CardioVascular and Interventional Radiology

, Volume 31, Issue 3, pp 468–476

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current Results

  • Joachim Kettenbach
  • Alfred Stadler
  • Isabella v. Katzler
  • Rüdiger Schernthaner
  • Melanie Blum
  • Johannes Lammer
  • Thomas Rand
Review/State of the Art


Transarterial chemoembolization (TACE) involves the emulsification of a chemotherapeutic agent in a viscous drug carrier, delivered intra-arterially to liver tumor for maximum effect. TACE reduces arterial inflow, diminishes washout of the chemotherapeutic agent, and decreases systemic exposure. Despite evidence of some clinical success with TACE, a new type of microspheres with drug-eluting capabilities may offer a precisely controlled and sustainable release of the chemotherapeutic agent into the tumor bed. In animal trials tumor necrosis (approaching 100%) was greatest at 7 days, with significantly lower plasma concentrations of doxorubicin than in control animals treated with doxorubicin intra-arterially. Clinically, drug-eluting microspheres loaded with doxorubicin, either at 75 mg/m2 or at a fixed dose of 150 mg, were used recently and no severe disorders of the hepatic function were observed postprocedure, while a substantial reduction of the fetoprotein levels occurred. An interim analysis of the first 15 patients from the Hong Kong group at 3 months showed an objective response rate of 61.54% and 53.84% according to EASL criteria and RECIST criteria, respectively, and a survival rate of 93.3%. In this paper we present how to use microspheres loaded with doxorubicin and review their clinical value and preliminary performance for treatment of unresectable liver cancer.


Carcinoma Hepatocellular Chemoembolization Therapeutic Liver Doxorubicin microspheres Embolic agents Drug delivery 


  1. 1.
    Aliberti C, Tilli M, Benea G, Fiorentini G (2006) Trans–arterial chemoembolization (tace) of liver metastases from colorectal cancer using irinotecan-eluting beads: preliminary results. Anticancer Res 26:3793–3795PubMedGoogle Scholar
  2. 2.
    Andresen TL, Jensen SS, Jorgensen K (2005) Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release. Prog Lipid Res 44:68–97PubMedCrossRefGoogle Scholar
  3. 3.
    Brown KT (2004) Fatal pulmonary complications after arterial embolization with 40–120-μm tris-acryl gelatin microspheres. J Vasc Interv Radiol 15:197–200PubMedCrossRefGoogle Scholar
  4. 4.
    Brown KT, Nevins AB, Getrajdman GI, Brody LA, Kurtz RC, Fong Y, Blumgart LH (1998) Particle embolization for hepatocellular carcinoma. J Vasc Interv Radiol 9:822–828PubMedGoogle Scholar
  5. 5.
    Bruix J, Llovet JM (2002) Prognostic assessment and evaluation of the benefits of treatment. J Clin Gastroenterol 35:S138–S142PubMedCrossRefGoogle Scholar
  6. 6.
    Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35:421–430PubMedCrossRefGoogle Scholar
  7. 7.
    Chung JW, Park JH, Han JK, Choi BI, Han MC, Lee HS, Kim CY (1996) Hepatic tumors: predisposing factors for complications of transcatheter oily chemoembolization. Radiology 198:33–40PubMedGoogle Scholar
  8. 8.
    Covey AM, Maluccio MA, Schubert J, BenPorat L, Brody LA, Sofocleous CT, Getrajdman GI, Fong Y, Brown KT (2006) Particle embolization of recurrent hepatocellular carcinoma after hepatectomy. Cancer 106:2181–2189PubMedCrossRefGoogle Scholar
  9. 9.
    de Baere T, Teriitehau C, Deschamps F, Cazejust J, Abdel Rehim M, Hechelhammer L (2006) Transarterial chemoembolization of patients with neuroendocrine hepatic metastases using drug eluting beads. Eur Radiol 16:C84Google Scholar
  10. 10.
    Dumortier J, Chapuis F, Borson O, Davril B, Scoazec JY, Poncet G, Henry L, Boillot O, Mion F, Berger F, Partensky C, Paliard P, Valette PJ (2006) Unresectable hepatocellular carcinoma: survival and prognostic factors after lipiodol chemoembolisation in 89 patients. Dig Liver Dis 38:125–133PubMedGoogle Scholar
  11. 11.
    Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987–992PubMedGoogle Scholar
  12. 12.
    Gabizon AA (1994) Liposomal anthracyclines. Hematol Oncol Clin North Am 8:431–450PubMedGoogle Scholar
  13. 13.
    Gao J, Qian F, Szymanski-Exner A, Stowe N, Haaga J (2002) In vivo drug distribution dynamics in thermoablated and normal rabbit livers from biodegradable polymers. J Biomed Mater Res 62:308–314PubMedCrossRefGoogle Scholar
  14. 14.
    Garnick MB, Ensminger WD, Israel M (1979) A clinical-pharmacological evaluation of hepatic arterial infusion of adriamycin. Cancer Res 39:4105–4110PubMedGoogle Scholar
  15. 15.
    Hong K, Georgiades CS, Geschwind JF (2006) Technology insight: Image-guided therapies for hepatocellular carcinoma—intra-arterial and ablative techniques. Nat Clin Pract Oncol 3:315–324PubMedCrossRefGoogle Scholar
  16. 16.
    Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF (2006) New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 12:2563–2567PubMedCrossRefGoogle Scholar
  17. 17.
    Johnson PJ, Kalayci C, Dobbs N, Raby N, Metivier EM, Summers L, Harper P, Williams R (1991) Pharmacokinetics and toxicity of intraarterial adriamycin for hepatocellular carcinoma: effect of coadministration of lipiodol. J Hepatol 13:120–127PubMedCrossRefGoogle Scholar
  18. 18.
    Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314PubMedCrossRefGoogle Scholar
  19. 19.
    Lewis AL, Gonzalez MV, Lloyd AW, Hall B, Tang Y, Willis SL, Leppard SW, Wolfenden LC, Palmer RR, Stratford PW (2006) DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 17:335–342PubMedCrossRefGoogle Scholar
  20. 20.
    Lewis AL, Taylor RR, Hall B, Gonzalez MV, Willis SL, Stratford PW (2006) Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of hepatic arterial embolization. J Vasc Interv Radiol 17:1335–1343PubMedGoogle Scholar
  21. 21.
    Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739PubMedCrossRefGoogle Scholar
  22. 22.
    Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171PubMedCrossRefGoogle Scholar
  23. 23.
    Lopez RR Jr., Pan SH, Hoffman AL, Ramirez C, Rojter SE, Ramos H, McMonigle M, Lois J (2002) Comparison of transarterial chemoembolization in patients with unresectable, diffuse vs focal hepatocellular carcinoma. Arch Surg 137:653–657, discussion 657–658PubMedCrossRefGoogle Scholar
  24. 24.
    Malagari K, Chatzimichail K, Alexopoulou E, Economou GP, Letsou DI, Vergadis V, Loggitsi D, Kelekis DA, Gouliamos A (2006) Hehepatocellular carcinoma chemoembolization with DC beads. Eur Radiol 16:C24Google Scholar
  25. 25.
    Muller HJ, Port RE, Grubert M, Hilger RA, Scheulen M, Mross K (2003) The influence of liver metastases on the pharmacokinetics of doxorubicin—a population-based pharmacokinetic project of the CESAR-APOH. Int J Clin Pharmacol Ther 41:598–599PubMedGoogle Scholar
  26. 26.
    Osuga K, Murakami T, Nakamura H, Hori S (2001) [A new embolic material: Sap-microsphere]. Nippon Rinsho 59(Suppl 6):534–538PubMedGoogle Scholar
  27. 27.
    Padhani AR, Ollivier L (2001) The recist (response evaluation criteria in solid tumors) criteria: implications for diagnostic radiologists. Br J Radiol 74:983–986PubMedGoogle Scholar
  28. 28.
    Pelage JP, Walker WJ, Dref OL (2002) Uterine necrosis after uterine artery embolization for leiomyoma. Obstet Gynecol 99:676–677, author reply 677PubMedCrossRefGoogle Scholar
  29. 29.
    Rand T, Loewe C, Schoder M, Schmook MT, Peck-Radosavljevic M, Kettenbach J, Wolf F, Schneider B, Lammer J (2005) Arterial embolization of unresectable hepatocellular carcinoma with use of microspheres, lipiodol, and cyanoacrylate. CardioVasc Interv Radiol 28:313–318CrossRefGoogle Scholar
  30. 30.
    Siegal T, Horowitz A, Gabizon A (1995) Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 83:1029–1037PubMedCrossRefGoogle Scholar
  31. 31.
    Sigurdson ER, Ridge JA, Daly JM (1986) Intra-arterial infusion of doxorubicin with degradable starch microspheres. Improvement of hepatic tumor drug uptake. Arch Surg 121:1277–1281PubMedCrossRefGoogle Scholar
  32. 32.
    Stadler A, Lomoschitz FM, Schernthaner RE, Kettenbach J, Katzler I, Lammer J (2006) Chemoembolization of unresectable hepatocellular carcinoma with doxorubicin loaded microspheres: a pilot study. In: Radiological Society of North America: Scientific Assembly and Annual Meeting Program, p 252Google Scholar
  33. 33.
    Tancredi T, McCuskey PA, Kan Z, Wallace S (1999) Changes in rat liver microcirculation after experimental hepatic arterial embolization: comparison of different embolic agents. Radiology 211:177–181PubMedGoogle Scholar
  34. 34.
    Taylor RR, Tang Y, Gonzalez MV, Stratford PW, Lewis AL (2007) Irinotecan drug eluting beads for use in chemoembolization: in vitro and in vivo evaluation of drug release properties. Eur J Pharm Sci 30:7–14PubMedCrossRefGoogle Scholar
  35. 35.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  36. 36.
    Varela M, Real MI, Brunet M, et al. (2005) Chemoembolization of hepatocellular carcinoma with drug eluting beads reduces the systemic availability of doxorubicin. A pharmacokinetic assessment. Presented at AASLD, San Francisco, CA, November 11–15, abstract P485Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Joachim Kettenbach
    • 1
  • Alfred Stadler
    • 1
  • Isabella v. Katzler
    • 1
  • Rüdiger Schernthaner
    • 1
  • Melanie Blum
    • 1
  • Johannes Lammer
    • 1
  • Thomas Rand
    • 1
  1. 1.Division of Angiography and Interventional Radiology, Department of RadiologyMedical University Vienna, General Hospital of ViennaViennaAustria

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