13]. Acetic acid injection is considered an alternative to PEI for chemical ablation of HCC, although it is not commonly used due to lower survival outcomes of patients . Among thermal ablative therapies used in clinical practice, radiofrequency ablation (RFA) which induces thermal injury to the cancer tissue through electromagnetic energy deposition, is considered as the standard treatment for local ablation of HCC due to its anticancer effects and survival benefit for patients [6,15-22]; . On the contrary, several clinical studies have demonstrated that radiofrequency ablation for HCC increased risk of local tumor progression and incomplete ablation [23-26]. To bypass these problems, novel thermal techniques (microwave ablation; MWA, laser ablation and cryoablation) [27-29] and non-thermal techniques (reversible electroporation ECT, irreversible electroporation IRE and light-activated drug therapy), for HCC tumor ablation have been developed. Clinical studies show that non-thermal techniques seem to overcome the limitations of chemical and thermal-based techniques in the treatment of HCC [30,31]. Another approach used to noninvasive multinodular HCC tumors at the intermediate stage, is TACE, which belongs to image-guided transcatheter tumor therapy. This technique is based on an intra-arterial infusion of a drug (mainly cisplatin or doxorubicin) with or without a viscous emulsion, followed by embolization of the blood vessel with embolic agents that leads to ischemia and cytotoxic effects or liver internal radiation using yttrium-90 (90Y) spheres. There are two types of TACE; the first one is called conventional TACE that consists in the administration of an anticancer in lipiodol emulsion followed by embolic agents [16,24,25,32]; and the second one, is called TACE with drug-eluting beads that uses embolic microspheres that release the drug in the sustained-released system [33,34]. Several studies have demonstrated that TACE with drug-eluting beads significantly increases efficacy and safety for patients respect to conventional TACE [35,36]. A new technique that can be considered a potential treatment for patients with HCC alternative to TACE, is TARE. This approach consists in the infusion of radioactive substances including microsphere containing yittrium-90 (90Y) or similar agents, into hepatic artery [37-39]. By using this technique, these microspheres will be delivered to the area which surrounds the tumor, with low-penetration to the tumor itself. Several clinical studies have demonstrated that radioembolization treatment with 90Y can be safely used in patients with HCC [40,41], although this technique leads to several possible side-effects (gastric ulceration, pancreatitis, radiation pneumonitis, etc.). Further investigations will be necessary in the setting of randomized controlled trials (RCT). It is important to underline that any loco-regional treatment described above, summarized in Table 1, leads to a high rate of tumor recurrence in patients. For this reason, new combined treatments for HCC have been developed. These combined strategies are focused on the synergy between molecular targeted drugs (i.e. sorafenib, etc.) and loco-regional treatments [42-46]. Clinical trials on these new techniques are currently ongoing and can be used as therapy of election for patients with HCC.
The efficacy of Loco-regional treatment in mouse models of hepatocellular carcinoma
Loco-regional therapies are considered the best treatments in patients with unresectable HCC. One of the principal obstacles implicated in their unsuccessful therapy is MDR. In order to improve the treatment outcome of patients diagnosed with HCC, several in vivo studies by using loco-regional techniques and combined treatments on HCC mouse models have been performed. The first study that tested an effective strategy for the treatment of HCC with MDR, demonstrated that chemicals in combination with adriamycin (ADM), mitomycin, 5-fluoruracil (5-FU), mutant human tumor necrosis factor-α (rmhTNF-α) and hydroxyapatite nanoparticles (nHAPs), could be beneficial for the local treatment of advanced HCC in vitro and in vivo experimental conditions. Specifically, it has been showed that the chemicals acted in synergism with rmhTNF-α and nHAP in suppressing the growth of human hepatoma MDR liver hepatocellular (HepG2)/ADM cells by inducing apoptosis and by reducing tumor growth in liver hepatocellular mouse model . Another group demonstrated that Glypican-3 (GPC3), a carcinoembryonic antigen, could be considered as an ideal target for anticancer immunotherapy against HCC. In this study, the authors compared the induction of the GPC3-specific T-cell-mediated immune response after loco regional therapies, such as RFA or TACE in HCC patients and tumor-bearing mice [53,54]. Recently has been developed a new bioelectrical technology in cancer therapy, the nanosecond pulsed electric field (nsPEF). NsPEF can generate pulsed high voltage electric field in ultra-short nanosecond duration, to produce immediate power which could ablate targeted tumor . It has been reported that nsPEF treatment, is efficient to control hepatocellular carcinoma growth in HCC mouse model. In this study, was investigated the use of nsPEF on a human HCC cell lines and a high pulmonary metastatic potential HCC xenograft mouse model (HCCLM3). The multiple fractionated dose of nsPEFs efficiently inhibited tumors without increasing the risk of secondary metastasis, indicating that nsPEF can be used as a loco-regional therapy for hepatocellular carcinoma . Recently it has been demonstrated that targeted gold nanoconjugates in combination with RF halted the growth of subcutaneous human hepatoma (Hep3B) xenografts. These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls . Taken together all these different data, summarized in Table 2, suggest that these combined treatments could represent new methods to deliver effective and safe therapies to patients with advanced HCC.
Percutaneous ethanol injection
Transcatheter arterial chemoembolization
Randomized controlled trials
Recombinant mutant human tumour necrosis factor-alpha
Liver hepatocellular carcinoma
Nanosecond pulsed electric field
High metastatic hepatocellular carcinoma
Human hepatoma 3b
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.
Izzo F, Albino V, Palaia R, Piccirillo M, Tatangelo F, Granata V, et al. Hepatocellular carcinoma: preclinical data on a dual-lumen catheter kit for fibrin sealant infusion following loco-regional treatments. Infect Agent Cancer. 2014;9(1):39.
Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138(2):513–21. 21 e1-6.
Olsen AH, Parkin DM, Sasieni P. Cancer mortality in the United Kingdom: projections to the year 2025. Br J Cancer. 2008;99(9):1549–54.
Boucher E, Forner A, Reig M, Bruix J. New drugs for the treatment of hepatocellular carcinoma. Liver Int. 2009;29 Suppl 1:148–58.
Kumagi T, Hiasa Y, Hirschfield GM. Hepatocellular carcinoma for the non-specialist. BMJ. 2009;339:b5039.
Lencioni R. Loco-regional treatment of hepatocellular carcinoma in the era of molecular targeted therapies. Oncology. 2010;78 Suppl 1:107–12.
Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. 2010;52(2):762–73.
Himoto T, Kurokohchi K, Watanabe S, Masaki T. Recent advances in radiofrequency ablation for the management of hepatocellular carcinoma. Hepat Mon. 2012;12(10 HCC):e5945.
Bleicher RJ, Allegra DP, Nora DT, Wood TF, Foshag LJ, Bilchik AJ. Radiofrequency ablation in 447 complex unresectable liver tumors: lessons learned. Ann Surg Oncol. 2003;10(1):52–8.
Breton M, Haggerty J, Roberge D, Freeman GK. Management continuity in local health networks. Int J Integr Care. 2012;12:e14.
Khan KN, Yatsuhashi H, Yamasaki K, Yamasaki M, Inoue O, Koga M, et al. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol. 2000;32(2):269–78.
Koda M, Tanaka H, Murawaki Y, Horie Y, Suou T, Kawasaki H, et al. Liver perforation: a serious complication of percutaneous acetic acid injection for hepatocellular carcinoma. Hepatogastroenterology. 2000;47(34):1110–2.
Huo TI, Lee SD, Wu JC. Screening for hepatocellular carcinoma in high-risk patients: Western versus Eastern virus. Hepatology. 2003;38(1):269. author reply 70.
Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003;228(1):235–40.
Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm. Gastroenterology. 2004;127(6):1714–23.
Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129(1):122–30.
Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut. 2005;54(8):1151–6.
Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009;49(2):453–9.
Curley SA, Izzo F, Delrio P, Ellis LM, Granchi J, Vallone P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg. 1999;230(1):1–8.
Pearson AS, Izzo F, Fleming RY, Ellis LM, Delrio P, Roh MS, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg. 1999;178(6):592–9.
Izzo F, Barnett Jr CC, Curley SA. Radiofrequency ablation of primary and metastatic malignant liver tumors. Adv Surg. 2001;35:225–50.
Komorizono Y, Oketani M, Sako K, Yamasaki N, Shibatou T, Maeda M, et al. Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency ablation. Cancer. 2003;97(5):1253–62.
Llovet JM, Vilana R, Bianchi L, Bru C. [Radiofrequency in the treatment of hepatocellular carcinoma]. Gastroenterol Hepatol. 2001;24(6):303–11.
Llovet JM, Vilana R, Bru C, Bianchi L, Salmeron JM, Boix L, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology. 2001;33(5):1124–9.
Teratani T, Yoshida H, Shiina S, Obi S, Sato S, Tateishi R, et al. Radiofrequency ablation for hepatocellular carcinoma in so-called high-risk locations. Hepatology. 2006;43(5):1101–8.
Yu NC, Lu DS, Raman SS, Dupuy DE, Simon CJ, Lassman C, et al. Hepatocellular carcinoma: microwave ablation with multiple straight and loop antenna clusters–pilot comparison with pathologic findings. Radiology. 2006;239(1):269–75.
Pacella CM, Francica G, Di Lascio FM, Arienti V, Antico E, Caspani B, et al. Long-term outcome of cirrhotic patients with early hepatocellular carcinoma treated with ultrasound-guided percutaneous laser ablation: a retrospective analysis. J Clin Oncol. 2009;27(16):2615–21.
Shimizu T, Sakuhara Y, Abo D, Hasegawa Y, Kodama Y, Endo H, et al. Outcome of MR-guided percutaneous cryoablation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2009;16(6):816–23.
Lencioni R, Crocetti L, De Simone P, Filipponi F. Loco-regional interventional treatment of hepatocellular carcinoma: techniques, outcomes, and future prospects. Transpl Int. 2010;23(7):698–703.
Guo Y, Zhang Y, Nijm GM, Sahakian AV, Yang GY, Omary RA, et al. Irreversible electroporation in the liver: contrast-enhanced inversion-recovery MR imaging approaches to differentiate reversibly electroporated penumbra from irreversibly electroporated ablation zones. Radiology. 2011;258(2):461–8.
Bruix J, Llovet JM. Hepatocellular carcinoma: is surveillance cost effective? Gut. 2001;48(2):149–50.
Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46(3):474–81.
Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52.
Malagari K, Pomoni M, Kelekis A, Pomoni A, Dourakis S, Spyridopoulos T, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010;33(3):541–51.
Nicolini A, Martinetti L, Crespi S, Maggioni M, Sangiovanni A. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21(3):327–32.
Geschwind JF, Salem R, Carr BI, Soulen MC, Thurston KG, Goin KA, et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology. 2004;127(5 Suppl 1):S194–205.
Ibrahim SM, Lewandowski RJ, Ryu RK, Sato KT, Gates VL, Mulcahy MF, et al. Radiographic response to yttrium-90 radioembolization in anterior versus posterior liver segments. Cardiovasc Intervent Radiol. 2008;31(6):1124–32.
Salem R, Hunter RD. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma: a review. Int J Radiat Oncol Biol Phys. 2006;66(2 Suppl):S83–8.
Sangro B, Bilbao JI, Boan J, Martinez-Cuesta A, Benito A, Rodriguez J, et al. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2006;66(3):792–800.
Kulik LM, Atassi B, van Holsbeeck L, Souman T, Lewandowski RJ, Mulcahy MF, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. 2006;94(7):572–86.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, 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(1):25–34.
Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49(5):523–9.
Virmani S, Rhee TK, Ryu RK, Sato KT, Lewandowski RJ, Mulcahy MF, et al. Comparison of hypoxia-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors. J Vasc Interv Radiol. 2008;19(10):1483–9.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60.
Raut CP, Izzo F, Marra P, Ellis LM, Vauthey JN, Cremona F, et al. Significant long-term survival after radiofrequency ablation of unresectable hepatocellular carcinoma in patients with cirrhosis. Ann Surg Oncol. 2005;12(8):616–28.
Curley SA, Izzo F. Radiofrequency ablation of hepatocellular carcinoma. Minerva Chir. 2002;57(2):165–76.
Curley SA, Izzo F. Radiofrequency ablation of primary and metastatic hepatic malignancies. Int J Clin Oncol. 2002;7(2):72–81.
Curley SA, Cusack Jr JC, Tanabe KK, Stoelzing O, Ellis LM. Advances in the treatment of liver tumors. Curr Probl Surg. 2002;39(5):449–571.
Golfieri R, Bilbao JI, Carpanese L, Cianni R, Gasparini D, Ezziddin S, et al. Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma. J Hepatol. 2013;59(4):753–61.
Li G, Dong S, Qu J, Sun Z, Huang Z, Ye L, et al. Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumour necrosis factor-alpha in chemotherapy of multidrug-resistant hepatocellular carcinoma. Liver Int. 2010;30(4):585–92.
Nobuoka D, Motomura Y, Shirakawa H, Yoshikawa T, Kuronuma T, Takahashi M, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012;40(1):63–70.
Beebe SJ, Fox PM, Rec LJ, Willis EL, Schoenbach KH. Nanosecond, high-intensity pulsed electric fields induce apoptosis in human cells. FASEB J. 2003;17(11):1493–5.
Yin S, Chen X, Hu C, Zhang X, Hu Z, Yu J, et al. Nanosecond pulsed electric field (nsPEF) treatment for hepatocellular carcinoma: a novel locoregional ablation decreasing lung metastasis. Cancer Lett. 2014;346(2):285–91.
Raoof M, Corr SJ, Zhu C, Cisneros BT, Kaluarachchi WD, Phounsavath S, et al. Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma. Nanomedicine. 2014;10(6):1121–30.
The authors would like to specially thank Massimiliano Spinelli Data Manager of S.S.D. Animal Sperimentation, from ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI “FONDAZIONE GIOVANNI PASCALE” – IRCCS - ITALIA, for kind help in providing informatics assistance.
The authors declare that they have no competing interests.
All authors performed the literature research and wrote the manuscript. All authors read and approved the final manuscript.
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Bimonte, S., Barbieri, A., Palaia, R. et al. An overview of loco-regional treatments in patients and mouse models for hepatocellular carcinoma. Infect Agents Cancer 10, 9 (2015). https://doi.org/10.1186/s13027-015-0004-2
- Loco-regional treatments
- Hepatocellular carcinoma
- Drug delivery