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The Timing of Liver Transplantation Following Downstaging: Wait of Not to Wait?

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Abstract

Purpose

HCC is a complex disease that is diagnosed in advanced stage and on the background of cirrhosis. Locoregional therapies provide sufficient downstaging to enable patients suitable for radical procedures such liver transplantation. However, the interval between locoregional therapies and definitive therapy is still controversial. We performed a review of literature to evaluate the role of waiting period between locoregional therapies and liver transplantation or resection from the perspective of cure and recurrence rates.

Methods

Thorough literature search was performed to evaluate the role of locoregional therapy and the interval to definitive therapies for the treatment of hepatocellular cancer.

Results

Usually, small tumors with lower tumor burden, in other words, tumors within Milan criteria, can be transplanted with an acceptable overall and disease-free survival. However, treating patients with locally advanced tumors is currently a matter of extensive research. Currently, locoregional therapies are applied to downstage the patients. However, the duration of waiting is a crucial point that needs further research. There is a consensus that the waiting interval between down-staging and transplantation should be no less than 3 months. This is important for selection of favorable tumor biology as well as from the point of antitumor immune response.

Conclusion

Currently, there are no surrogate markers for surveillance of response to locoregional therapies as well as the antitumor immune response that develops as a result of down-staging.

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Abbreviations

DDLT:

Deceased donor liver transplantation

HCC:

Hepatocellular carcinoma

IDO:

Indoleamine 2,3-dioxygenase

LDLT:

Living donor liver transplantation

LRT:

Locoregional therapies

LT:

Liver transplantation

RFA:

Radiofrequency ablation

SBRT:

Stereotactic body radiation therapy

TAA:

Tumor-associated antigens

TACE:

Trans-arterial chemoembolization

TARE:

Trans-arterial radioembolization with Yttrium-90

References

  1. Carr BI. Hepatocellular carcinoma: current management and future trends. Gastroenterology. 2004;127:S218–24. https://doi.org/10.1053/j.gastro.2004.09.036 W.B. Saunders.

    Article  Google Scholar 

  2. Carr BI. Rapidly changing landscape. 2019. https://doi.org/10.20517/2394-5079.2018.113 Review.

  3. Santopaolo F, Lenci I, Milana M, Manzia TM, Baiocchi L. Liver transplantation for hepatocellular carcinoma: where do we stand? World J Gastroenterol. 2019;25:2591–602. https://doi.org/10.3748/wjg.v25.i21.2591.

    Article  Google Scholar 

  4. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9. https://doi.org/10.1056/NEJM199603143341104.

    Article  CAS  Google Scholar 

  5. Spreafico C, Sposito C, Vaiani M, Cascella T, Bhoori S, Morosi C, et al. Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion. J Hepatol. 2018;68:724–32. https://doi.org/10.1016/j.jhep.2017.12.026.

    Article  Google Scholar 

  6. Cascales-Campos P, Martinez-Insfran LA, Ramirez P, Ferreras D, Gonzalez-Sanchez MR, Sanchez-Bueno F, et al. Liver transplantation in patients with hepatocellular carcinoma outside the Milan criteria after downstaging: is it worth it? Transplant Proc. 2018;50:591–4. https://doi.org/10.1016/j.transproceed.2017.09.063.

    Article  CAS  Google Scholar 

  7. Lo CM, Fan ST, Liu CL, Chan SC, Ng IOL, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94:78–86. https://doi.org/10.1002/bjs.5528.

    Article  CAS  Google Scholar 

  8. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, 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. https://doi.org/10.1016/S1470-2045(08)70284-5.

    Article  Google Scholar 

  9. Gra̧t M, Kornasiewicz O, Hołówko W, Lewandowski Z, Zieniewicz K, Pa̧czek L, et al. Evaluation of total tumor volume and pretransplantation α-fetoprotein level as selection criteria for liver transplantation in patients with hepatocellular cancer. Transplant Proc. 2013;45:1899–903. https://doi.org/10.1016/j.transproceed.2012.12.010.

    Article  CAS  Google Scholar 

  10. Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology. 2016;64:2077–88. https://doi.org/10.1002/hep.28643.

    Article  Google Scholar 

  11. Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery. 2013;154:1053–60. https://doi.org/10.1016/j.surg.2013.04.056.

    Article  Google Scholar 

  12. Shimamura T, Akamatsu N, Fujiyoshi M, Kawaguchi A, Morita S, Kawasaki S, et al. Expanded living-donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: the 5-5-500 rule - a retrospective study. Transpl Int. 2019;32:356–68. https://doi.org/10.1111/tri.13391.

    Article  CAS  Google Scholar 

  13. Mazzaferro V, Sposito C, Zhou J, Pinna AD, De Carlis L, Fan J, et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology. 2018;154:128–39. https://doi.org/10.1053/j.gastro.2017.09.025.

    Article  Google Scholar 

  14. Ince V, Akbulut AS, Otan E, Ersan V, Karakas S, Sahin TT, et al. Liver transplantation for hepatocellular carcinoma: Malatya experience and proposals for expanded criteria. J Gastrointest Cancer. 2020;51:998–1005. https://doi.org/10.1007/s12029-020-00424-w.

    Article  CAS  Google Scholar 

  15. Abreu P, Gorgen A, Griffiths C, Ivanics T, Sapisochin G. Downstaging and expanded criteria hepatocellular carcinoma liver transplantation. Curr Hepatol Rep. 2019;18:400–7. https://doi.org/10.1007/s11901-019-00492-y.

    Article  Google Scholar 

  16. Clavien PA, Lesurtel M, Bossuyt PMM, Gores GJ, Langer B, Perrier A. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11–22. https://doi.org/10.1016/S1470-2045(11)70175-9.

    Article  Google Scholar 

  17. Yao FY, Fidelman N. Reassessing the boundaries of liver transplantation for hepatocellular carcinoma: where do we stand with tumor down-staging? Hepatology. 2016;63:1014–25. https://doi.org/10.1002/hep.28139.

    Article  Google Scholar 

  18. Yao FY, Mehta N, Flemming J, Dodge J, Hameed B, Fix O, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology. 2015;61:1968–77. https://doi.org/10.1002/hep.27752.

    Article  Google Scholar 

  19. Mehta N, Dodge JL, Roberts JP, Hirose R, Yao FY. Alpha-fetoprotein decrease from >1000 to <500 ng/ml in patients with hepatocellular carcinoma leads to improved post-transplant outcomes. Hepatology. 2018;36:hep.30413. https://doi.org/10.1002/hep.30413.

    Article  CAS  Google Scholar 

  20. Sapisochin G, Barry A, Doherty M, Fischer S, Goldaracena N, Rosales R, et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J Hepatol. 2017;67:92–9. https://doi.org/10.1016/j.jhep.2017.02.022.

    Article  Google Scholar 

  21. Lencioni R, De Baere T, Martin RC, Nutting CW, Narayanan G. Image-guided ablation of malignant liver tumors: recommendations for clinical validation of novel thermal and non-thermal technologies - a western perspective. Liver Cancer. 2015;4:208–14. https://doi.org/10.1159/000367747.

    Article  CAS  Google Scholar 

  22. Ravaioli M, Grazi GL, Piscaglia F, Trevisani F, Cescon M, Ercolani G, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–57. https://doi.org/10.1111/j.1600-6143.2008.02409.x.

    Article  CAS  Google Scholar 

  23. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80. https://doi.org/10.1002/hep.29086.

    Article  Google Scholar 

  24. Kulik L, Heimbach JK, Zaiem F, Almasri J, Prokop LJ, Wang Z, et al. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: a systematic review and meta-analysis. Hepatology. 2018;67:381–400. https://doi.org/10.1002/hep.29485.

    Article  CAS  Google Scholar 

  25. Unzueta A, Cabrera R. Treatment options in patients awaiting liver transplantation with hepatocellular carcinoma and cholangiocarcinoma. Clin Liver Dis. 2017;21:231–51. https://doi.org/10.1016/j.cld.2016.12.002.

    Article  Google Scholar 

  26. Kim DG, Lee JG, Joo DJ, Kim SI, Kim MS. Favourable outcome of pathologic downstaging by locoregional treatment for hepatocellular carcinoma in liver transplantation. Sci Rep. 2019;9:1–7. https://doi.org/10.1038/s41598-019-46871-9.

    Article  CAS  Google Scholar 

  27. Gordon-Weeks AN, Snaith A, Petrinic T, Friend PJ, Burls A, Silva MA. Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria. Br J Surg. 2011;98:1201–8. https://doi.org/10.1002/bjs.7561.

    Article  CAS  Google Scholar 

  28. Jeng KS, Huang CC, Lin CK, Lin CC, Huang CT, Chung CS, et al. Reappraisal of failures in downstaging treatment of hepatocellular carcinoma prior to liver transplant—preliminary report on the impact of underestimations of tumor numbers and tumor sizes as measured from imaging before transplant. Transplant Proc. 2019;51:1428–34. https://doi.org/10.1016/j.transproceed.2019.03.020.

    Article  Google Scholar 

  29. Londoño MC, Abraldes JG, Altamirano J, Decaens T, Forns X. Clinical trial watch: reports from the AASLD liver meeting®, Boston, November 2014. J Hepatol. 2015;62:1196–203. https://doi.org/10.1016/j.jhep.2015.01.028.

    Article  Google Scholar 

  30. Yao FY, Breitenstein S, Broelsch CE, Dufour J-F, Sherman M. Does a patient qualify for liver transplantation after the down-staging of hepatocellular carcinoma? Liver Transpl. 2011;17:S109–16. https://doi.org/10.1002/lt.22335.

    Article  Google Scholar 

  31. Kulik LM, Fisher RA, Rodrigo DR, Brown RS, Freise CE, Shaked A, et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am J Transplant. 2012;12:2997–3007. https://doi.org/10.1111/j.1600-6143.2012.04272.x.

    Article  CAS  Google Scholar 

  32. Chapman WC, Garcia-Aroz S, Vachharajani N, Fowler K, Saad N, Lin Y, et al. Liver transplantation for advanced hepatocellular carcinoma after downstaging without up-front stage restrictions. J Am Coll Surg. 2017;224:610–21. https://doi.org/10.1016/j.jamcollsurg.2016.12.020.

    Article  Google Scholar 

  33. Lei J, Wang W, Yan L. Downstaging advanced hepatocellular carcinoma to the Milan criteria may provide a comparable outcome to conventional Milan criteria. J Gastrointest Surg. 2013;17:1440–6. https://doi.org/10.1007/s11605-013-2229-y.

    Article  Google Scholar 

  34. Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular carcinoma: a systematic review and pooled analysis. Liver Transpl. 2015;21:1142–52. https://doi.org/10.1002/lt.24169.

    Article  Google Scholar 

  35. Bryce K, Tsochatzis EA. Downstaging for hepatocellular cancer: harm or benefit? Transl Gastroenterol Hepatol. 2017;2. https://doi.org/10.21037/tgh.2017.11.18.

  36. Pommergaard HC, Rostved AA, Adam R, Thygesen LC, Salizzoni M, Gómez Bravo MA, et al. Locoregional treatments before liver transplantation for hepatocellular carcinoma: a study from the European liver transplant registry. Transpl Int. 2018;31:531–9. https://doi.org/10.1111/tri.13123.

    Article  Google Scholar 

  37. Lai Q, Di Martino M, Lucatelli P, Mennini G. Locoregional therapy response in patients with hepatocellular cancer waiting for liver transplantation: only selection or biological effect? World J Gastroenterol. 2018;24:3469–71. https://doi.org/10.3748/wjg.v24.i31.3469.

    Article  Google Scholar 

  38. He Y, Liu F, Mou S, Li Q, Wang S. Prognostic analysis of hepatocellular carcinoma on the background of liver cirrhosis via contrast-enhanced ultrasound and pathology. Oncol Lett. 2018;15:3746–52. https://doi.org/10.3892/ol.2018.7792.

    Article  CAS  Google Scholar 

  39. Shi W, Hu J, Zhu S, Shen X, Zhang X, Yang C, et al. Expression of MTA2 and Ki-67 in hepatocellular carcinoma and their correlation with prognosis. Int J Clin Exp Pathol. 2015;8:13083–9.

    CAS  Google Scholar 

  40. Luo Y, Ren F, Liu Y, Shi Z, Tan Z, Xiong H, et al. Clinicopathological and prognostic significance of high Ki-67 labeling index in hepatocellular carcinoma patients: a meta-analysis. Int J Clin Exp Med. 2015;8:10235–47.

    Google Scholar 

  41. Singh P, Toom S, Avula A, Kumar V, Rahma OE. The immune modulation effect of locoregional therapies and its potential synergy with immunotherapy in hepatocellular carcinoma. 2020;7:11–7. https://doi.org/10.2147/JHC.S187121.

  42. Goossens N, Sun X, Hoshida Y. Molecular classification of hepatocellular carcinoma: potential therapeutic implications. Hepatic Oncol. 2015;2:371–9. https://doi.org/10.2217/hep.15.26.

    Article  Google Scholar 

  43. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 2009;50:799–807. https://doi.org/10.1002/hep.23054.

    Article  CAS  Google Scholar 

  44. Ilkovitch D, Lopez DM. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res. 2009;69:5514–21. https://doi.org/10.1158/0008-5472.CAN-08-4625.

    Article  CAS  Google Scholar 

  45. Knoll P, Schlaak J, Uhrig A, Kempf P, zum Büschenfelde KHM, Gerken G. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol. 1995;22:226–9. https://doi.org/10.1016/0168-8278(95)80433-1.

    Article  Google Scholar 

  46. Yan ML, Wang YD, Tian YF, De Lai Z, Yan LN. Inhibition of allogeneic T-cell response by Kupffer cells expressing indoleamine 2,3-dioxygenase. World J Gastroenterol. 2010;16:636–40. https://doi.org/10.3748/wjg.v16.i5.636.

    Article  CAS  Google Scholar 

  47. Cantor HM, Dumont AE. Hepatic suppression of sensitization to antigen absorbed into the portal system [23]. Nature. 1967;215:744–5. https://doi.org/10.1038/215744a0.

    Article  CAS  Google Scholar 

  48. Obeid JM, Kunk PR, Zaydfudim VM, Bullock TN, Slingluff CL, Rahma OE. Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time? Cancer Immunol Immunother. 2018;67:161–74. https://doi.org/10.1007/s00262-017-2082-z.

    Article  CAS  Google Scholar 

  49. Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14:996–1006. https://doi.org/10.1038/ni.2691.

    Article  CAS  Google Scholar 

  50. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma review-article. Nat Immunol. 2018;19:222–32. https://doi.org/10.1038/s41590-018-0044-z.

    Article  CAS  Google Scholar 

  51. Greten TF, Mauda-Havakuk M, Heinrich B, Korangy F, Wood BJ. Combined locoregional-immunotherapy for liver cancer. J Hepatol. 2019;70:999–1007. https://doi.org/10.1016/j.jhep.2019.01.027.

    Article  Google Scholar 

  52. Den Brok MHMGM, Sutmuller RPM, Nierkens S, Bennink EJ, Frielink C, Toonen LWJ, et al. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer. 2006;95:896–905. https://doi.org/10.1038/sj.bjc.6603341.

    Article  CAS  Google Scholar 

  53. Dromi SA, Walsh MP, Herby S, Traughber B, Xie J, Sharma KV, et al. Radiofrequency ablation induces antigen-presenting cell infiltration and amplification of weak tumor-induced immunity. Radiology. 2009;251:58–66. https://doi.org/10.1148/radiol.2511072175.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey

    Veysel Ersan & Bora Barut

  2. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 44280, Malatya, Turkey

    Sezai Yilmaz

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  1. Veysel Ersan
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Ersan, V., Barut, B. & Yilmaz, S. The Timing of Liver Transplantation Following Downstaging: Wait of Not to Wait?. J Gastrointest Canc 51, 1152–1156 (2020). https://doi.org/10.1007/s12029-020-00491-z

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