Annals of Surgical Oncology

, Volume 24, Issue 7, pp 1843–1851 | Cite as

Liver Transplantation is a Preferable Alternative to Palliative Therapy for Selected Patients with Advanced Hepatocellular Carcinoma

  • Aloysious D. Aravinthan
  • Silvio G. Bruni
  • Adam C. Doyle
  • Hla-Hla Thein
  • Nicolas Goldaracena
  • Assaf Issachar
  • Leslie B. Lilly
  • Nazia Selzner
  • Mamatha Bhat
  • Boraiah Sreeharsha
  • Markus Selzner
  • Anand Ghanekar
  • Mark S. Cattral
  • Ian D. McGilvray
  • Paul D. Greig
  • Eberhard L. Renner
  • David R. Grant
  • Gonzalo Sapisochin
Hepatobiliary Tumors



Patients with hepatocellular carcinoma (HCC) beyond the traditional criteria (advanced HCC) are typically offered palliation, which is associated with a 3-year survival rate lower than 30%. This study aimed to describe the outcomes for a subset of patients with advanced HCC who satisfied the Extended Toronto Criteria (ETC) and were listed for liver transplantation (LT).


All patients listed in the Toronto liver transplantation program with HCC beyond both the Milan and University of California, San Francisco criteria were included in this study. Data were extracted from the prospectively collected electronic database. All radiologic images were reviewed by two independent radiologists. The primary end point was patient survival.


Between January 1999 and August 2014, 96 patients with advanced HCC were listed for LT, and 62 (65%) of these patients received bridging therapy while on the waiting list. Bridging therapy led to a significant reduction in tumor progression (p = 0.02) and tumor burden (p < 0.001). The majority of those listed underwent LT (n = 69, 72%). Both tumor progression on waiting list (hazard ratio [HR] 4.973; range1.599–15.464; p = 0.006) and peak alpha-fetoprotein (AFP) at 400 ng/ml or higher (HR, 4.604; range 1.660–12.768; p = 0.003) were independently associated with waiting list dropout. Post-LT HCC recurrence occurred in 35% of the patients (n = 24). Among those with HCC recurrence, survival was significantly better for those who received curative treatment (p = 0.004). The overall actuarial survival rates from the listing were 76% at 1 year, 56% at 3 years, and 47% at 5 years, and the corresponding rates from LT were 93, 71, and 66%.


Liver transplantation provides significantly better survival rates than palliation for patients with selected advanced HCC.


Liver Transplantation Sorafenib Tace Tumor Burden Stereotactic Body Radiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



There are no conflicts of interest.

Supplementary material

10434_2017_5789_MOESM1_ESM.docx (34 kb)
Supplementary material 1 (DOCX 34 kb)


  1. 1.
    Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    European Association for the Study of the L, European Organisation for R, Treatment of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.CrossRefGoogle Scholar
  3. 3.
    Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 2011;17(Suppl 2):S44–57.CrossRefPubMedGoogle Scholar
  5. 5.
    Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–403.CrossRefPubMedGoogle Scholar
  6. 6.
    Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007;7:2587–96.CrossRefPubMedGoogle Scholar
  7. 7.
    Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150:835–53.CrossRefPubMedGoogle Scholar
  8. 8.
    Iwatsuki S, Gordon RD, Shaw BW Jr, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg. 1985;202:401–7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Cillo U, Giuliani T, Polacco M, et al. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J Gastroenterol. 2016;22:232–52.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology. 2016;64:2077–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Sandroussi C, Dawson LA, Lee M, et al. Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma. Transpl Int. 2010;23:299–306.CrossRefPubMedGoogle Scholar
  15. 15.
    Toso C, Meeberg G, Hernandez-Alejandro R, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology. 2015;62:158–65.CrossRefPubMedGoogle Scholar
  16. 16.
    Yang P, Zeng ZC, Wang BL, et al. The degree of Lipiodol accumulation can be an indicator of successful treatment for unresectable hepatocellular carcinoma (HCC) patients—in the case of transcatheter arterial chemoembolization (TACE) and external beam radiotherapy (EBRT). J Cancer. 2016;7:1413–20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhao Y, Li H, Bai W, et al. Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: a multicenter clinical study of 606 HCC patients. Int J Cancer. 2016;139:928–37.CrossRefPubMedGoogle Scholar
  18. 18.
    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;64:1090–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Lance C, McLennan G, Obuchowski N, et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2011;22:1697–705.CrossRefPubMedGoogle Scholar
  20. 20.
    Moreno-Luna LE, Yang JD, Sanchez W, et al. Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2013;36:714–23.CrossRefPubMedGoogle Scholar
  21. 21.
    El Fouly A, Ertle J, El Dorry A, et al. In intermediate-stage hepatocellular carcinoma: radioembolization with yttrium-90 or chemoembolization? Liver Int. 2015;35:627–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Thein HH, Isaranuwatchai W, Campitelli MA, et al. Health care costs associated with hepatocellular carcinoma: a population-based study. Hepatology. 2013;58:1375–84.CrossRefPubMedGoogle Scholar
  23. 23.
    Belli LS, Berenguer M, Cortesi PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J Hepatol. 2016;65:524–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Mazzaferro V. Squaring the circle of selection and allocation in liver transplantation for HCC: an adaptive approach. Hepatology. 2016;63:1707–17.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Olthoff KM, Smith AR, Abecassis M, et al. Defining long-term outcomes with living donor liver transplantation in North America. Ann Surg. 2015;262:465–75, discussion 473–465.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Selzner M, Kashfi A, Cattral MS, et al. Live donor liver transplantation in high MELD score recipients. Ann Surg. 2010;251:153–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Rossler F, Sapisochin G, Song G, et al. Defining benchmarks for major liver surgery: a multicenter analysis of 5202 living liver donors. Ann Surg. 2016;264:492–500.CrossRefPubMedGoogle Scholar
  29. 29.
    Bittermann T, Niu B, Hoteit MA, Goldberg D. Waitlist priority for hepatocellular carcinoma beyond milan criteria: a potentially appropriate decision without a structured approach. Am J Transplant. 2014;14:79–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Schmitt TM, Kumer SC, Shah N, et al. Liver transplantation for T3 lesions has higher waiting list mortality but similar survival compared to T1 and T2 lesions. Ann Hepatol. 2010;9:390–6.PubMedGoogle Scholar
  31. 31.
    Mehta N, Sarkar M, Dodge JL, et al. Intention to treat outcome of T1 hepatocellular carcinoma with the “wait and not ablate” approach until meeting T2 criteria for liver transplant listing. Liver Transpl. 2016;22:178–87.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Vitale A, D’Amico F, Frigo AC, et al. Response to therapy as a criterion for awarding priority to patients with hepatocellular carcinoma awaiting liver transplantation. Ann Surg Oncol. 2010;17:2290–302.CrossRefPubMedGoogle Scholar
  33. 33.
    Merani S, Majno P, Kneteman NM, et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J Hepatol. 2011;55:814–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Sapisochin G, Goldaracena N, Astete S, et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series. Ann Surg Oncol. 2015;22:2286–94.CrossRefPubMedGoogle Scholar
  35. 35.
    Bodzin AS, Lunsford KE, Markovic D, et al. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg. 2016.Google Scholar
  36. 36.
    Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant. 2008;8:1982–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Toso C, Mentha G, Kneteman NM, Majno P. The place of downstaging for hepatocellular carcinoma. J Hepatol. 2010;52:930–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Roberts JP, Venook A, Kerlan R, Yao F. Hepatocellular carcinoma: ablate and wait versus rapid transplantation. Liver Transpl. 2010;16:925–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. 2010;16:262–78.CrossRefPubMedGoogle Scholar
  40. 40.
    Mulligan DC. The ongoing quest to find the appropriate patients to transplant with hepatocellular carcinoma: Milan to San Francisco to Toronto and beyond. Hepatology. 2016;64:1853–55.CrossRefPubMedGoogle Scholar
  41. 41.
    Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35–43.CrossRefPubMedGoogle Scholar
  42. 42.
    Lee HW, Suh KS. Liver transplantation for advanced hepatocellular carcinoma. Clin Mol Hepatol. 2016;22:309–18.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Moray G, Karakayali F, Yilmaz U, et al. Expanded criteria for hepatocellular carcinoma and liver transplantation. Transplant Proc. 2007;39:1171–4.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2017

Authors and Affiliations

  • Aloysious D. Aravinthan
    • 1
    • 2
  • Silvio G. Bruni
    • 3
  • Adam C. Doyle
    • 1
  • Hla-Hla Thein
    • 4
  • Nicolas Goldaracena
    • 1
  • Assaf Issachar
    • 1
  • Leslie B. Lilly
    • 1
  • Nazia Selzner
    • 1
  • Mamatha Bhat
    • 1
  • Boraiah Sreeharsha
    • 1
  • Markus Selzner
    • 1
  • Anand Ghanekar
    • 1
  • Mark S. Cattral
    • 1
  • Ian D. McGilvray
    • 1
  • Paul D. Greig
    • 1
  • Eberhard L. Renner
    • 1
    • 5
  • David R. Grant
    • 1
  • Gonzalo Sapisochin
    • 1
    • 6
  1. 1.Multiorgan Transplant Program, Toronto General HospitalUniversity of TorontoTorontoCanada
  2. 2.National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham Digestive Diseases CentreUniversity of NottinghamNottinghamUK
  3. 3.Department of Medical ImagingUniversity of TorontoTorontoCanada
  4. 4.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  5. 5.Department of Medicine, Max Rady College of Medicine/Rady Faculty of Health SciencesUniversity of ManitobaWinnipegCanada
  6. 6.Abdominal Transplant & HPB Surgical Oncology, Toronto General HospitalUniversity of TorontoTorontoCanada

Personalised recommendations