Skip to main content
SpringerLink
Log in

Evaluating the Benefits of TACE Combined with Lenvatinib Plus PD-1 Inhibitor for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

This study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus programmed death (PD)-1 inhibitor (TACE-L-P) versus TACE combined with sorafenib plus PD-1 inhibitor (TACE-S-P) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).

Methods

The clinical data of patients with HCC and PVTT treated with TACE-L-P or TACE-S-P from January 2018 to March 2022 were collected. The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST (mRECIST) standard were used to evaluate the therapeutic effect. The progression-free survival (PFS) and overall survival (OS) of the two groups were compared. Blood samples were collected before and after treatment to detect the changes of biochemical indicators, and the adverse events (AEs) related to treatment were recorded.

Results

A total of 165 patients were included in the study, including 80 patients receiving TACE-L-P treatment and 85 patients receiving TACE-S-P. Patients in the TACE-L-P group had longer median OS (21.7 months vs. 15.6 months, P = 0.0027), longer median PFS (6.3 months vs. 3.2 months, P < 0.0001), higher objective response rate (41.25% vs. 30.59%, P = 0.008), and higher disease control rate (86.25% vs. 62.35%, P = 0.008) than those in the TACE-S-P group. Multivariate analysis of the TACE-L-P group showed that VP classification of PVTT, Child–Pugh grade, interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), procalcitonin (PCT), and C-reactive protein (CRP) were independent factors significantly affecting patients’ OS (P < 0.05). There was no significant difference in the incidence and severity of AEs between the two groups.

Conclusion

TACE-L-P treatment can improve the survival of patients with HCC and PVTT with an acceptable safety, but higher inflammatory indicators will affect the therapeutic effect.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  2. Khan AR, Wei X, Xu X. Portal vein tumor thrombosis and hepatocellular carcinoma—the changing tides. J Hepatocell Carcinoma. 2021;8:1089–115. https://doi.org/10.2147/JHC.S318070.

    Article  PubMed  PubMed Central  Google Scholar 

  3. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019.

    Article  Google Scholar 

  4. Liu K, Min XL, Peng J, Yang K, Yang L, Zhang XM. The changes of HIF-1α and VEGF expression after TACE in patients with hepatocellular carcinoma. J Clin Med Res. 2016;8(4):297–302. https://doi.org/10.14740/jocmr2496w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–50. https://doi.org/10.1002/hep.29913.

    Article  PubMed  Google Scholar 

  6. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. https://doi.org/10.1056/NEJMoa0708857.

    Article  CAS  PubMed  Google Scholar 

  7. Kudo M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel). 2020;12(5):1089. https://doi.org/10.3390/cancers12051089.

    Article  CAS  PubMed  Google Scholar 

  8. Cai M, Huang W, Huang J, et al. Transarterial chemoembolization combined with lenvatinib plus PD-1 inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study. Front Immunol. 2022;13: 848387. https://doi.org/10.3389/fimmu.2022.848387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou J, Sun H, Wang Z, et al. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition). Liver Cancer. 2020;9(6):682–720. https://doi.org/10.1159/000509424.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Renzulli M, Peta G, Vasuri F, et al. Standardization of conventional chemoembolization for hepatocellular carcinoma. Ann Hepatol. 2021;22: 100278. https://doi.org/10.1016/j.aohep.2020.10.006.

    Article  CAS  PubMed  Google Scholar 

  11. Prajapati HJ, Xing M, Spivey JR, et al. Survival, efficacy, and safety of small versus large doxorubicin drug-eluting beads TACE chemoembolization in patients with unresectable HCC. AJR Am J Roentgenol. 2014;203(6):W706–14. https://doi.org/10.2214/AJR.13.12308.

    Article  PubMed  Google Scholar 

  12. Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014;106(9):dju244. https://doi.org/10.1093/jnci/dju244.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60. https://doi.org/10.1055/s-0030-1247132.

    Article  CAS  PubMed  Google Scholar 

  14. Sato Y, Watanabe H, Sone M, et al. Tumor response evaluation criteria for HCC (hepatocellular carcinoma) treated using TACE (transcatheter arterial chemoembolization): RECIST (response evaluation criteria in solid tumors) version 1.1 and mRECIST (modified RECIST): JIVROSG-0602. Ups J Med Sci. 2013;118(1):16–22. https://doi.org/10.3109/03009734.2012.729104.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Yu H, Bai Y, Xie X, Feng Y, Yang Y, Zhu Q. RECIST 1.1 versus mRECIST for assessment of tumour response to molecular targeted therapies and disease outcomes in patients with hepatocellular carcinoma: a systematic review and meta-analysis. BMJ Open. 2022;12(6): e052294. https://doi.org/10.1136/bmjopen-2021-052294.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.

    Article  CAS  PubMed  Google Scholar 

  17. 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(10126):1163–73. https://doi.org/10.1016/S0140-6736(18)30207-1.

    Article  CAS  PubMed  Google Scholar 

  18. Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol. 2015;62(5):1187–95. https://doi.org/10.1016/j.jhep.2015.02.010.

    Article  PubMed  Google Scholar 

  19. Yang B, Jie L, Yang T, et al. TACE plus lenvatinib versus TACE plus sorafenib for unresectable hepatocellular carcinoma with portal vein tumor thrombus: a prospective cohort study. Front Oncol. 2021;11: 821599. https://doi.org/10.3389/fonc.2021.821599.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ding X, Sun W, Li W, et al. Transarterial chemoembolization plus lenvatinib versus transarterial chemoembolization plus sorafenib as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: a prospective randomized study. Cancer. 2021;127(20):3782–93. https://doi.org/10.1002/cncr.33677.

    Article  CAS  PubMed  Google Scholar 

  21. Doycheva I, Thuluvath PJ. Systemic therapy for advanced hepatocellular carcinoma: an update of a rapidly evolving field. J Clin Exp Hepatol. 2019;9(5):588–96. https://doi.org/10.1016/j.jceh.2019.07.012.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yamashita T, Kudo M, Ikeda K, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020;55(1):113–22. https://doi.org/10.1007/s00535-019-01642-1.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang X, Wang K, Wang M, et al. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. Oncotarget. 2017;8(17):29416–27. https://doi.org/10.18632/oncotarget.15075.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kuzuya T, Ishigami M, Ito T, et al. Sorafenib vs. lenvatinib as first-line therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Anticancer Res. 2020;40(4):2283–90. https://doi.org/10.21873/anticanres.14193.

    Article  CAS  PubMed  Google Scholar 

  25. Mahipal A, Tella SH, Kommalapati A, Lim A, Kim R. Immunotherapy in hepatocellular carcinoma: is there a light at the end of the tunnel? Cancers (Basel). 2019;11(8):1078. https://doi.org/10.3390/cancers11081078.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang L, Mai W, Jiang W, Geng Q. Sintilimab: a promising anti-tumor PD-1 antibody. Front Oncol. 2020;10: 594558. https://doi.org/10.3389/fonc.2020.594558.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52. https://doi.org/10.1016/S1470-2045(18)30351-6.

    Article  PubMed  Google Scholar 

  28. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193–202. https://doi.org/10.1200/JCO.19.01307.

    Article  CAS  PubMed  Google Scholar 

  29. Deng H, Kan A, Lyu N, et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer. 2020;9(3):338–57. https://doi.org/10.1159/000505695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu J, Fang P, Wang C, et al. The immunomodulatory activity of lenvatinib prompts the survival of patients with advanced hepatocellular carcinoma. Cancer Med. 2021;10(22):7977–87. https://doi.org/10.1002/cam4.4312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Torrens L, Montironi C, Puigvehí M, et al. Immunomodulatory effects of lenvatinib plus anti-programmed cell death protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma. Hepatology. 2021;74(5):2652–69. https://doi.org/10.1002/hep.32023.

    Article  CAS  PubMed  Google Scholar 

  32. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960–70. https://doi.org/10.1200/JCO.20.00808.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen SC, Huang YH, Chen MH, et al. Anti-PD-1 combined sorafenib versus anti-PD-1 alone in the treatment of advanced hepatocellular cell carcinoma: a propensity score-matching study. BMC Cancer. 2022;22(1):55. https://doi.org/10.1186/s12885-022-09173-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Llovet JM, Vogel A, Madoff DC, et al. Randomized phase 3 LEAP-012 study: transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment. Cardiovasc Interv Radiol. 2022;45(4):405–12. https://doi.org/10.1007/s00270-021-03031-9.

    Article  Google Scholar 

  35. Kumada T, Toyoda H, Tada T, Yasuda S, Tanaka J. Changes in background liver function in patients with hepatocellular carcinoma over 30 years: comparison of Child–Pugh classification and albumin bilirubin grade. Liver Cancer. 2020;9(5):518–28. https://doi.org/10.1159/000507933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Khabbaz RC, Lokken RP, Chen YF, et al. Albumin–bilirubin and platelet–albumin–bilirubin grades do not predict survival after transjugular intrahepatic portosystemic shunt creation. Cardiovasc Interv Radiol. 2018;41(7):1029–34. https://doi.org/10.1007/s00270-018-1923-2.

    Article  Google Scholar 

  37. Minagawa M, Makuuchi M, Takayama T, Ohtomo K. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg. 2001;233(3):379–84. https://doi.org/10.1097/00000658-200103000-00012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hiraoka A, Kumada T, Atsukawa M, et al. Important clinical factors in sequential therapy including lenvatinib against unresectable hepatocellular carcinoma. Oncology. 2019;97(5):277–85. https://doi.org/10.1159/000501281.

    Article  CAS  PubMed  Google Scholar 

  39. Stroescu C, Dragnea A, Ivanov B, et al. Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma. J Gastrointest Liver Dis. 2008;17(4):411–7.

    Google Scholar 

  40. Gao Y, Wang PX, Cheng JW, et al. Chemotherapeutic perfusion of portal vein after tumor thrombectomy and hepatectomy benefits patients with advanced hepatocellular carcinoma: a propensity score-matched survival analysis. Cancer Med. 2019;8(16):6933–44. https://doi.org/10.1002/cam4.2556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jun J, Lee SR, Lee JY, et al. Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment: three case reports and literature review. Medicine (Baltimore). 2019;98(25): e16158. https://doi.org/10.1097/MD.0000000000016158.

    Article  PubMed  Google Scholar 

  42. Liu G, Sun J, Yang ZF, et al. Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis. Cell Death Dis. 2021;12(3):260. https://doi.org/10.1038/s41419-021-03545-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ma HY, Yamamoto G, Xu J, et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. 2020;72(5):946–59. https://doi.org/10.1016/j.jhep.2019.12.016.

    Article  CAS  PubMed  Google Scholar 

  44. Elovic AE, Ohyama H, Sauty A, et al. IL-4-dependent regulation of TGF-alpha and TGF-beta1 expression in human eosinophils. J Immunol. 1998;160(12):6121–7.

    Article  CAS  PubMed  Google Scholar 

  45. Myojin Y, Kodama T, Sakamori R, et al. Interleukin-6 is a circulating prognostic biomarker for hepatocellular carcinoma patients treated with combined immunotherapy. Cancers (Basel). 2022;14(4):883. https://doi.org/10.3390/cancers14040883.

    Article  CAS  PubMed  Google Scholar 

  46. Lazzarotto C, Ronsoni MF, Fayad L, et al. Acute phase proteins for the diagnosis of bacterial infection and prediction of mortality in acute complications of cirrhosis. Ann Hepatol. 2013;12(4):599–607.

    Article  PubMed  Google Scholar 

  47. Bota DP, Van Nuffelen M, Zakariah AN, Vincent JL. Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med. 2005;146(6):347–51. https://doi.org/10.1016/j.lab.2005.08.005.

    Article  CAS  PubMed  Google Scholar 

  48. Maruna P, Nedelníková K, Gürlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000;49(Suppl 1):S57–61.

    CAS  PubMed  Google Scholar 

  49. Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta. 2002;323(1–2):17–29. https://doi.org/10.1016/s0009-8981(02)00101-8.

    Article  CAS  PubMed  Google Scholar 

  50. Connert S, Stremmel W, Elsing C. Procalcitonin is a valid marker of infection in decompensated cirrhosis. Z Gastroenterol. 2003;41(2):165–70. https://doi.org/10.1055/s-2003-37314.

    Article  CAS  PubMed  Google Scholar 

  51. Nardone V, Giannicola R, Bianco G, et al. Inflammatory markers and procalcitonin predict the outcome of metastatic non-small-cell-lung-cancer patients receiving PD-1/PD-L1 immune-checkpoint blockade. Front Oncol. 2021;11: 684110. https://doi.org/10.3389/fonc.2021.684110.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nardone V, Giannicola R, Giannarelli D, et al. Distinctive role of the systemic inflammatory profile in non-small-cell lung cancer younger and elderly patients treated with a PD-1 immune checkpoint blockade: a real-world retrospective multi-institutional analysis. Life (Basel). 2021;11(11):1235. https://doi.org/10.3390/life11111235.

    Article  CAS  PubMed  Google Scholar 

  53. Kang SJ, Kim UJ, Kim SE, et al. Predictive value of procalcitonin for bacterial infection after transarterial chemoembolization or radiofrequency ablation for hepatocellular carcinoma. Dis Markers. 2018;2018:9120878. https://doi.org/10.1155/2018/9120878.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Han S, Ye Y, Wu J, et al. Procalcitonin levels in post TACE infection. Cancer Manag Res. 2020;12:12197–203. https://doi.org/10.2147/CMAR.S281667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Scheiner B, Pomej K, Kirstein MM, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy—development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353–63. https://doi.org/10.1016/j.jhep.2021.09.035.

    Article  CAS  PubMed  Google Scholar 

  56. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44. https://doi.org/10.1038/nature07205.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all participants for their involvement in the study.

Funding

The interventional radiology research project of Jiangsu Medical Association (210012021081) supported this study and provided funding for the journal’s Rapid Service fee.

Author Contributions

Writing and editing, Xinhua Zou, Qingyu Xu and Guowen Yin; Formal analysis, Xinhua Zou; Conceptualization, Guowen Yin; Methodology, Xinhua Zou and Ran You; Data curation and validation, Qingyu Xu and Guowen Yin. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Disclosures

The authors Xinhua Zou, Qingyu Xu, Ran You and Guowen Yin declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Compliance with Ethics Guidelines

This study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent to participate in the study, and the trial was approved by the ethics committee of Jiangsu Institute of Cancer Research (No. 2022LC0165).

Data Availability

The data sets analyzed during the present study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. Department of Tumor Interventional Therapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China

    Xinhua Zou, Qingyu Xu, Ran You & Guowen Yin

Authors
  1. Xinhua Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qingyu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ran You
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guowen Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guowen Yin.

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

Zou, X., Xu, Q., You, R. et al. Evaluating the Benefits of TACE Combined with Lenvatinib Plus PD-1 Inhibitor for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. Adv Ther 40, 1686–1704 (2023). https://doi.org/10.1007/s12325-023-02449-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-023-02449-6

Keywords

Search

Navigation