Locoregional Therapies for Hepatocellular Carcinoma

  • Beau ToskichEmail author
Part of the Molecular Pathology Library book series (MPLB)


Despite the widespread implementation of surveillance programs for populations with chronic liver disease, more than half of patients with hepatocellular carcinoma (HCC) are diagnosed outside of criteria for curative treatment [1]. Many who receive therapy are subject to new or recurrent disease as a result of an underlying malignant hepatic parenchymal field defect [2]. Management of liver cancer is further complicated by variable hepatic substrate function which, in advanced disease, may pose greater threat to life than HCC [3]. Unlike traditional TNM staging systems, HCC treatment algorithms must factor physiologic reserve, patient performance, and expected disease control rates after transplantation. The Barcelona Clinic Liver Cancer (BCLC) classification is generally adopted in Western nations as the standard protocol to manage patients with HCC as endorsed by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) [3, 4].


  1. 1.
    Kim WR, Gores GJ, Benson JT, Therneau TM, Melton LJ. Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology. 2005;129(2):486–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Cucchetti A, Piscaglia F, Caturelli E, Benvegnù L, Vivarelli M, Ercolani G, et al. Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population. Ann Surg Oncol. 2009;16(2):413–22. Available from: PubMedCrossRefGoogle Scholar
  3. 3.
    Bruix J, Sherman M. AASLD PRACTICE GUIDELINE Management of hepatocellular carcinoma : an update. Hepatology. 2010;42:1–35. Available from: Google Scholar
  4. 4.
    Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35(3):421–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. HPB (Oxford). 2005;7(1):26–34.CrossRefGoogle Scholar
  6. 6.
    Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, Marrero JA, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37–47.PubMedCrossRefGoogle Scholar
  7. 7.
    McEvoy SH, McCarthy CJ, Lavelle LP, Moran DE, Cantwell CP, Skehan SJ, et al. Hepatocellular carcinoma: illustrated guide to systematic radiologic diagnosis and staging according to guidelines of the American Association for the Study of Liver Diseases. Radiographics. 2013;33(6):1653–68. Available from: Scholar
  8. 8.
    Erhardt A, Lörke J, Vogt C, Poremba C, Willers R, Sagir A, et al. [Transient elastography for diagnosing liver cirrhosis]. Dtsch Med Wochenschr. 2006;131(49):2765–9. Available from:
  9. 9.
    Shiina S, Tateishi R, Imamura M, Teratani T, Koike Y, Sato S, et al. Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors. Liver Int. 2012;32(9):1434–42. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bouza C, López-Cuadrado T, Alcázar R, Saz-Parkinson Z, Amate J. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol. 2009;9(1):31. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Gervais DA, Goldberg SN, Brown DB, Soulen MC, Millward SF, Rajan DK. Society of Interventional Radiology position statement on percutaneous radiofrequency ablation for the treatment of liver tumors. J Vasc Interv Radiol. 2009;20(7):S342–7. PubMedCrossRefGoogle Scholar
  12. 12.
    Dufour JF, Greten TF, Raymond E, Roskams T, De T, Ducreux M, et al. Clinical Practice Guidelines EASL – EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma European Organisation for Research and Treatment of Cancer. J Hepatol. 2012;56(4):908–43. Available from: CrossRefGoogle Scholar
  13. 13.
    Brace CL. Radiofrequency and microwave ablation of the liver, lung, kidney, and bone: what are the differences? Curr Probl Diagn Radiol. 2009;38(3):135–43. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Weis S, Franke A, Mössner J, Jakobsen JC, Schoppmeyer K. Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma. Cochrane database Syst Rev. 2013;12:CD003046. Available from:
  15. 15.
    Lencioni R, Crocetti L. Local-regional treatment of hepatocellular carcinoma. Radiology. 2012;262(1):43–58. Available from: PubMedCrossRefGoogle Scholar
  16. 16.
    Feng K, Ma K-S. Value of radiofrequency ablation in the treatment of hepatocellular carcinoma. World J Gastroenterol. 2014;20(20):5987–98. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK. Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev. 2007;33(5):437–47. Available from: PubMedCrossRefGoogle Scholar
  18. 18.
    Kumar N, Gaba RC, Knuttinen MG, Omene BO, Martinez BK, Owens CA, et al. Tract seeding following radiofrequency ablation for hepatocellular carcinoma: prevention, detection, and management. Semin Intervent Radiol. 2011;28:187–92.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Brace CL. Microwave tissue ablation: biophysics, technology, and applications. Crit Rev Biomed Eng. 2010;38(1):65–78. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Zhang L, Wang N, Shen Q, Cheng W, Qian GJ. Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma. PLoS One. 2013;8(10):1–8.Google Scholar
  21. 21.
    Groeschl RT, Pilgrim CHC, Hanna EM, Simo KA, Swan RZ, Sindram D, et al. Microwave ablation for hepatic malignancies: a multiinstitutional analysis. Ann Surg. 2014;259(6):1195–200. Available from: PubMedCrossRefGoogle Scholar
  22. 22.
    Gage AA. History of cryosurgery. Semin Surg Oncol. 1998;14(2):99–109. Available from: PubMedCrossRefGoogle Scholar
  23. 23.
    Yiu WK, Basco MT, Aruny JE, Cheng SWK, Sumpio BE. Cryosurgery: a review. Int J Angiol. 2007;16(1):1–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Seifert JK, Stewart GJ, Hewitt PM, Bolton EJ, Junginger T, Morris DL. Interleukin-6 and tumor necrosis factor-alpha levels following hepatic cryotherapy: association with volume and duration of freezing. World J Surg. 1999;23(10):1019–26. Available from: PubMedCrossRefGoogle Scholar
  25. 25.
    Kariappa SM, Morris DL. Cryotherapy—a mature ablation technique. HPB (Oxford). 2006;8(3):179–81. Available from: CrossRefGoogle Scholar
  26. 26.
    Awad T, Thorlund K, Gluud C. Cryotherapy for hepatocellular carcinoma. Cochrane Database Syst Rev. 2009;7(4):CD007611.Google Scholar
  27. 27.
    Rong G, Bai W, Wang C. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases. Front Med. 2015;9(1):63–71.PubMedCrossRefGoogle Scholar
  28. 28.
    Granot Y, Rubinsky B. Mass transfer model for drug delivery in tissue cells with reversible electroporation. Int J Heat Mass Transf. 2008;51(23–24):5610–6. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Faroja M, Ahmed M, Appelbaum L, Ben-David E, Moussa M, Sosna J, et al. Irreversible electroporation ablation: is all the damage nonthermal? Radiology. 2013;266(2):462–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Onik G, Mikus P, Rubinsky B. Irreversible electroporation: implications for prostate ablation. Technol Cancer Res Treat. 2007;6:295–300.PubMedCrossRefGoogle Scholar
  31. 31.
    Scheffer HJ, Nielsen K, De Jong MC, Van Tilborg AA, Vieveen JM, Bouwman A, et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy. J Vasc Interv Radiol. 2014;25(7):997–1011. PubMedCrossRefGoogle Scholar
  32. 32.
    Martin RCG. Irreversible electroporation of locally advanced pancreatic head adenocarcinoma. J Gastrointest Surg. 2013;17(10):1850–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Cannon R, Ellis S, Hayes D, Narayanan G, Martin RCG. Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. J Surg Oncol. 2013;107(5):544–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Lencioni R, Izzo F, Vilgrain V, Crocetti L, Ricke J, Bruix J. Irreversible electroporation for the treatment of early-stage hepatocellular carcinoma: a prospective multicenter phase II clinical trial. J Vasc Interv Radiol. 2012;23 (6):853.e3. Available from:\n Scholar
  35. 35.
    Eichler K, Zangos S, Gruber-Rouh T, Vogl TJ, Mack MG. Magnetic resonance-guided laser-induced thermotherapy in patients with oligonodular hepatocellular carcinoma: long-term results over a 15-year period. J Clin Gastroenterol. 2012;46(9):796–801. Available from: PubMedCrossRefGoogle Scholar
  36. 36.
    Kennedy A, Nag S, Salem R, Murthy R, McEwan AJ, Nutting C, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007;68(1):13–23. Available from: PubMedCrossRefGoogle Scholar
  37. 37.
    Kruskal JB, Hlatky L, Hahnfeldt P, Teramoto K, Stokes KR, Clouse ME. In vivo and in vitro analysis of the effectiveness of doxorubicin combined with temporary arterial occlusion in liver tumors. J Vasc Interv Radiol. 1993;4(6):741–7. Available from: PubMedCrossRefGoogle Scholar
  38. 38.
    Lewandowski RJ, Mulcahy MF, Kulik LM, Riaz A, Ryu RK, Baker TB, et al. Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort. Radiology. 2010;255(3):955–65. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    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. PubMedCrossRefGoogle Scholar
  40. 40.
    Luo D, Wang Z, Wu J, Jiang C, Wu J. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int. 2014;2014:409272. Available from: PubMedPubMedCentralGoogle Scholar
  41. 41.
    Gurney H. How to calculate the dose of chemotherapy. Br J Cancer. 2002;86:1297–302.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Quirk M, Yun K, Saab S. Management of hepatocellular carcinoma with portal vein thrombosis. World J Gatroenterol. 2015;21(12):3462–71.CrossRefGoogle Scholar
  43. 43.
    Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet (London, England). 2002;359(9319):1734–9. Available from: CrossRefGoogle Scholar
  44. 44.
    Lo C-M, Ngan H, Tso W-K, Liu C-L, Lam C-M, Poon RT-P, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164–71. Available from: PubMedCrossRefGoogle Scholar
  45. 45.
    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. Available from: PubMedCrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    Aoki T, Imamura H, Hasegawa K, Matsukura A, Sano K, Sugawara Y, et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg. 2004;139(7):766–74.PubMedCrossRefGoogle Scholar
  48. 48.
    May BJ, Madoff DC. Portal vein embolization: rationale, technique, and current application. Semin Intervent Radiol. 2012;29(212):81–9.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ribero D, Abdalla E. Tumor progression after preoperative portal vein embolization. Br J Surg. 2007;256(5):812–7; discussion 817–8. Available from:
  50. 50.
    Kataria T, Rawat S, Sinha SN, Negi PS, Garg C, Bhalla NK, et al. Intensity modulated radiotherapy in abdominal malignancies: our experience in reducing the dose to normal structures as compared to the gross tumor. J Cancer Res Ther. 2006;2(4):161–5. Available from: PubMedCrossRefGoogle Scholar
  51. 51.
    Cremonesi M, Chiesa C, Strigari L, Ferrari M, Botta F, Guerriero F, et al. Radioembolization of hepatic lesions from a radiobiology and dosimetric perspective. Front Oncol. 2014;4:210. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lewandowski RJ, Salem R. Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. Semin Intervent Radiol. 2006;23(1):64–72.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Padia SA, Kwan SW, Roudsari B, Monsky WL, Coveler A, Harris WP. Superselective yttrium-90 radioembolization for hepatocellular carcinoma yields high response rates with minimal toxicity. J Vasc Interv Radiol. 2014;25(7):1067–73. Available from:\n\n
  54. 54.
    Vouche M, Habib A, Ward TJ, Kim E, Kulik L, Ganger D, et al. Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy. Hepatology. 2014;60(1):192–201.PubMedCrossRefGoogle Scholar
  55. 55.
    Thuluvath P. Vascular invasion is the most important predictor of survival in HCC, but how do we find it? J Clin Gastroenterol. 2009;2(43):101–2.CrossRefGoogle Scholar
  56. 56.
    Pracht M, Edeline J, Lenoir L, Latournerie M, Mesbah H, Audrain O, et al. Lobar hepatocellular carcinoma with ipsilateral portal vein tumor thrombosis treated with yttrium-90 glass microsphere radioembolization: preliminary results. Int J Hepatol. 2013;2013:827649. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Lau W-Y, Sangro B, Chen P-J, Cheng S-Q, Chow P, Lee R-C, et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology. 2013;84(5):311–8. Available from: PubMedCrossRefGoogle Scholar
  58. 58.
    Siddiqi NH, Devlin PM. Radiation lobectomy-a minimally invasive treatment model for liver cancer: case report. J Vasc Interv Radiol. 2009;20(5):664–9. PubMedCrossRefGoogle Scholar
  59. 59.
    Vouche M, Lewandowski RJ, Atassi R, Memon K, Gates VL, Ryu RK, et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013;59(5):1029–36. PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hilgard P, Hamami M, Fouly AE, Scherag A, Müller S, Ertle J, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology. 2010;52(5):1741–9. Available from: PubMedCrossRefGoogle Scholar
  61. 61.
    Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47(1):71–81.PubMedCrossRefGoogle Scholar
  62. 62.
    Lewandowski RJ, Kulik LM, Riaz A, Senthilnathan S, Mulcahy MF, Ryu RK, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9:1920–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140(2):497–507.e2. PubMedCrossRefGoogle Scholar
  64. 64.
    Salem R, Gilbertsen M, Butt Z, Memon K, Vouche M, Hickey R, et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol. 2013;11(10):1358–65.e1. Available from: PubMedCrossRefGoogle Scholar
  65. 65.
    Seinstra BA, Defreyne L, Lambert B, Lam MGEH, Verkooijen HM, van Erpecum KJ, et al. Transarterial radioembolization versus chemoembolization for the treatment of hepatocellular carcinoma (TRACE): study protocol for a randomized controlled trial. Trials. 2012;13:144. Available from: /pmc/articles/PMC3493260/?report=abstractPubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yan S, Xu D, Sun B. Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: a meta-analysis. Dig Dis Sci. 2013;58(7):2107–13. Available from: PubMedCrossRefGoogle Scholar
  67. 67.
    Jiang G, Xiaojun X, Sontgao R. Combining transarterial chemoembolization with radiofrequency ablation for hepatocellular carcinoma. Tumor Biol. 2014;35(4):3405–8.CrossRefGoogle Scholar
  68. 68.
    Lu Z, Wen F, Guo Q, Liang H, Mao X, Sun H. Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: a meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol. 2012;25(2):187–94. Available from: CrossRefGoogle Scholar
  69. 69.
    Maluccio M, Covey AM, Gandhi R, Gonen M, Getrajdman GI, Brody LA, et al. Comparison of survival rates after bland arterial embolization and ablation versus surgical resection for treating solitary hepatocellular carcinoma up to 7 cm. J Vasc Interv Radiol. 2005;16(7):955–61. Available from: PubMedCrossRefGoogle Scholar
  70. 70.
    Erhardt A, Kolligs F, Dollinger M, Schott E, Wege H, Bitzer M, et al. TACE plus sorafenib for the treatment of hepatocellular carcinoma: results of the multicenter, phase II SOCRATES trial. Cancer Chemother Pharmacol. 2014;74(5):947–54. Available from: PubMedCrossRefGoogle Scholar
  71. 71.
    Hickey R, Mulcahy MF, Lewandowski RJ, Gates VL, Vouche M, Habib A, et al. Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization. Int J Radiat Oncol Biol Phys. 2014;88(5):1025–31. Available from: PubMedCrossRefGoogle Scholar
  72. 72.
    Ricke J, Bulla K, Kolligs F, Peck-Radosavljevic M, Reimer P, Sangro B, et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2014;35:620–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Kulik L, Vouche M, Koppe S, Lewandowski RJ, Mulcahy MF, Ganger D, et al. Prospective randomized pilot study of Y90+/−sorafenib as bridge to transplantation in hepatocellular carcinoma. J Hepatol. 2014;61(2):309–17. Available from: PubMedCrossRefGoogle Scholar
  74. 74.
    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60. Available from: PubMedCrossRefGoogle Scholar
  75. 75.
    Riaz A, Memon K, Miller FH, Nikolaidis P, Kulik LM, Lewandowski RJ, et al. Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic-pathologic correlation. J Hepatol. 2011;54(4):695–704. Available from: PubMedCrossRefGoogle Scholar
  76. 76.
    Bibault J-E, Dewas S, Vautravers-Dewas C, Hollebecque A, Jarraya H, Lacornerie T, et al. Stereotactic body radiation therapy for hepatocellular carcinoma: prognostic factors of local control, overall survival, and toxicity. PLoS One. 2013;8(10):e77472. Available from: PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Chan ACY, Cheung TT, Fan ST, Chok KSH, Chan SC, Poon RTP, et al. Survival analysis of high-intensity focused ultrasound therapy versus radiofrequency ablation in the treatment of recurrent hepatocellular carcinoma. Ann Surg. 2013;257(4):686–92. Available from: PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of RadiologyUniversity of Florida College of MedicineGainesvilleUSA

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