Advertisement

Radiation Therapy in Hepatocellular Carcinoma

  • Maria A. Hawkins
Living reference work entry

Abstract

Hepatocellular carcinoma is a global problem as is the fourth cause of cancer death and the incidence is increasing. There are several models for classifying the disease which include biologocal features such as tumor number, size and clinical features such as liver function and performance status. The most commonly used in Barcelona liver clinic classification. This guides the different liver directed therapy options that are available including surgery, transarterial chemoembolization, radiofrequency ablation. Advances in radiation oncology offer the opportunity to deliver high dose of radiation using either stereotactic ablative radiotherapy or protons. The aim is to maximise the tumour dose and minimize the non involved liver toxicity. The initial prospective data shows promising local control and currently radiotherapy presents an alternative or combined modality to use with other local directed therapies. Further research is required to incorporate radiotherapy in standard of care.

Keywords

Hepatocellular carcinoma Liver directed therapies Stereotactic ablative radiotherapy Protons 

References

  1. Aitken KL, Hawkins MA. The role of radiotherapy and Chemoradiation in the Management of Primary Liver Tumours. Clin Oncol (R Coll Radiol). 2014;26:569.CrossRefGoogle Scholar
  2. Aitken KL, Hawkins MA. Stereotactic body radiotherapy for liver metastases. Clin Oncol (R Coll Radiol). 2015;27(5):307–15.CrossRefGoogle Scholar
  3. Benedict SH, Yenice KM, Followill D, Galvin JM, Hinson W, Kavanagh B, Keall P, Lovelock M, Meeks S, Papiez L, Purdie T, Sadagopan R, Schell MC, Salter B, Schlesinger DJ, Shiu AS, Solberg T, Song DY, Stieber V, Timmerman R, Tome WA, Verellen D, Wang L, Yin FF. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):4078–101.CrossRefPubMedGoogle Scholar
  4. Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri E. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67(2):302–9.CrossRefPubMedGoogle Scholar
  5. Bouza C, Lopez-Cuadrado T, Alcazar R, Saz-Parkinson Z, Amate JM. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol. 2009;9:31.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, Sofocleous CT, Jarnagin WR, D’Angelica MI, Allen PJ, Erinjeri JP, Brody LA, O’Neill GP, Johnson KN, Garcia AR, Beattie C, Zhao B, Solomon SB, Schwartz LH, DeMatteo R, Abou-Alfa GK. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046–53.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J, E. P. o. E. o. HCC. 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.CrossRefPubMedGoogle Scholar
  8. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G, Investigators R. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66.CrossRefPubMedGoogle Scholar
  9. Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, Dinniwell RE, Kassam Z, Ringash J, Cummings B, Sykes J, Sherman M, Knox JJ, Dawson LA. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31(13):1631–9.CrossRefPubMedGoogle Scholar
  10. Cardenes HR, Price TR, Perkins SM, Maluccio M, Kwo P, Breen TE, Henderson MA, Schefter TE, Tudor K, Deluca J, Johnstone PA. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol. 2010;12(3):218–25.CrossRefPubMedGoogle Scholar
  11. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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.CrossRefPubMedGoogle Scholar
  12. Cheng AL, Thongprasert S, Lim HY, Sukeepaisarnjaroen W, Yang TS, Wu CC, Chao Y, Chan SL, Kudo M, Ikeda M, Kang YK, Pan H, Numata K, Han G, Balsara B, Zhang Y, Rodriguez AM, Zhang Y, Wang Y, Poon RT. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2016;64(3): 774–84.CrossRefPubMedGoogle Scholar
  13. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85.PubMedGoogle Scholar
  14. Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, Choo SP, Cheow PC, Chotipanich C, Lim K, Lesmana LA, Manuaba TW, Yoong BK, Raj A, Law CS, Cua IHY, Lobo RR, Teh CSC, Kim YH, Jong YW, Han HS, Bae SH, Yoon HK, Lee RC, Hung CF, Peng CY, Liang PC, Bartlett A, Kok KYY, Thng CH, Low AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC, G. Asia-Pacific Hepatocellular Carcinoma Trials. SIRveNIB: selective internal radiation therapy versus Sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36:1913. JCO2017760892.CrossRefPubMedGoogle Scholar
  15. Duran R, Chapiro J, Schernthaner RE, Geschwind JF. Systematic review of catheter-based intra-arterial therapies in hepatocellular carcinoma: state of the art and future directions. Br J Radiol. 2015;88(1052):20140564.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Edge SB, American Joint Committee on Cancer. AJCC cancer staging manual. In: New York. London: Springer; 2010.Google Scholar
  17. European Association for Study of, L., R. European Organisation for and C. Treatment of. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Eur J Cancer. 2012;48(5):599–641.CrossRefGoogle Scholar
  18. Hanna GG, Murray L, Patel R, Jain S, Aitken KL, Franks KN, van As N, Tree A, Hatfield P, Harrow S, McDonald F, Ahmed M, Saran FH, Webster GJ, Khoo V, Landau D, Eaton DJ, Hawkins MA. UK consensus on normal tissue dose constraints for stereotactic radiotherapy. Clin Oncol (R Coll Radiol). 2018;30(1):5–14.CrossRefGoogle Scholar
  19. Hong TS, Wo JY, Yeap BY, Ben-Josef E, McDonnell EI, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Goyal L, Murphy JE, Javle MM, Wolfgang JA, Drapek LC, Arellano RS, Mamon HJ, Mullen JT, Yoon SS, Tanabe KK, Ferrone CR, Ryan DP, DeLaney TF, Crane CH, Zhu AX. 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(5):460–8.CrossRefPubMedGoogle Scholar
  20. Ibarra RA, Rojas D, Snyder L, Yao M, Fabien J, Milano M, Katz A, Goodman K, Stephans K, El-Gazzaz G, Aucejo F, Miller C, Fung J, Lo S, Machtay M, Sanabria JR. Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta Oncol. 2012;51(5):575–83.CrossRefPubMedGoogle Scholar
  21. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Avina J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24.CrossRefPubMedGoogle Scholar
  22. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O’Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33(6):550–8.CrossRefPubMedGoogle Scholar
  23. Kang JK, Kim MS, Cho CK, Yang KM, Yoo HJ, Kim JH, Bae SH, Jung DH, Kim KB, Lee DH, Han CJ, Kim J, Park SC, Kim YH. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer. 2012;118(21):5424–31.CrossRefPubMedGoogle Scholar
  24. Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N, Kaneko S, Tsubouchi H, Suh DJ, Furuse J, Okusaka T, Tanaka K, Matsui O, Wada M, Yamaguchi I, Ohya T, Meinhardt G, Okita K. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011;47(14):2117–27.CrossRefPubMedGoogle Scholar
  25. Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, Yang J, Lu L, Tak WY, Yu X, Lee JH, Lin SM, Wu C, Tanwandee T, Shao G, Walters IB, Dela Cruz C, Poulart V, Wang JH. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology. 2014;60(5):1697–707.CrossRefPubMedGoogle Scholar
  26. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163.CrossRefPubMedGoogle Scholar
  27. Kutlu OC, Chan JA, Aloia TA, Chun YS, Kaseb AO, Passot G, Yamashita S, Vauthey JN, Conrad C. Comparative effectiveness of first-line radiofrequency ablation versus surgical resection and transplantation for patients with early hepatocellular carcinoma. Cancer. 2017;123(10):1817–27.CrossRefPubMedGoogle Scholar
  28. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37(2):429–42.CrossRefPubMedGoogle Scholar
  29. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, S. I. S. Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.CrossRefPubMedGoogle Scholar
  30. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31(4):864–71.CrossRefPubMedGoogle Scholar
  31. Mendez Romero A, Wunderink W, Hussain SM, De Pooter JA, Heijmen BJ, Nowak PC, Nuyttens JJ, Brandwijk RP, Verhoef C, Ijzermans JN, Levendag PC. Stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase i–ii study. Acta Oncol. 2006;45(7):831–7.CrossRefPubMedGoogle Scholar
  32. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, Stubbs C, Stocken DD, Wall L, Watkinson A, Hacking N, Evans TRJ, Collins P, Hubner RA, Cunningham D, Primrose JN, Johnson PJ, Palmer DH. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565–75.CrossRefPubMedGoogle Scholar
  33. Ohri N, Tome WA, Mendez Romero A, Miften M, Ten Haken RK, Dawson LA, Grimm J, Yorke E, Jackson A. Local control after stereotactic body radiation therapy for liver tumors. Int J Radiat Oncol Biol Phys. 2018; 6. pii: S0360-3016(17)34525-X.  https://doi.org/10.1016/j.ijrobp.2017.12.288 [Epub ahead of print].
  34. Pineda JA, Aguilar-Guisado M, Rivero A, Giron-Gonzalez JA, Ruiz-Morales J, Merino D, Rios-Villegas MJ, Macias J, Lopez-Cortes LF, Camacho A, Merchante N, Del Valle J, I. Grupo para el Estudio de las Hepatitis Viricas de la Sociedad Andaluza de Enfermedades. Natural history of compensated hepatitis C virus-related cirrhosis in HIV-infected patients. Clin Infect Dis. 2009;49(8):1274–82.CrossRefPubMedGoogle Scholar
  35. Pollom EL, Chin AL, Diehn M, Loo BW, Chang DT. Normal tissue constraints for abdominal and thoracic stereotactic body radiotherapy. Semin Radiat Oncol. 2017;27(3):197–208.CrossRefPubMedGoogle Scholar
  36. Qi WX, Fu S, Zhang Q, Guo XM. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol. 2015;114(3):289–95.CrossRefPubMedGoogle Scholar
  37. Sahgal A, Roberge D, Schellenberg D, Purdie TG, Swaminath A, Pantarotto J, Filion E, Gabos Z, Butler J, Letourneau D, Masucci GL, Mulroy L, Bezjak A, Dawson LA, Parliament M, F. The Canadian Association of Radiation Oncology-Stereotactic Body Radiotherapy Task. The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy. Clin Oncol (R Coll Radiol). 2012;24(9):629–39.CrossRefGoogle Scholar
  38. Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57(11):1592–6.CrossRefGoogle Scholar
  39. Teh SH, Sheppard BC, Schwartz J, Orloff SL. Model for end-stage liver disease score fails to predict perioperative outcome after hepatic resection for hepatocellular carcinoma in patients without cirrhosis. Am J Surg. 2008;195(5):697–701.CrossRefPubMedGoogle Scholar
  40. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, Sherman M, Dawson LA. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008;26(4):657–64.CrossRefPubMedGoogle Scholar
  42. Vauthey JN, Dixon E, Abdalla EK, Helton WS, Pawlik TM, Taouli B, Brouquet A, Adams RB, A. American Hepato-Pancreato-Biliary, O. Society of Surgical and T. Society for Surgery of the Alimentary. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12(5):289–99.CrossRefGoogle Scholar
  43. Velec M, Haddad CR, Craig T, Wang L, Lindsay P, Brierley J, Brade A, Ringash J, Wong R, Kim J, Dawson LA. Predictors of liver toxicity following stereotactic body radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2017;97(5): 939–46.CrossRefPubMedGoogle Scholar
  44. Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aube C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G, S. T. Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624–36.CrossRefPubMedGoogle Scholar
  45. Wallace MC, Preen D, Jeffrey GP, Adams LA. The evolving epidemiology of hepatocellular carcinoma: a global perspective. Expert Rev Gastroenterol Hepatol. 2015;9(6):765–79.CrossRefPubMedGoogle Scholar
  46. Yang B, Zan RY, Wang SY, Li XL, Wei ML, Guo WH, You X, Li J, Liao ZY. Radiofrequency ablation versus percutaneous ethanol injection for hepatocellular carcinoma: a meta-analysis of randomized controlled trials. World J Surg Oncol. 2015;13:96.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Yu J, Yu XL, Han ZY, Cheng ZG, Liu FY, Zhai HY, Mu MJ, Liu YM, Liang P. Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial. Gut. 2017;66(6):1172–3.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.CRUK MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK

Personalised recommendations