Liver transplantation for advanced hepatocellular carcinoma after downstaging with consequential lenvatinib, transcatheter arterial chemoembolization and camrelizumab

Introduction

To select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT), Milan criteria are still mainly used worldwide¹. Several selection criteria that sought to expand the Milan criteria have been proposed and acceptable post-LT survival may be obtained². However, none of the selection criteria challenged advanced HCC with macrovascular invasion. This is generally regarded as a contraindication for LT. Recently, several studies showed that combinations of locoregional and systemic treatment could significantly improve tumour response and overall survival for patients with advanced HCC^3–5. This included promising results of lenvatinib, transcatheter arterial chemoembolization (TACE) and programmed cell death protein 1 (PD-1) inhibitor (LEN-TAP) for advanced HCC⁶. With the improvement of combination therapy, the authors wondered whether LT could serve as another option for patients with advanced HCC after successful downstaging. The present study described the perioperative and postoperative outcome of patients who opted for LT when they failed to receive salvage liver resection due to decompensated liver function after successful downstaging.

Methods

LEN-TAP is an investigator-initiated trial that was designed to investigate efficacy and safety of salvage liver resection after conversion therapy of lenvatinib, TACE and PD-1 inhibitor in patients with unresectable HCC⁷. The study protocol was approved by ethics committee of West China Hospital (2020-836) and the study was registered at ClinicalTrial.gov (NCT04997850). Details of LEN-TAP study design are available in Supplementary material. Clinical data of patients who opted for LT when they failed to receive salvage liver resection due to decompensated liver function after successful downstaging were reviewed and analysed. LT was suggested after several multidisciplinary team meetings based upon the following considerations: advanced stage disease was downstaged within Milan criteria and complete tumour necrosis was found⁸ on enhanced computed tomography; and decompensated liver function and high risk of posthepatectomy liver failure. Additional methods are shown in the supplementary file.

Results

Between October 2020 and March 2022, 142 patients were enrolled in the LEN-TAP trial, and 71 patients received the triple combination therapy. According to LEN-TAP study protocol, 62 (87.3%) patients were amenable to receive salvage liver resection after the conversion therapy. Finally, 42 (59.2%) patients successfully received salvage liver resection whereas 4 patients failed to received salvage liver resection due to decompensated liver function (Fig. S1). Finally, two patients received marginal donor LT and one patient received living donor LT. All these three patients had advanced HCC with portal vein tumour thrombus. Baseline characteristics and perioperative outcomes are shown in Table S1.

Images obtained before therapy, before LT and one year after LT, and pathological response of explanted liver and alpha-fetoprotein trends are shown in Fig. 1. All three patients remained alive with stable graft function and without tumour recurrence or metastasis (Fig. 1). Two patients had uneventful postoperative recoveries and one patient experienced acute rejection after LT. Timely administration of steroid pulse therapy and adjustment of the immunosuppression drug dosage led to a successful recovery.

Fig. 1.

Outcome for patients who underwent LT in LEN-TAP trial

a Radiological and pathological response for three patients who underwent LT. Target lesion and tumour thrombus (indicated by red arrows) necrosis and ascites were found after treatment; tumour-free images were obtained one year after LT; no residual tumour cells were found in explanted liver. b AFP trends between initiation of LEN-TAP therapy and pre-transplant. AFP decreased dramatically in these three patients after downstaging therapy. c Programmed cell death protein 1 inhibitor cycles before transplant, pathological response and survival time for patients received LT. LT, liver transplantation; LEN-TAP, lenvatinib, transarterial chemoembolization and PD-1 inhibitor therapy; AFP, alpha-fetoprotein; RFS, recurrence-free survival; OS, overall survival; pCR, pathological complete response.

Discussion

Combination of locoregional and systemic therapies has shown synergistic effects and plays a significant role in conversion therapy for unresectable HCC. The purpose is salvage resection for the tumour⁹. Several retrospective studies reported promising response rates and salvage resection rate following triple combination of TACE, tyrosine kinase inhibitor (TKI) and PD-1 inhibitor for unresectable HCC^10,11. The authors’ pilot study and interim results of LEN-TAP trial showed promising tumour response and conversion resection rate^6,7. Here, the authors reported the outcomes of salvage LT after successful downstaging by triple combination of lenvatinib, TACE and PD-1 inhibitors for advanced HCC.

Due to the potential induction of immune-related hepatitis and potentially fatal allograft rejection, the use of immunotherapy is controversial in the pre-transplant setting¹². Therefore, aggressive induction immunosuppression with intravenous methylprednisolone and basiliximab was implemented prior to LT. The occurrence of acute rejection may be related to the relatively short interval between the last dose of PD-1 inhibitor and LT. The timing of deceased donor LT is uncertain, which complicates the decision of when to discontinue immunotherapy before LT. Studies have shown that discontinuing immunotherapy for at least 3 months prior to LT may be helpful to prevent acute rejection and graft loss¹³.

Continuing systemic therapy has been the standard of care for these patients. Then, disease progression usually occurs within 1–1.5 years after achieving a response¹⁴. For patients with resectable HCC it is generally accepted that complete removal of tumour provides the best opportunity of cure and offers favourable survival¹⁵. It is reasonable to believe that salvage LT for patients who were not feasible for salvage liver resection after successful downstaging might provide an acceptable post-LT survival. Further prospectively designed studies are needed to provide solid evidence.

Funding

This study was funded by National Natural Science Foundation of China (Grant No. 82200691) and Key Research and Development Program of Sichuan Province (Grant No. 2022YFS0377).

Disclosure

Dr Wei Peng reports receiving grant support from Zelgen and lecture fees from Bayer, Merk, Roche, Hengrui and SciClone. Dr Xiaoyun Zhang receives grant support from Innovent, Eisai and lecture fees from Bayer, Merk, Roche and Hengrui. Dr Chuan Li receives grant support from Eisai and Merk, and advisor board fees from Bayer, Merk and Roche. Dr Tianfu Wen reports receiving grant support from AstraZeneca, Zelgen, Merk, Roche, Eisai and Innovent, and advisory board fees and lecture fees from Bayer, Merk, Roche and Hengrui. No other potential conflict of interest was reported.

Supplementary material

Supplementary material is available at BJS online.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contributions

Wei Peng (Conceptualization, Data curation, Methodology, Writing—original draft, Writing—review & editing), Youwei Wu (Methodology, Software, Validation, Writing—review & editing), Xiaoyun Zhang (Investigation, Writing—review & editing), Chuan Li (Investigation, Writing—review & editing), Junyi Shen (Data curation, Investigation, Writing—review & editing), Weixia Chen (Supervision, Writing—review & editing), Qiu Li (Project administration, Supervision, Writing—review & editing), Ji Ma (Writing—review & editing), Yu Yang (Methodology, Writing—review & editing), Wu-sheng Lu (Data curation, Supervision, Writing—review & editing), Zuojin Liu (Data curation, Investigation, Writing—review & editing), Xin Sun (Investigation, Methodology, Project administration), Jiayin Yang (Supervision, Writing—review & editing), Yongjie Zhou (Conceptualization, Formal analysis, Funding acquisition, Writing—review & editing), and Tianfu Wen (Conceptualization, Funding acquisition, Investigation, Project administration, Writing—original draft, Writing—review & editing)