Skip to main content
SpringerLink
Log in

Prognostic Advantages of Individual Additional Interventions After Lenvatinib Therapy in Patients with Advanced Hepatocellular Carcinoma

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery

Abstract

Background

Increasing number of patients with advanced hepatocellular carcinoma (HCC) has recently achieved salvage interventions after introduction of new biologic agents, while there are insufficient data to determine if such additional intervention(s) after treatment with newer biologic agents are truly advantageous for patients with advanced HCC.

Methods

The clinical records of 107 consecutive patients who underwent lenvatinib treatment for advanced HCC were extensively reviewed and the prognostic advantages of individual additional treatments after lenvatinib treatment were investigated through a regression analysis considering time-dependent covariates.

Results

Multivariate analysis revealed that R0 resection or curative-intent radiofrequency ablation (RFA) (hazard ratio [HR], 0.07; 95% CI, 0.01–0.32), transarterial chemoembolization or transarterial infusion therapy (HR, 0.39; 95% CI, 0.19–0.81), and subsequent line of systemic therapy (HR, 0.25; 95% CI, 0.10–0.63) were associated with improved disease-specific survival (DSS), while R2 resection or palliative-intent RFA showed no correlation with DSS. The best response during lenvatinib therapy, nutritional status, plasma des-gamma-carboxyprothrombin level, a baseline CT enhancement pattern, and BCLC stage were also selected as independent predictors for DSS. Among the various treatments performed after lenvatinib therapy, R0 resection also showed clear prognostic advantage in both progression-free survival (HR, 0.30; 95% CI, 0.16–0.58) and time-to-treatment failure (HR, 0.08; 95% CI, 0.02–0.39), suggesting that successful conversion to surgery may prolong survival outcomes through prolonged cancer-free interval in advanced HCC.

Conclusions

Additional intervention(s)/treatment(s) after lenvatinib therapy for advanced HCC may have prognostic advantage in strictly selected populations. Successful conversion to curative resection may offer survival benefit with acceptable clinical 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

Similar content being viewed by others

References

  1. Arii S, Yamaoka Y, Futagawa S et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000; 32: 1224-1229.

    Article  CAS  Google Scholar 

  2. Takayama T, Makuuchi M, Hirohashi S et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998; 28: 1241-1246.

    Article  CAS  Google Scholar 

  3. Livraghi T, Meloni F, Di Stasi M et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 2008; 47: 82-89.

    Article  Google Scholar 

  4. Shiina S, Tateishi R, Arano T et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107: 569-577; quiz 578.

    Article  CAS  Google Scholar 

  5. Clavien PA, Lesurtel M, Bossuyt PM et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13: e11-22.

    Article  Google Scholar 

  6. Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004; 240: 451-459; discussion 459-461.

    Article  Google Scholar 

  7. Zhu XD, Huang C, Shen YH et al. Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations. Liver Cancer 2021; 10: 320-329.

    Article  CAS  Google Scholar 

  8. Matsuki R, Kawai K, Suzuki Y et al. Pathological Complete Response in Conversion Hepatectomy Induced by Lenvatinib for Advanced Hepatocellular Carcinoma. Liver Cancer 2020; 9: 358-360.

    Article  Google Scholar 

  9. Ohya Y, Hayashida S, Tsuji A et al. Conversion hepatectomy for advanced hepatocellular carcinoma after right portal vein transection and lenvatinib therapy. Surg Case Rep 2020; 6: 318.

    Article  Google Scholar 

  10. Sato N, Beppu T, Kinoshita K et al. Conversion Hepatectomy for Huge Hepatocellular Carcinoma With Arterioportal Shunt After Chemoembolization and Lenvatinib Therapy. Anticancer Res 2019; 39: 5695-5701.

    Article  Google Scholar 

  11. Tomonari T, Sato Y, Tanaka H et al. Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib: Three case reports. Medicine (Baltimore) 2020; 99: e22782.

    Article  Google Scholar 

  12. Wang Y, Lu LC, Guan Y et al. Atezolizumab plus bevacizumab combination enables an unresectable hepatocellular carcinoma resectable and links immune exclusion and tumor dedifferentiation to acquired resistance. Exp Hematol Oncol 2021; 10: 45.

    Article  Google Scholar 

  13. Shindoh J, Kawamura Y, Kobayashi Y et al. Prognostic Impact of Surgical Intervention After Lenvatinib Treatment for Advanced Hepatocellular Carcinoma. Ann Surg Oncol 2021.

  14. Salem R, Li D, Sommer N et al. Characterization of response to atezolizumab + bevacizumab versus sorafenib for hepatocellular carcinoma: Results from the IMbrave150 trial. Cancer Med 2021; 10: 5437-5447.

    Article  CAS  Google Scholar 

  15. Kokudo N, Takemura N, Hasegawa K et al. Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res 2019; 49: 1109-1113.

    Article  Google Scholar 

  16. National Cancer Institute, Division of Cancer Treated and Diagnosis. Cancer Therapy Evaluation Program. Adverse events/CTCAE. Available at: https: //ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#-ctc_40. Accessed December 23, 2018.

  17. Kawamura Y, Ikeda K, Hirakawa M et al. New classification of dynamic computed tomography images predictive of malignant characteristics of hepatocellular carcinoma. Hepatol Res 2010; 40: 1006-1014.

    Article  Google Scholar 

  18. Kawamura Y, Kobayashi M, Shindoh J et al. Pretreatment Heterogeneous Enhancement Pattern of Hepatocellular Carcinoma May Be a Useful New Predictor of Early Response to Lenvatinib and Overall Prognosis. Liver Cancer 2020; 9: 275-292.

    Article  CAS  Google Scholar 

  19. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52-60.

    Article  CAS  Google Scholar 

  20. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.

    Article  CAS  Google Scholar 

  21. Cheng AL, Kang YK, Chen Z et al. 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: 25-34.

    Article  CAS  Google Scholar 

  22. Abou-Alfa GK, Meyer T, Cheng AL et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018; 379: 54-63.

    Article  CAS  Google Scholar 

  23. Bruix J, Qin S, Merle P 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: 56-66.

    Article  CAS  Google Scholar 

  24. Finn RS, Qin S, Ikeda M et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020; 382: 1894-1905.

    Article  CAS  Google Scholar 

  25. Kudo M, Finn RS, Qin S 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: 1163-1173.

    Article  CAS  Google Scholar 

  26. Zhu AX, Kang YK, Yen CJ et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 282-296.

    Article  CAS  Google Scholar 

  27. Shindoh J, Kaseb A, Vauthey JN. Surgical strategy for liver cancers in the era of effective chemotherapy. Liver Cancer 2013; 2: 47-54.

    Article  CAS  Google Scholar 

  28. Naganuma A, Suzuki Y, Hoshino T et al. A case of conversion hepatectomy for huge ruptured hepatocellular carcinoma after transarterial embolization and lenvatinib therapy. Clin J Gastroenterol 2021.

  29. Sugimoto R, Inada H, Tanaka Y et al. Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma. Clin J Gastroenterol 2021; 14: 1484-1490.

    Article  Google Scholar 

  30. Takahashi K, Kim J, Takahashi A et al. Conversion hepatectomy for hepatocellular carcinoma with main portal vein tumour thrombus after lenvatinib treatment: A case report. World J Hepatol 2021; 13: 384-392.

    Article  Google Scholar 

  31. Yano S, Kawaoka T, Johira Y et al. Advanced hepatocellular carcinoma with response to lenvatinib after atezolizumab plus bevacizumab. Medicine (Baltimore) 2021; 100: e27576.

    Article  Google Scholar 

  32. Yokoo H, Takahashi H, Hagiwara M et al. Successful hepatic resection for recurrent hepatocellular carcinoma after lenvatinib treatment: A case report. World J Hepatol 2020; 12: 1349-1357.

    Article  Google Scholar 

  33. Shindoh J, Kawamura Y, Kobayashi Y et al. Prognostic Impact of Surgical Intervention After Lenvatinib Treatment for Advanced Hepatocellular Carcinoma. Ann Surg Oncol 2021; 28: 7663-7672.

    Article  Google Scholar 

  34. Mise Y, Hasegawa K, Shindoh J et al. The Feasibility of Third or More Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma. Ann Surg 2015; 262: 347-357.

    Article  Google Scholar 

  35. Meniconi RL, Komatsu S, Perdigao F et al. Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic profile of the first resection. Surgery 2015; 157: 454-462.

    Article  Google Scholar 

  36. Yang W, Chen MH, Wang MQ et al. Combination therapy of radiofrequency ablation and transarterial chemoembolization in recurrent hepatocellular carcinoma after hepatectomy compared with single treatment. Hepatol Res 2009; 39: 231-240.

    Article  CAS  Google Scholar 

  37. Shindoh J, Kawamura Y, Kobayashi Y et al. Time-to-Interventional Failure as a New Surrogate Measure for Survival Outcomes after Resection of Hepatocellular Carcinoma. J Gastrointest Surg 2020; 24: 50-57.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hepatobiliary-Pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Junichi Shindoh, Satoshi Okubo, Masaru Matsumura & Masaji Hashimoto

  2. Okinaka Memorial Institute for Medical Disease, Tokyo, Japan

    Junichi Shindoh

  3. Department of Hepatology, Toranomon Hospital, Tokyo, Japan

    Yusuke Kawamura, Masahiro Kobayashi, Norio Akuta & Yoshiyuki Suzuki

Authors
  1. Junichi Shindoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yusuke Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masahiro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norio Akuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masaru Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiyuki Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masaji Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junichi Shindoh.

Ethics declarations

Competing Interests

Junichi Shindoh and Yusuke Kawamura receive honoraria from Eisai Pharmaceutical Co., Ltd. for this study. All other authors declare no competing interests.

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 (DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shindoh, J., Kawamura, Y., Kobayashi, M. et al. Prognostic Advantages of Individual Additional Interventions After Lenvatinib Therapy in Patients with Advanced Hepatocellular Carcinoma. J Gastrointest Surg 26, 1637–1646 (2022). https://doi.org/10.1007/s11605-022-05388-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-022-05388-9

Keywords

Search

Navigation