Skip to main content

Advertisement

SpringerLink
Log in

Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), lenvatinib and programmed death receptor-1 signaling inhibitors (PD1s) all alone have been proven effective in treating advanced hepatocellular carcinoma (HCC), yet the efficacy and safety of the tri-combination therapy in treating HCC patients with portal vein tumor thrombosis (PVTT) remains unknown.

Methods

In this retrospective study, HCC patients with PVTT received either induction therapy of HAIC and lenvatinib plus PD1s in the initial period of treatment and then dual maintenance therapy of lenvatinib and PD1s (HAIC-Len-PD1) or continuous lenvatinib combined with PD1s (Len-PD1).

Results

In total, 53 and 89 patients were enrolled into the Len-PD1 group and HAIC-Len-PD1 group, respectively. The median overall survival times were 13.8 months in the Len-PD1 group and 26.3 months in the HAIC-Len-PD1 group (hazard ratio (HR) = 0.43, P < 0.001). The median progression-free survival (PFS) time was significantly longer in the HAIC-Len-PD1 group than in the Len-PD1 group (11.5 months versus 5.5 months, HR = 0.43, P < 0.001). Induction therapy showed an objective response rate (ORR) 3 times higher than lenvatinib combined with PD1s therapy (61.8% versus 20.8%, P < 0.001), and exhibited inspiring intra- and extra-hepatic tumor control ability. Induction therapy led to more adverse events than lenvatinib combined with PD1s therapy, most of which were tolerable and controllable.

Conclusion

The induction therapy of FOLFOX-HAIC and lenvatinib plus PD1s is an effective and safe treatment for HCC patients with PVTT. The concept of induction therapy could be applied to other local–regional treatments and drugs combinations in HCC management.

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

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;6:394–424.

    Article  Google Scholar 

  2. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394:1145–58.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Article  PubMed  Google Scholar 

  4. Lu J, Zhang XP, Zhong BY, et al. Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: comparing east and west. Lancet Gastroenterol Hepatol. 2019;4:721–30.

    Article  PubMed  Google Scholar 

  5. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76:681–93.

    Article  PubMed  Google Scholar 

  6. Su GL, Altayar O, O’Shea R, et al. AGA clinical practice guideline on systemic therapy for hepatocellular carcinoma. Gastroenterology. 2022;162:920–34.

    Article  PubMed  Google Scholar 

  7. 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;38:2960–70.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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;391:1163–73.

    Article  CAS  PubMed  Google Scholar 

  9. Kudo M, Kawamura Y, Hasegawa K, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10:181–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lyu N, Kong Y, Mu L, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69:60–9.

    Article  PubMed  Google Scholar 

  12. Lyu N, Wang X, Li JB, et al. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2022;40:468–80.

    Article  PubMed  Google Scholar 

  13. Li QJ, He MK, Chen HW, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III Trial. J Clin Oncol. 2022;40:150–60.

    Article  CAS  PubMed  Google Scholar 

  14. Kosaka Y, Kimura T, Kawaoka T, et al. Hepatic arterial infusion chemotherapy combined with radiation therapy for advanced hepatocellular carcinoma with tumor thrombosis of the main trunk or bilobar of the portal vein. Liver Cancer. 2021;10:151–60.

    Article  PubMed  PubMed Central  Google Scholar 

  15. He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5:953–60.

    Article  PubMed  PubMed Central  Google Scholar 

  16. European Association for the Study of the Liver. Electronic address eee, European association for the study of the L: EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  17. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis treatment and follow-up. Ann Oncol. 2018;29:iv238–55.

    Article  CAS  PubMed  Google Scholar 

  18. Llovet JM, Lencioni R. mRECIST for HCC: performance and novel refinements. J Hepatol. 2020;72:288–306.

    Article  PubMed  Google Scholar 

  19. 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;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  20. Wei X, Jiang Y, Zhang X, et al. Neoadjuvant three-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: a randomized, open-label. Multicenter Controlled Study J Clin Oncol. 2019;37:2141–51.

    Article  CAS  PubMed  Google Scholar 

  21. Altman DG, De Stavola BL, Love SB, et al. Review of survival analyses published in cancer journals. Br J Cancer. 1995;72:511–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80.

    Article  PubMed  Google Scholar 

  23. Cheng S, Chen M, Cai J, et al. Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus (2018 edition). Liver Cancer. 2020;9:28–40.

    Article  PubMed  Google Scholar 

  24. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.

    Article  CAS  PubMed  Google Scholar 

  25. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40:379.

    Article  Google Scholar 

  26. Bejjani AC, Finn RS. Hepatocellular carcinoma: pick the winner-tyrosine kinase inhibitor versus immuno-oncology agent-based combinations. J Clin Oncol. 2022;40:2763–73.

    Article  CAS  PubMed  Google Scholar 

  27. Finn RS, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, Xu R, Edeline J, Ryoo B, Ren Z, Cheng A, Galle PR, Kaneko S, Kumada H, Wang A, Mody K, Dubrovsky L, Siegel AB, Llovet: Primary results from the phase III LEAP-002 study. Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Annal Oncol. 2022;33:S808–69.

    Article  Google Scholar 

  28. Emens LA, Ascierto PA, Darcy PK, et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116–29.

    Article  CAS  PubMed  Google Scholar 

  29. Peng Z, Fan W, Zhu B, 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;41:117–27.

    Article  PubMed  Google Scholar 

  30. Zheng K, Zhu X, Fu S, et al. Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib for hepatocellular carcinoma with major portal vein tumor thrombosis: a randomized trial. Radiology. 2022;303:455–64.

    Article  PubMed  Google Scholar 

  31. Chabanon RM, Rouanne M, Lord CJ, et al. Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer. 2021;21:701–17.

    Article  CAS  PubMed  Google Scholar 

  32. Guo J, Yu Z, Sun D, et al. Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma. Mol Cancer. 2021;20:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Herrera FG, Irving M, Kandalaft LE, et al. Rational combinations of immunotherapy with radiotherapy in ovarian cancer. Lancet Oncol. 2019;20:e417–33.

    Article  CAS  PubMed  Google Scholar 

  34. Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14:5459–65.

    Article  CAS  PubMed  Google Scholar 

  35. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122:664–71.

    Article  CAS  PubMed  Google Scholar 

  36. Huang J, Huang W, Zhan M, et al. Drug-eluting bead transarterial chemoembolization combined with FOLFOX-based hepatic arterial infusion chemotherapy for large or huge hepatocellular carcinoma. J Hepatocell Carcinoma. 2021;8:1445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work is funded by the National Natural Science Foundation of China (No: 81874070).

Author information

Author notes

  1. Yizhen Fu, Wei Peng and Weixiang Zhang contributed equally to this work.

Authors and Affiliations

  1. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China

    Yizhen Fu, Wei Peng, Zhenyun Yang, Zili Hu, Yanxun Pang, Dandan Hu, Jinbin Chen, Juncheng Wang, Zhongguo Zhou, Li Xu, Minshan Chen & Yaojun Zhang

  2. Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China

    Yizhen Fu, Wei Peng, Zhenyun Yang, Zili Hu, Yanxun Pang, Dandan Hu, Jinbin Chen, Juncheng Wang, Zhongguo Zhou, Li Xu, Minshan Chen & Yaojun Zhang

  3. Department of Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510060, People’s Republic of China

    Weixiang Zhang

Authors
  1. Yizhen Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weixiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenyun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zili Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanxun Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dandan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinbin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Juncheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhongguo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Li Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Minshan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yaojun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YF: conceptualization, methodology, software, formal analysis, writing—original draft; WP: methodology, software, formal analysis; WZ: conceptualization, software, resources, data curation; ZY: conceptualization, software, resources, data curation; ZH: resources, investigation; YP: resources, investigation; DH: resources, investigation; JC: resources, investigation; JW: visualization, supervision; ZZ: supervision, data curation; LX: supervision, data curation; MC: conceptualization, funding acquisition, project administration, supervision; YZ: conceptualization, methodology, project administration, supervision, writing—review & editing.

Corresponding authors

Correspondence to Minshan Chen or Yaojun Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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.

535_2023_1976_MOESM1_ESM.docx

Supplementary file1 Fig. S1. Flowchart for patient inclusion. Abbreviations: HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombosis; TKIs, multi-tyrosine kinase inhibitors; ICIs, immune checkpoint inhibitors; HAIC, hepatic arterial infusion chemotherapy (DOCX 27 KB)

535_2023_1976_MOESM2_ESM.docx

Supplementary file2 Fig. S2. The median follow-up times of the two groups calculated by the reversed Kaplan–Meier method (DOCX 27 KB)

535_2023_1976_MOESM3_ESM.tif

Supplementary file3 Fig. S3. The detailed treatment courses of the two groups of patients and the second-line treatments after initial tumor progression. The number after each bar represents the total number of patients who received the corresponding treatment in the two groups (left: Len-PD1 group, right: HAIC-Len-PD1 group). Abbreviations: HAIC, hepatic arterial infusion chemotherapy; Len, lenvatinib; PD1s, programmed death receptor-1 signaling inhibitors; TACE, transarterial chemoembolization; TKIs, multi-tyrosine kinase inhibitors; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy (TIF 1594 KB)

535_2023_1976_MOESM4_ESM.tif

Supplementary file4 Fig S4. The progression-free survival of the two groups of patients receiving second-line treatments after initial tumor progression (a), and the efficacy of HAIC combined with lenvatinib plus PD1s versus other treatments as second-line therapy in the Len-PD1 group (b). Abbreviations: PFS, progression-free survival; HAIC, hepatic arterial infusion chemotherapy; Len, lenvatinib; PD1s, programmed death receptor-1 signaling inhibitors (TIF 1068 KB)

535_2023_1976_MOESM5_ESM.tif

Supplementary file5 Fig. S5. Subgroup analysis for the overall survival and progression-free survival of the two groups of patients after propensity score matching. Kaplan–Meier curves of (a-c) overall survival and (d-f) progression-free survival for patients with different portal vein tumor thrombosis stages. Kaplan–Meier curves of (g and h) overall survival and (i and j) progression-free survival for patients with or without extra-hepatic metastasis at the beginning of the treatments. Abbreviations: OS, overall survival; PFS, progression-free survival; Vp, Japan's portal vein invasion classification (TIF 3226 KB)

535_2023_1976_MOESM6_ESM.tif

Supplementary file6 Fig. S6. Comparison of efficacy regarding progression-free survival (a, c, e, and g) and overall survival (b, d, f, and h) among different PD1 drugs in the two groups both before and after propensity score matching. Abbreviations: PFS, progression-free survival; OS, overall survival; HAIC, hepatic arterial infusion chemotherapy; Len, lenvatinib; PD1s, programmed death receptor-1 signaling inhibitors; Pembro, Pembrolizumab; Sinti, Sintilimab; Tori, Toripalimab; Camre, Camrelizumab, Tisle, Tislelizumab (TIF 3445 KB)

535_2023_1976_MOESM7_ESM.tif

Supplementary file7 Fig. S7. The Sankey diagram of the dynamic changes of ALBI grades in the two groups of patients. The number above each bar represents the corresponding number of patients. Abbreviations: HAIC, hepatic arterial infusion chemotherapy; Len, lenvatinib; PD1s, programmed death receptor-1 signaling inhibitors; ALBI, Albumin-Bilirubin grade (TIF 1248 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

Fu, Y., Peng, W., Zhang, W. et al. Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis. J Gastroenterol 58, 413–424 (2023). https://doi.org/10.1007/s00535-023-01976-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-023-01976-x

Keywords

Search

Navigation