UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization

Authors
Steven A Curley, MD, FACS
Keith E Stuart, MD
Jonathan M Schwartz, MD
Robert L Carithers, Jr, MD
Klaudia U Hunter, MD
Section Editors
Kenneth K Tanabe, MD
Christopher G Willett, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently occurs in the setting of cirrhosis. The two factors that are most important in determining a patient's prognosis and potential treatment options are the tumor mass and the patient's hepatic reserve. A patient with a solitary tumor <5 cm in diameter and well-preserved hepatic function has an excellent long-term prognosis given the therapeutic options now available. In contrast, patients with multifocal disease and marginal hepatic function have a worse prognosis, and treatment options can be quite limited.

Treatment options are divided into surgical therapies (ie, resection and orthotopic liver transplantation [OLT]) and nonsurgical therapies (ie, radiofrequency ablation [RFA] and other thermal methods of tumor ablation, percutaneous ethanol injection [PEI], cryoablation, transarterial chemoembolization [TACE], radiation therapy [RT], radioembolization, and systemic therapy) [1]. This topic review will cover transarterial embolization, including radioembolization, and external beam RT. Other nonsurgical therapies (RFA, PEI, cryoablation, microwave and laser coagulation) are discussed elsewhere, as are resection, liver transplantation, and systemic therapy for HCC. (See "Nonsurgical therapies for localized hepatocellular carcinoma: Radiofrequency ablation, percutaneous ethanol injection, thermal ablation, and cryoablation" and "Surgical management of potentially resectable hepatocellular carcinoma" and "Liver transplantation for hepatocellular carcinoma" and "Systemic treatment for advanced hepatocellular carcinoma".)

TREATMENT ALGORITHMS AND GENERAL APPROACH TO THE PATIENT WITH LOCALIZED DISEASE

An algorithmic approach to the treatment of hepatocellular cancer (HCC) is shown in the figure (algorithm 1). An alternative treatment algorithm is used by the Barcelona group (algorithm 2) [2]. However, attempts to generate algorithmic approaches to the treatment of HCC are difficult since new treatments and indications for various treatments are evolving rapidly. Furthermore, therapeutic approaches tend to vary based upon underlying liver function, available expertise, as well as variability in the criteria for hepatic resection and orthotopic liver transplantation (OLT). These issues are discussed in detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma".)

With regard to patients who have a single HCC 5 cm or less in diameter and who are not candidates for surgical resection or OLT, the choice of nonsurgical treatment modality is empiric and influenced by local expertise, institutional practice, and location of the lesion. Few trials have directly compared any of the available therapies with one another, and there is little consensus as to when one modality should be chosen over another. Each of these modalities should be employed only in patients in whom liver function is relatively well preserved and in whom there is no extrahepatic tumor spread, vascular invasion, or main portal vein thrombus.

In general, hepatic transarterial embolization is reserved for treatment of an unresectable HCC that is either too large or multifocal for percutaneous ablation techniques such as radiofrequency ablation (RFA) or stereotactic radiotherapy. Transarterial embolization may also be preferred if the location of the lesion makes percutaneous ablation impractical (eg, up against a major vessel, in the dome of the liver). Transarterial embolization is frequently used as a "bridge" to maintain liver transplant eligibility when waiting times for liver transplantation are long.

                                     

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Oct 20 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379:1245.
  2. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100:698.
  3. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359:1734.
  4. Meyer T, Kirkwood A, Roughton M, et al. A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. Br J Cancer 2013; 108:1252.
  5. Brown KT, Do RK, Gonen M, et al. Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone. J Clin Oncol 2016; 34:2046.
  6. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164.
  7. Bruix, J, Sherman, M. Management of hepatocellular carcinoma: an update. AASLD Practice Guideline. Available online at http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf (Accessed on September 21, 2010).
  8. Schwarz RE, Abou-Alfa GK, Geschwind JF, et al. Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement. HPB (Oxford) 2010; 12:313.
  9. Brown KT, Nevins AB, Getrajdman GI, et al. Particle embolization for hepatocellular carcinoma. J Vasc Interv Radiol 1998; 9:822.
  10. Covey AM, Maluccio MA, Schubert J, et al. Particle embolization of recurrent hepatocellular carcinoma after hepatectomy. Cancer 2006; 106:2181.
  11. Hanks BA, Suhocki PV, DeLong DM, et al. The efficacy and safety of transarterial chemoembolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (abstract). J Clin Oncol 2008; 26:236s.
  12. Cammà C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224:47.
  13. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30:6.
  14. Lladó L, Virgili J, Figueras J, et al. A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. Cancer 2000; 88:50.
  15. Chan AO, Yuen MF, Hui CK, et al. A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma. Cancer 2002; 94:1747.
  16. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology 1998; 27:1578.
  17. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. N Engl J Med 1995; 332:1256.
  18. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol 1998; 29:129.
  19. Riaz A, Ryu RK, Kulik LM, et al. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol 2009; 27:5734.
  20. Castrucci M, Sironi S, De Cobelli F, et al. Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization. Abdom Imaging 1996; 21:488.
  21. Takayasu K, Arii S, Matsuo N, et al. Comparison of CT findings with resected specimens after chemoembolization with iodized oil for hepatocellular carcinoma. AJR Am J Roentgenol 2000; 175:699.
  22. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37:429.
  23. Bruix J, Sherman M, Llovet JM, 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; 35:421.
  24. Doffoël M, Bonnetain F, Bouché O, et al. Multicentre randomised phase III trial comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402). Eur J Cancer 2008; 44:528.
  25. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011; :CD004787.
  26. Georgiades CS, Hong K, D'Angelo M, Geschwind JF. Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2005; 16:1653.
  27. Cho YK, Chung JW, Kim JK, et al. Comparison of 7 staging systems for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Cancer 2008; 112:352.
  28. Georgiades CS, Liapi E, Frangakis C, et al. Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization. J Vasc Interv Radiol 2006; 17:1619.
  29. Pentecost MJ, Daniels JR, Teitelbaum GP, Stanley P. Hepatic chemoembolization: safety with portal vein thrombosis. J Vasc Interv Radiol 1993; 4:347.
  30. Luo J, Guo RP, Lai EC, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011; 18:413.
  31. Park JW, Koh YH, Kim HB, et al. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol 2012; 56:1336.
  32. Erhardt A, Kolligs F, Dollinger M, et al. TACE plus sorafenib for the treatment of hepatocellular carcinoma: results of the multicenter, phase II SOCRATES trial. Cancer Chemother Pharmacol 2014; 74:947.
  33. Chao Y, Chung YH, Han G, et al. The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: final results of the START trial. Int J Cancer 2015; 136:1458.
  34. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47:2117.
  35. Sansonno D, Lauletta G, Russi S, et al. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist 2012; 17:359.
  36. Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. J Hepatol 2016; 64:1090.
  37. Liu L, Chen H, Wang M, et al. Combination therapy of sorafenib and TACE for unresectable HCC: a systematic review and meta-analysis. PLoS One 2014; 9:e91124.
  38. Trial information available online at http://www.clinicaltrials.gov/ct2/show/NCT01324076?term=TACE2&rank=1 (Accessed on December 18, 2012).
  39. http://clinicaltrials.gov/ct2/show/NCT01004978?term=sorafenib+and+TACE+and+ECOG&rank=1 (Accessed on July 26, 2013).
  40. Castells A, Bruix J, Ayuso C, et al. Transarterial embolization for hepatocellular carcinoma. Antibiotic prophylaxis and clinical meaning of postembolization fever. J Hepatol 1995; 22:410.
  41. Wigmore SJ, Redhead DN, Thomson BN, et al. Postchemoembolisation syndrome--tumour necrosis or hepatocyte injury? Br J Cancer 2003; 89:1423.
  42. Paye F, Farges O, Dahmane M, et al. Cytolysis following chemoembolization for hepatocellular carcinoma. Br J Surg 1999; 86:176.
  43. Chung JW, Park JH, Han JK, et al. Hepatic tumors: predisposing factors for complications of transcatheter oily chemoembolization. Radiology 1996; 198:33.
  44. Garwood ER, Fidelman N, Hoch SE, et al. Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction. Liver Transpl 2013; 19:164.
  45. Song SY, Chung JW, Han JK, et al. Liver abscess after transcatheter oily chemoembolization for hepatic tumors: incidence, predisposing factors, and clinical outcome. J Vasc Interv Radiol 2001; 12:313.
  46. Kim HK, Chung YH, Song BC, et al. Ischemic bile duct injury as a serious complication after transarterial chemoembolization in patients with hepatocellular carcinoma. J Clin Gastroenterol 2001; 32:423.
  47. Leung TK, Lee CM, Chen HC. Anatomic and technical skill factor of gastroduodenal complication in post-transarterial embolization for hepatocellular carcinoma: a retrospective study of 280 cases. World J Gastroenterol 2005; 11:1554.
  48. Wu GC, Perng WC, Chen CW, et al. Acute respiratory distress syndrome after transcatheter arterial chemoembolization of hepatocellular carcinomas. Am J Med Sci 2009; 338:357.
  49. Kim JT, Heo SH, Choi SM, et al. Cerebral embolism of iodized oil (lipiodol) after transcatheter arterial chemoembolization for hepatocellular carcinoma. J Neuroimaging 2009; 19:394.
  50. Kwok PC, Lam TW, Lam CL, et al. Rare pulmonary complications after transarterial chemoembolisation for hepatocellular carcinoma: two case reports. Hong Kong Med J 2003; 9:457.
  51. Jouneau S, Vauléon E, Caulet-Maugendre S, et al. ¹³¹I-labeled lipiodol-induced interstitial pneumonia: a series of 15 cases. Chest 2011; 139:1463.
  52. Brown DB, Chapman WC, Cook RD, et al. Chemoembolization of hepatocellular carcinoma: patient status at presentation and outcome over 15 years at a single center. AJR Am J Roentgenol 2008; 190:608.
  53. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46:474.
  54. Kruskal JB, Hlatky L, Hahnfeldt P, et al. In vivo and in vitro analysis of the effectiveness of doxorubicin combined with temporary arterial occlusion in liver tumors. J Vasc Interv Radiol 1993; 4:741.
  55. Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2002; 13:S211.
  56. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010; 33:541.
  57. Lammer J, Malagari K, Vogl T, 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; 33:41.
  58. Vogl TJ, Lammer J, Lencioni R, et al. Liver, gastrointestinal, and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: results from the PRECISION V randomized trial. AJR Am J Roentgenol 2011; 197:W562.
  59. van Malenstein H, Maleux G, Vandecaveye V, et al. A randomized phase II study of drug-eluting beads versus transarterial chemoembolization for unresectable hepatocellular carcinoma. Onkologie 2011; 34:368.
  60. Ferrer Puchol MD, la Parra C, Esteban E, et al. [Comparison of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) with conventional transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma]. Radiologia 2011; 53:246.
  61. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22:1545.
  62. Gao S, Yang Z, Zheng Z, et al. Doxorubicin-eluting bead versus conventional TACE for unresectable hepatocellular carcinoma: a meta-analysis. Hepatogastroenterology 2013; 60:813.
  63. Prajapati HJ, Dhanasekaran R, El-Rayes BF, et al. Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with advanced hepatocellular carcinoma. J Vasc Interv Radiol 2013; 24:307.
  64. Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014; 111:255.
  65. www.AngioDynamics.com/pages/products/lc/asp.
  66. Prajapati HJ, Xing M, Spivey JR, et al. Survival, efficacy, and safety of small versus large doxorubicin drug-eluting beads TACE chemoembolization in patients with unresectable HCC. AJR Am J Roentgenol 2014; 203:W706.
  67. Martin RC, Howard J, Tomalty D, et al. Toxicity of irinotecan-eluting beads in the treatment of hepatic malignancies: results of a multi-institutional registry. Cardiovasc Intervent Radiol 2010; 33:960.
  68. Bower M, Metzger T, Robbins K, et al. Surgical downstaging and neo-adjuvant therapy in metastatic colorectal carcinoma with irinotecan drug-eluting beads: a multi-institutional study. HPB (Oxford) 2010; 12:31.
  69. Martin RC, Robbins K, Tomalty D, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World J Surg Oncol 2009; 7:80.
  70. Chung JW. Transcatheter arterial chemoembolization of hepatocellular carcinoma. Hepatogastroenterology 1998; 45 Suppl 3:1236.
  71. Brown DB, Pilgram TK, Darcy MD, et al. Hepatic arterial chemoembolization for hepatocellular carcinoma: comparison of survival rates with different embolic agents. J Vasc Interv Radiol 2005; 16:1661.
  72. Shi M, Lu LG, Fang WQ, et al. Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial. J Natl Cancer Inst 2013; 105:59.
  73. Brown DB, Geschwind JF, Soulen MC, et al. Society of Interventional Radiology position statement on chemoembolization of hepatic malignancies. J Vasc Interv Radiol 2006; 17:217.
  74. Soulen MC. Chemoembolization of hepatic malignancies. Oncology (Williston Park) 1994; 8:77.
  75. Bronowicki JP, Vetter D, Dumas F, et al. Transcatheter oily chemoembolization for hepatocellular carcinoma. A 4-year study of 127 French patients. Cancer 1994; 74:16.
  76. Solomon B, Soulen MC, Baum RA, et al. Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S. population. J Vasc Interv Radiol 1999; 10:793.
  77. Trinchet JC, Ganne-Carrie N, Beaugrand M. Intra-arterial chemoembolization in patients with hepatocellular carcinoma. Hepatogastroenterology 1998; 45 Suppl 3:1242.
  78. Yuen MF, Ooi CG, Hui CK, et al. A pilot study of transcatheter arterial interferon embolization for patients with hepatocellular carcinoma. Cancer 2003; 97:2776.
  79. Stuart K. Chemoembolization in the management of liver tumors. Oncologist 2003; 8:425.
  80. Lin DY, Lin SM, Liaw YF. Non-surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol 1997; 12:S319.
  81. Plentz RR, Lankisch TO, Bastürk M, et al. Prospective analysis of German patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization with or without prophylactic antibiotic therapy. J Gastroenterol Hepatol 2005; 20:1134.
  82. Sieghart W, Hucke F, Pinter M, et al. The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma. Hepatology 2013; 57:2261.
  83. Uchida M, Kohno H, Kubota H, et al. Role of preoperative transcatheter arterial oily chemoembolization for resectable hepatocellular carcinoma. World J Surg 1996; 20:326.
  84. Sueyoshi E, Hayashida T, Sakamoto I, Uetani M. Vascular complications of hepatic artery after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. AJR Am J Roentgenol 2010; 195:245.
  85. Maeda N, Osuga K, Mikami K, et al. Angiographic evaluation of hepatic arterial damage after transarterial chemoembolization for hepatocellular carcinoma. Radiat Med 2008; 26:206.
  86. Kim HC, Chung JW, Lee W, et al. Recognizing extrahepatic collateral vessels that supply hepatocellular carcinoma to avoid complications of transcatheter arterial chemoembolization. Radiographics 2005; 25 Suppl 1:S25.
  87. Adhoute X, Penaranda G, Raoul JL, Bourlière M. Reply to: ''Repeated transarterial chemoembolization: An overfitting effort?''. J Hepatol 2015; 62:1442.
  88. Toyoda H, Kumada T, Tada T, et al. Transarterial chemoembolization for hepatitis B virus-associated hepatocellular carcinoma: improved survival after concomitant treatment with nucleoside analogues. J Vasc Interv Radiol 2012; 23:317.
  89. Perrillo RP. Reactivated hepatitis B due to medical interventions: the clinical spectrum expands. Antivir Ther 2011; 16:947.
  90. Kennedy A, Nag S, Salem R, 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; 68:13.
  91. Raoul JL, Guyader D, Bretagne JF, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med 1994; 35:1782.
  92. Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 1997; 26:1156.
  93. Chua TC, Chu F, Butler SP, et al. Intra-arterial iodine-131-lipiodol for unresectable hepatocellular carcinoma. Cancer 2010; 116:4069.
  94. Carr BI, Kondragunta V, Buch SC, Branch RA. Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study. Cancer 2010; 116:1305.
  95. Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998; 40:583.
  96. Cao X, He N, Sun J, et al. Hepatic radioembolization with Yttrium-90 glass microspheres for treatment of primary liver cancer. Chin Med J (Engl) 1999; 112:430.
  97. Dancey JE, Shepherd FA, Paul K, et al. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres. J Nucl Med 2000; 41:1673.
  98. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 2006; 94:572.
  99. Sangro B, Bilbao JI, Boan J, et al. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006; 66:792.
  100. Vente MA, Wondergem M, van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol 2009; 19:951.
  101. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138:52.
  102. Kokabi N, Camacho JC, Xing M, et al. Open-label prospective study of the safety and efficacy of glass-based yttrium 90 radioembolization for infiltrative hepatocellular carcinoma with portal vein thrombosis. Cancer 2015; 121:2164.
  103. Kolligs FT, Bilbao JI, Jakobs T, et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int 2015; 35:1715.
  104. Kooby DA, Egnatashvili V, Srinivasan S, et al. Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2010; 21:224.
  105. Abdel-Rahman OM, Elsayed Z. Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2016; 2:CD011313.
  106. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008; 47:71.
  107. Salem R, Lewandowski R, Roberts C, et al. Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol 2004; 15:335.
  108. Tsai AL, Burke CT, Kennedy AS, et al. Use of yttrium-90 microspheres in patients with advanced hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2010; 21:1377.
  109. Woodall CE, Scoggins CR, Ellis SF, et al. Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis? J Am Coll Surg 2009; 208:375.
  110. Lau WY, Sangro B, Chen PJ, et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology 2013; 84:311.
  111. Hilgard P, Hamami M, Fouly AE, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010; 52:1741.
  112. D'Avola D, Lñarrairaegui M, Bilbao JI, et al. A retrospective comparative analysis of the effect of Y90-radioembolization on the survival of patients with unresectable hepatocellular carcinoma. Hepatogastroenterology 2009; 56:1683.
  113. Lam MG, Louie JD, Iagaru AH, et al. Safety of repeated yttrium-90 radioembolization. Cardiovasc Intervent Radiol 2013; 36:1320.
  114. Atassi B, Bangash AK, Lewandowski RJ, et al. Biliary sequelae following radioembolization with Yttrium-90 microspheres. J Vasc Interv Radiol 2008; 19:691.
  115. Riaz A, Lewandowski RJ, Kulik LM, et al. Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J Vasc Interv Radiol 2009; 20:1121.
  116. Salem R, Lewandowski RJ, Atassi B, et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol 2005; 16:1627.
  117. Riaz A, Awais R, Salem R. Side effects of yttrium-90 radioembolization. Front Oncol 2014; 4:198.
  118. Sangro B, Gil-Alzugaray B, Rodriguez J, et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 2008; 112:1538.
  119. Young JY, Rhee TK, Atassi B, et al. Radiation dose limits and liver toxicities resulting from multiple yttrium-90 radioembolization treatments for hepatocellular carcinoma. J Vasc Interv Radiol 2007; 18:1375.
  120. Kennedy AS, McNeillie P, Dezarn WA, et al. Treatment parameters and outcome in 680 treatments of internal radiation with resin 90Y-microspheres for unresectable hepatic tumors. Int J Radiat Oncol Biol Phys 2009; 74:1494.
  121. Gil-Alzugaray B, Chopitea A, Iñarrairaegui M, et al. Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology 2013; 57:1078.
  122. Gaba RC, Lewandowski RJ, Kulik LM, et al. Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium-90 radioembolization. Ann Surg Oncol 2009; 16:1587.
  123. Jakobs TF, Saleem S, Atassi B, et al. Fibrosis, portal hypertension, and hepatic volume changes induced by intra-arterial radiotherapy with 90yttrium microspheres. Dig Dis Sci 2008; 53:2556.
  124. Lam MG, Abdelmaksoud MH, Chang DT, et al. Safety of 90Y radioembolization in patients who have undergone previous external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013; 87:323.
  125. Riaz A, Gates VL, Atassi B, et al. Radiation segmentectomy: a novel approach to increase safety and efficacy of radioembolization. Int J Radiat Oncol Biol Phys 2011; 79:163.
  126. Ayav A, Habib N, Jiao LR. Portal hypertension secondary to 90Yttrium microspheres: an unknown complication. J Clin Oncol 2005; 23:8275.
  127. Carr BI, Metes DM. Peripheral blood lymphocyte depletion after hepatic arterial 90Yttrium microsphere therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012; 82:1179.
  128. Ohri N, Dawson LA, Krishnan S, et al. Radiotherapy for Hepatocellular Carcinoma: New Indications and Directions for Future Study. J Natl Cancer Inst 2016; 108.
  129. Culleton S, Jiang H, Haddad CR, et al. Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma. Radiother Oncol 2014; 111:412.
  130. Lanciano R, Lamond J, Yang J, et al. Stereotactic body radiation therapy for patients with heavily pretreated liver metastases and liver tumors. Front Oncol 2012; 2:23.
  131. Seol SW, Yu JI, Park HC, et al. Treatment outcome of hepatic re-irradiation in patients with hepatocellular carcinoma. Radiat Oncol J 2015; 33:276.
  132. Park W, Lim DH, Paik SW, et al. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2005; 61:1143.
  133. Seong J, Park HC, Han KH, Chon CY. Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: a retrospective study of 158 patients. Int J Radiat Oncol Biol Phys 2003; 55:329.
  134. Seo YS, Kim JN, Keum B, et al. Radiotherapy for 65 patients with advanced unresectable hepatocellular carcinoma. World J Gastroenterol 2008; 14:2394.
  135. Koom WS, Seong J, Han KH, et al. Is local radiotherapy still valuable for patients with multiple intrahepatic hepatocellular carcinomas? Int J Radiat Oncol Biol Phys 2010; 77:1433.
  136. Liang SX, Zhu XD, Lu HJ, et al. Hypofractionated three-dimensional conformal radiation therapy for primary liver carcinoma. Cancer 2005; 103:2181.
  137. Ben-Josef E, Normolle D, Ensminger WD, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 2005; 23:8739.
  138. Kim DY, Park W, Lim DH, et al. Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma. Cancer 2005; 103:2419.
  139. Yamada K, Izaki K, Sugimoto K, et al. Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2003; 57:113.
  140. Oh D, Lim DH, Park HC, et al. Early three-dimensional conformal radiotherapy for patients with unresectable hepatocellular carcinoma after incomplete transcatheter arterial chemoembolization: a prospective evaluation of efficacy and toxicity. Am J Clin Oncol 2010; 33:370.
  141. Mornex F, Girard N, Beziat C, et al. Feasibility and efficacy of high-dose three-dimensional-conformal radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies--mature results of the French Phase II RTF-1 trial. Int J Radiat Oncol Biol Phys 2006; 66:1152.
  142. Voroney JP, Brock KK, Eccles C, et al. Prospective comparison of computed tomography and magnetic resonance imaging for liver cancer delineation using deformable image registration. Int J Radiat Oncol Biol Phys 2006; 66:780.
  143. Chia-Hsien Cheng J, Chuang VP, Cheng SH, et al. Unresectable hepatocellular carcinoma treated with radiotherapy and/or chemoembolization. Int J Cancer 2001; 96:243.
  144. Guo WJ, Yu EX. Evaluation of combined therapy with chemoembolization and irradiation for large hepatocellular carcinoma. Br J Radiol 2000; 73:1091.
  145. Seong J, Keum KC, Han KH, et al. Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 1999; 43:393.
  146. Yasuda S, Ito H, Yoshikawa M, et al. Radiotherapy for large hepatocellular carcinoma combined with transcatheter arterial embolization and percutaneous ethanol injection therapy. Int J Oncol 1999; 15:467.
  147. Li B, Yu J, Wang L, et al. Study of local three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for patients with stage III hepatocellular carcinoma. Am J Clin Oncol 2003; 26:e92.
  148. Guo WJ, Yu EX. The long-term efficacy of combined chemoembolization and local irradiation in the treatment of patients with large hepatocellular carcinoma. Hepatogastroenterology 2003; 50:500.
  149. Ishikura S, Ogino T, Furuse J, et al. Radiotherapy after transcatheter arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Clin Oncol 2002; 25:189.
  150. Tazawa J, Maeda M, Sakai Y, et al. Radiation therapy in combination with transcatheter arterial chemoembolization for hepatocellular carcinoma with extensive portal vein involvement. J Gastroenterol Hepatol 2001; 16:660.
  151. Lin CS, Jen YM, Chiu SY, et al. Treatment of portal vein tumor thrombosis of hepatoma patients with either stereotactic radiotherapy or three-dimensional conformal radiotherapy. Jpn J Clin Oncol 2006; 36:212.
  152. Yoon SM, Lim YS, Won HJ, et al. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. Int J Radiat Oncol Biol Phys 2012; 82:2004.
  153. Huo YR, Eslick GD. Transcatheter Arterial Chemoembolization Plus Radiotherapy Compared With Chemoembolization Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol 2015; 1:756.
  154. Huang YJ, Hsu HC, Wang CY, et al. The treatment responses in cases of radiation therapy to portal vein thrombosis in advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2009; 73:1155.
  155. Nakagawa K, Yamashita H, Shiraishi K, et al. Radiation therapy for portal venous invasion by hepatocellular carcinoma. World J Gastroenterol 2005; 11:7237.
  156. Yamada K, Soejima T, Sugimoto K, et al. Pilot study of local radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Jpn J Clin Oncol 2001; 31:147.
  157. Toya R, Murakami R, Baba Y, et al. Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular carcinoma. Radiother Oncol 2007; 84:266.
  158. Kim JY, Yoo EJ, Jang JW, et al. Hypofractionated radiotheapy using helical tomotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Radiat Oncol 2013; 8:15.
  159. Tanaka Y, Nakazawa T, Komori S, et al. Radiotherapy for patients with unresectable advanced hepatocellular carcinoma with invasion to intrahepatic large vessels: efficacy and outcomes. J Gastroenterol Hepatol 2014; 29:352.
  160. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer 2010; 10:475.
  161. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013; 31:1631.
  162. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma. J Clin Oncol 2016; 34:452.
  163. Kang JK, Kim MS, Cho CK, et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012; 118:5424.
  164. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011; 81:e447.
  165. Huang WY, Jen YM, Lee MS, et al. Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012; 84:355.
  166. Dewas S, Bibault JE, Mirabel X, et al. Prognostic factors affecting local control of hepatic tumors treated by Stereotactic Body Radiation Therapy. Radiat Oncol 2012; 7:166.
  167. Honda Y, Kimura T, Aikata H, et al. Pilot study of stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma. Hepatogastroenterology 2014; 61:31.
  168. Sanuki N, Takeda A, Oku Y, et al. Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients. Acta Oncol 2014; 53:399.
  169. Jang WI, Kim MS, Bae SH, et al. High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. Radiat Oncol 2013; 8:250.
  170. Ohri N, Jackson A, Mendez Romero A, et al. Local control following stereotactic body radiotherapy for liver tumors: a preliminary report of the AAPM Working Group for SBRT (abstract). Int J Radiat Oncol Biol Phys 2014; 90 (1, suppl):S52.
  171. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008; 26:657.
  172. Choi BO, Jang HS, Kang KM, et al. Fractionated stereotactic radiotherapy in patients with primary hepatocellular carcinoma. Jpn J Clin Oncol 2006; 36:154.
  173. Price TR, Perkins SM, Sandrasegaran K, et al. Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer 2012; 118:3191.
  174. Yoon SM, Lim YS, Park MJ, et al. Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One 2013; 8:e79854.
  175. Xi M, Zhang L, Zhao L, et al. Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis. PLoS One 2013; 8:e63864.
  176. Facciuto ME, Singh MK, Rochon C, et al. Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response. J Surg Oncol 2012; 105:692.
  177. Dawson LA, Normolle D, Balter JM, et al. Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys 2002; 53:810.
  178. Cheng JC, Liu HS, Wu JK, et al. Inclusion of biological factors in parallel-architecture normal-tissue complication probability model for radiation-induced liver disease. Int J Radiat Oncol Biol Phys 2005; 62:1150.
  179. Chiba T, Tokuuye K, Matsuzaki Y, et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res 2005; 11:3799.
  180. Bush DA, Hillebrand DJ, Slater JM, Slater JD. High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial. Gastroenterology 2004; 127:S189.
  181. Sugahara S, Oshiro Y, Nakayama H, et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2010; 76:460.
  182. Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2005; 104:794.
  183. Kawashima M, Furuse J, Nishio T, et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005; 23:1839.
  184. Nakayama H, Sugahara S, Tokita M, et al. Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer 2009; 115:5499.
  185. Fukumitsu N, Sugahara S, Nakayama H, et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2009; 74:831.
  186. Hong TS, Wo JY, Yeap BY, et al. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol 2016; 34:460.
  187. Dawson LA. Protons or photons for hepatocellular carcinoma? Let's move forward together. Int J Radiat Oncol Biol Phys 2009; 74:661.
  188. Reed GB Jr, Cox AJ Jr. The human liver after radiation injury. A form of veno-occlusive disease. Am J Pathol 1966; 48:597.
  189. Sanuki N, Takeda A, Oku Y, et al. Influence of liver toxicities on prognosis after stereotactic body radiation therapy for hepatocellular carcinoma. Hepatol Res 2015; 45:540.
  190. Park HC, Seong J, Han KH, et al. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002; 54:150.
  191. Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 2006; 106:1653.
  192. Osmundson EC, Wu Y, Luxton G, et al. Predictors of toxicity associated with stereotactic body radiation therapy to the central hepatobiliary tract. Int J Radiat Oncol Biol Phys 2015; 91:986.
  193. Takahashi S, Kimura T, Kenjo M, et al. Case reports of portal vein thrombosis and bile duct stenosis after stereotactic body radiation therapy for hepatocellular carcinoma. Hepatol Res 2014; 44:E273.