Skip to main content
Top
Published in: Annals of Surgical Oncology 5/2023

Open Access 30-09-2022 | Systemic Therapy | Hepatobiliary Tumors

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma

Authors: Xiao-Dong Zhu, MD, PhD, Cheng Huang, MD, PhD, Ying-Hao Shen, MD, Bin Xu, MSc, Ning-Ling Ge, MD, Yuan Ji, MD, Xu-Dong Qu, MD, Lingli Chen, MSc, Yi Chen, MD, Mei-Ling Li, BS, Jin-Jin Zhu, BS, Zhao-You Tang, MD, Jian Zhou, MD, PhD, Jia Fan, MD, PhD, Hui-Chuan Sun, MD, PhD

Published in: Annals of Surgical Oncology | Issue 5/2023

Login to get access

Abstract

Background

Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported.

Methods

A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors’ hospital between August 2018 and September 2020 was eligible for this study. Patients who were responding to systemic therapy and met the criteria for hepatectomy underwent liver resection with curative intention. The study also investigated the association of clinical factors with successful conversion resection and postoperative recurrence.

Results

The study enrolled 101 patients including 24 patients (23.8 %) who underwent R0 resection a median of 3.9 months (interquartile range: 2.5–5.9 months) after initiation of systemic therapy. Patients with an Eastern cooperative oncology group performance status of 0, fewer intrahepatic tumors, or a radiographic response to systemic therapy were more likely to be able to receive curative resection. After a median follow-up period of 21.5 months, hepatectomy was independently associated with a favorable overall survival (hazard ratio [HR], 0.050; 95 % confidence interval [CI], 0.007–0.365; P = 0.003). For the 24 patients who underwent surgery, the 12-month recurrence-free survival and overall survival rates were respectively 75% and 95.8%. Achieving a pathologic complete response (n = 10) to systemic therapy was associated with a favorable recurrence-free survival after resection, with a trend toward significance (HR, 0.345; 95% CI, 0.067–1.785; P = 0.187).

Conclusions

Selected patients with initially unresectable HCC can undergo hepatectomy after systemic therapy with combined TKI/anti-PD-1 antibodies. In this study, conversion resection was associated with a favorable prognosis.
Literature
1.
go back to reference Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35:2155–66.CrossRefPubMedPubMedCentral Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35:2155–66.CrossRefPubMedPubMedCentral
2.
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
6.
go back to reference Xu J, Shen J, Gu S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res. 2021;27:1003–11.CrossRefPubMed Xu J, Shen J, Gu S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res. 2021;27:1003–11.CrossRefPubMed
7.
go back to reference Huang C, Zhu XD, Shen YH, et al. Organ-specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res. 2021;9:19.CrossRefPubMedPubMedCentral Huang C, Zhu XD, Shen YH, et al. Organ-specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res. 2021;9:19.CrossRefPubMedPubMedCentral
8.
go back to reference Zhang W, Hu B, Han J, et al. Surgery after conversion therapy with PD-1 inhibitors plus tyrosine kinase inhibitors are effective and safe for advanced hepatocellular carcinoma: a pilot study of ten patients. Front Oncol. 2021;11:747950.CrossRefPubMedPubMedCentral Zhang W, Hu B, Han J, et al. Surgery after conversion therapy with PD-1 inhibitors plus tyrosine kinase inhibitors are effective and safe for advanced hepatocellular carcinoma: a pilot study of ten patients. Front Oncol. 2021;11:747950.CrossRefPubMedPubMedCentral
9.
go back to reference 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;10:320–9.CrossRefPubMedPubMedCentral 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;10:320–9.CrossRefPubMedPubMedCentral
10.
go back to reference Ho WJ, Zhu Q, Durham J, et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat Cancer. 2021;2:891–903.CrossRefPubMedPubMedCentral Ho WJ, Zhu Q, Durham J, et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat Cancer. 2021;2:891–903.CrossRefPubMedPubMedCentral
11.
go back to reference Sun HC, Zhu XD. Downstaging conversion therapy in patients with initially unresectable advanced hepatocellular carcinoma: an overview. Front Oncol. 2021;11:772195.CrossRefPubMedPubMedCentral Sun HC, Zhu XD. Downstaging conversion therapy in patients with initially unresectable advanced hepatocellular carcinoma: an overview. Front Oncol. 2021;11:772195.CrossRefPubMedPubMedCentral
12.
go back to reference Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21:571–80.CrossRefPubMed Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21:571–80.CrossRefPubMed
13.
go back to reference Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22:977–90.CrossRefPubMed Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22:977–90.CrossRefPubMed
14.
go back to reference Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(15 Suppl):4076.CrossRef Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(15 Suppl):4076.CrossRef
15.
16.
go back to reference Shen Y-H, Huang C, Zhu X-D, et al. The safety profile of hepatectomy following preoperative systemic therapy with lenvatinib plus anti-PD-1 antibodies versus hepatectomy alone in patients with hepatocellular carcinoma. Ann Surg Open. 2022;3:e163.CrossRef Shen Y-H, Huang C, Zhu X-D, et al. The safety profile of hepatectomy following preoperative systemic therapy with lenvatinib plus anti-PD-1 antibodies versus hepatectomy alone in patients with hepatocellular carcinoma. Ann Surg Open. 2022;3:e163.CrossRef
17.
go back to reference Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from Imbrave150: atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862–73.CrossRefPubMed Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from Imbrave150: atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862–73.CrossRefPubMed
18.
go back to reference Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed
19.
go back to reference Kudo M. A novel treatment strategy for patients with intermediate-stage HCC who are not suitable for TACE: upfront systemic therapy followed by curative conversion. Liver Cancer. 2021;10:539–44.CrossRefPubMedPubMedCentral Kudo M. A novel treatment strategy for patients with intermediate-stage HCC who are not suitable for TACE: upfront systemic therapy followed by curative conversion. Liver Cancer. 2021;10:539–44.CrossRefPubMedPubMedCentral
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference Ducreux M, Zhu AX, Cheng A-L, et al. Imbrave150: exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor). J Clin Oncol. 2021;39(15 Suppl):4071–4071.CrossRef Ducreux M, Zhu AX, Cheng A-L, et al. Imbrave150: exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor). J Clin Oncol. 2021;39(15 Suppl):4071–4071.CrossRef
22.
go back to reference Kudo M, Finn R, Ikeda M, et al. 68P a phase Ib study of lenvatinib + pembrolizumab (LEN + PEMBRO) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): study 116 follow-up analysis. Ann Oncol. 2021;32:S1401–2.CrossRef Kudo M, Finn R, Ikeda M, et al. 68P a phase Ib study of lenvatinib + pembrolizumab (LEN + PEMBRO) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): study 116 follow-up analysis. Ann Oncol. 2021;32:S1401–2.CrossRef
23.
go back to reference Sun H-C, Shen F, Liu L, et al. TALENTop: a multicenter, randomized study evaluating the efficacy and safety of hepatic resection for selected hepatocellular carcinoma with macrovascular invasion after initial atezolizumab plus bevacizumab treatment. J Clin Oncol. 2022;40(16 Suppl):TPS4175–TPS4175.CrossRef Sun H-C, Shen F, Liu L, et al. TALENTop: a multicenter, randomized study evaluating the efficacy and safety of hepatic resection for selected hepatocellular carcinoma with macrovascular invasion after initial atezolizumab plus bevacizumab treatment. J Clin Oncol. 2022;40(16 Suppl):TPS4175–TPS4175.CrossRef
24.
go back to reference Sun H-C, Huang C, Zhu X-D, et al. Radiological response as a predictor of pathological response to combined tyrosine kinase inhibitor (TKI) and anti-PD-1 antibodies in hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(15 Suppl):e16144–e16144.CrossRef Sun H-C, Huang C, Zhu X-D, et al. Radiological response as a predictor of pathological response to combined tyrosine kinase inhibitor (TKI) and anti-PD-1 antibodies in hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(15 Suppl):e16144–e16144.CrossRef
26.
go back to reference He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.CrossRefPubMedPubMedCentral He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.CrossRefPubMedPubMedCentral
27.
go back to reference Zhang J, Zhang X, Mu H, et al. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729764.CrossRefPubMedPubMedCentral Zhang J, Zhang X, Mu H, et al. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729764.CrossRefPubMedPubMedCentral
28.
go back to reference Yang X, Xu H, Zuo B, et al. Downstaging and resection of hepatocellular carcinoma in patients with extrahepatic metastases after stereotactic therapy. Hepatobil Surg Nutr. 2021;10:434–42.CrossRef Yang X, Xu H, Zuo B, et al. Downstaging and resection of hepatocellular carcinoma in patients with extrahepatic metastases after stereotactic therapy. Hepatobil Surg Nutr. 2021;10:434–42.CrossRef
29.
go back to reference Shindoh J, Kawamura Y, Kobayashi Y, et al. Prognostic impact of surgical intervention after lenvatinib treatment for advanced hepatocellular carcinoma. Ann Surg Oncol. 2021;28:7663–72.CrossRefPubMed Shindoh J, Kawamura Y, Kobayashi Y, et al. Prognostic impact of surgical intervention after lenvatinib treatment for advanced hepatocellular carcinoma. Ann Surg Oncol. 2021;28:7663–72.CrossRefPubMed
Metadata
Title
Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma
Authors
Xiao-Dong Zhu, MD, PhD
Cheng Huang, MD, PhD
Ying-Hao Shen, MD
Bin Xu, MSc
Ning-Ling Ge, MD
Yuan Ji, MD
Xu-Dong Qu, MD
Lingli Chen, MSc
Yi Chen, MD
Mei-Ling Li, BS
Jin-Jin Zhu, BS
Zhao-You Tang, MD
Jian Zhou, MD, PhD
Jia Fan, MD, PhD
Hui-Chuan Sun, MD, PhD
Publication date
30-09-2022
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 5/2023
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-022-12530-z

Other articles of this Issue 5/2023

Annals of Surgical Oncology 5/2023 Go to the issue