Skip to main content

Advertisement

SpringerLink
Log in

Treatment strategy for hepatocellular carcinoma recurrence in the transplant era: Focusing on the Japan criteria

  • Original Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

Purpose

To clarify the Japan criteria (JC), as proposed in 2019, in order to identify the most appropriate treatment methods for hepatocellular carcinoma (HCC) recurrence and assess the feasibility of pre-living donor liver transplantation (LDLT) downstaging within these criteria.

Methods

The subjects of this study were 169 LDLT patients with HCC recurrence. We performed univariate and multivariate analyses of the factors contributing to HCC recurrence after LDLT and clarified the post-transplant outcomes of pre-LDLT downstaging.

Results

Univariate and multivariate analysis identified beyond the JC (p = 0.0018) and a neutrophil-to-lymphocyte ratio > 2.01 (p = 0.029) as independent risk factors. Patients who met the JC had significantly higher recurrence-free and overall survival rates after LDLT (p < 0.0001) than those who did not (p = 0.0002). The post-transplant outcomes of patients within the JC after downstaging were significantly better than those of patients beyond the JC (p = 0.034) and equivalent to those within the JC without downstaging.

Conclusion

Even for HCC recurrence, the JC could play an important role in deciding on the best treatment strategy, and downstaging within the JC had good post-transplant outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–62.

    Article  PubMed  CAS  Google Scholar 

  2. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10(3):181–223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 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(11):693–9.

    Article  PubMed  CAS  Google Scholar 

  4. 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(4):356–68.

    Article  PubMed  CAS  Google Scholar 

  5. Tabrizian P, Holzner ML, Mehta N, Halazun K, Agopian VG, Yao F, et al. Ten-year outcomes of liver transplant and downstaging for hepatocellular carcinoma. JAMA Surg. 2022;157(9):779–88.

    PubMed  PubMed Central  Google Scholar 

  6. Tran NH, Muñoz S, Thompson S, Hallemeier CL, Bruix J. Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy. Hepatology. 2022;76(4):1203–18.

    Article  PubMed  CAS  Google Scholar 

  7. Taketomi A, Sanefuji K, Soejima Y, Yoshizumi T, Uhciyama H, Ikegami T, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation. 2009;87(4):531–7.

    Article  PubMed  Google Scholar 

  8. Toshima T, Yoshizumi T, Shimagaki T, Wang H, Kurihara T, Nagao Y, et al. Which is better to use “body weight” or “standard liver weight”, for predicting small-for-size graft syndrome after living donor liver transplantation? Ann Gastroenterol Surg. 2021;5(3):363–72.

    Article  PubMed  Google Scholar 

  9. Yonemura Y, Yoshizumi T, Inokuchi S, Kosai-Fujimoto Y, Harada N, Itoh S, et al. Predictor of outcome after living donor liver transplantation for patients with hepatocellular carcinoma beyond the Japan criteria. Ann Gastroenterol Surg. 2020;4(4):413–21.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yoshiya S, Harada N, Tomiyama T, Takeishi K, Toshima T, Iguchi T, et al. The significant prognostic factors in prolonged intensive/high care unit stay after living donor liver transplantation. Transplant Proc. 2021;53(5):1630–8.

    Article  PubMed  Google Scholar 

  11. Yoshiya S, Shirabe K, Kimura K, Yoshizumi T, Ikegami T, Kayashima H, et al. The causes, risk factors, and outcomes of early relaparotomy after living-donor liver transplantation. Transplantation. 2012;94(9):947–52.

    Article  PubMed  Google Scholar 

  12. Xu L, Chen L, Zhang W. Neoadjuvant treatment strategies for hepatocellular carcinoma. World J Gastrointest Surg. 2021;13(12):1550–66.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shimada M, Takenaka K, Taguchi K, Fujiwara Y, Gion T, Kajiyama K, et al. Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg. 1998;227(1):80–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Yamashita Y, Shirabe K, Tsuijita E, Takeishi K, Ikegami T, Yoshizumi T, et al. Third or more repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery. 2013;154(5):1038–45.

    Article  PubMed  Google Scholar 

  15. Yamashita Y, Yoshida Y, Kurihara T, Itoh S, Harimoto N, Ikegami T, et al. Surgical results for recurrent hepatocellular carcinoma after curative hepatectomy: Repeat hepatectomy versus salvage living donor liver transplantation. Liver Transpl. 2015;21(7):961–8.

    Article  PubMed  Google Scholar 

  16. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  PubMed  CAS  Google Scholar 

  17. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73.

    Article  PubMed  CAS  Google Scholar 

  18. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. 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.

    Article  PubMed  CAS  Google Scholar 

  19. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase III, randomized clinical trial (LAUNCH). J Clin Oncol. 2022;41(1):117–27.

    Article  PubMed  Google Scholar 

  21. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905.

    Article  PubMed  CAS  Google Scholar 

  22. Acuna SA, Zhang W, Yoon PD, Ivanics T, Zhu MP, Claasen M, et al. Right lobe versus left lobe living donor liver transplantation: a systematic review and meta-analysis of donor and recipient outcomes. Transplantation. 2022;106:2370.

    Article  PubMed  Google Scholar 

  23. 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(1):381–400.

    Article  PubMed  CAS  Google Scholar 

  24. Schwacha-Eipper B, Minciuna I, Banz V, Dufour JF. Immunotherapy as a downstaging therapy for liver transplantation. Hepatology. 2020;72(4):1488–90.

    Article  PubMed  Google Scholar 

  25. Nordness MF, Hamel S, Godfrey CM, Shi C, Johnson DB, Goff LW, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant. 2020;20(3):879–83.

    Article  PubMed  Google Scholar 

  26. Qiao ZY, Zhang ZJ, Lv ZC, Tong H, Xi ZF, Wu HX, et al. Neoadjuvant programmed cell death 1 (PD-1) inhibitor treatment in patients with hepatocellular carcinoma before liver transplant: a cohort study and literature review. Front Immunol. 2021;12: 653437.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. DiNorcia J, Florman SS, Haydel B, Tabrizian P, Ruiz RM, Klintmalm GB, et al. Pathologic response to pretransplant locoregional therapy is predictive of patient outcome after liver transplantation for hepatocellular carcinoma: analysis from the us multicenter hcc transplant consortium. Ann Surg. 2020;271(4):616–24.

    Article  PubMed  Google Scholar 

  28. Harding-Theobald E, Yao FYK, Mehta N. Neutrophil-to-lymphocyte ratio predicts high-risk explant features and waitlist survival but is not independently associated with recurrence or survival following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2021;27(6):818–29.

    Article  PubMed  Google Scholar 

  29. Motomura T, Shirabe K, Mano Y, Muto J, Toshima T, Umemoto Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol. 2013;58(1):58–64.

    Article  PubMed  CAS  Google Scholar 

  30. Mano Y, Shirabe K, Yamashita Y, Harimoto N, Tsujita E, Takeishi K, et al. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis. Ann Surg. 2013;258(2):301–5.

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by the following three grants: the Program for Basic and Clinical Research on Hepatitis, from the Japan Agency for Medical Research and Development, AMED (Numbers 20fk0210035s0503, 20fk0310106h0204, and 19fm0208009h0003); JSPS KAKENHI Grant Numbers JP-18K08542; and Taiju Life Social Welfare Foundation 2020. The funding sources had no role in the collection, analysis, or interpretation of the data, or in the decision to submit the article for publication.

Author information

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Shohei Yoshiya, Noboru Harada, Takeo Toshima, Katsuya Toshida, Yukiko Kosai, Takahiro Tomino, Yoshihiro Nagao, Hiroto Kayashima, Shinji Itoh & Tomoharu Yoshizumi

Authors
  1. Shohei Yoshiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noboru Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takeo Toshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katsuya Toshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yukiko Kosai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahiro Tomino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshihiro Nagao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroto Kayashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shinji Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tomoharu Yoshizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SY participated in research design, data analysis, and writing of the manuscript. NH, TT, and TY contributed to the discussion and reviewed the manuscript. YN, HK, and SI participated in data analysis and interpretation. KT, YK, and T. Tomino participated in data collection.

Corresponding author

Correspondence to Shohei Yoshiya.

Ethics declarations

Conflict of interest

We have no conflicts of interest to declare.

Ethical approval

This retrospective study was approved by the ethics committee of Kyushu University (ID number: 2019–186).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 85 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoshiya, S., Harada, N., Toshima, T. et al. Treatment strategy for hepatocellular carcinoma recurrence in the transplant era: Focusing on the Japan criteria. Surg Today 54, 64–72 (2024). https://doi.org/10.1007/s00595-023-02710-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00595-023-02710-z

Keywords

Search

Navigation