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Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

39148191
CMJ-2024-824
10.1097/CM9.0000000000003237
00001
3
Concensus Statement
Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma
Wang Zhengxin 1
Yang Jiayin 2
Li Guangming 3
Zhou Sihan
Hao Xiuyuan
1 Liver Transplantation Center, General Surgery Department, Huashan Hospital Affiliated to Fudan University, Organ Transplantation Institute of Fudan University, Shanghai 200040, China
2 Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China
3 Liver Transplantation Center, General Surgery Department of Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
Correspondence to: Zhengxin Wang, Liver Transplantation Center, General Surgery Department, Huashan Hospital Affiliated to Fudan University, Organ Transplantation Institute of Fudan University, Shanghai 200040, China E-Mail: wangzhengxin@huashan.org.cn;
Jiayin Yang, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610044, China E-Mail: doctoryjy@scu.edu.cn;
Guangming Li, Liver Transplantation Center, General Surgery Department of Beijing Youan Hospital, Capital Medical University, Beijing 100069, China E-Mail: liguangming@ccmu.edu.cn
15 8 2024
20 9 2024
137 18 21432145
18 3 2024
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

OPEN-ACCESSTRUE
SDCT
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pmcPrimary liver cancer (PLC) is the fourth-most common malignancy and second leading cause of tumor-related deaths in China. Hepatocellular carcinoma (HCC) accounts for 75–85% of PLCs.[1] At present, radical surgery remains the most effective treatment option for HCC, including liver resection and liver transplantation (LT). The indications of LT for HCC are relatively strict because of a shortage of donor livers and the risk of postoperative tumor recurrence and metastasis. Patients with tumor burdens exceeding LT criteria may undergo downstaging treatment to meet the criteria. In recent years, new drugs for HCC have been continuously developed. Among them, systemic therapeutic drugs represented by molecular targeted drugs and immune checkpoint inhibitors (ICIs) have created a new era in the treatment of HCC.[2] After LT, the main problems for recipients are tumor recurrence and metastasis. Previous studies showed that the 5-year tumor recurrence rate after LT was 20.0–57.8%, and the median survival time of recipients after HCC recurrence was only 12.9 months.[3,4] Various regional treatments, such as ablation, intervention, and radiation therapy, can be adopted for tumor recurrence and metastasis after LT. Systemic treatment, such as targeted drugs and chemotherapy, is also used in clinical practice. However, there is still some controversies regarding the application of ICIs for preventing or treating tumor recurrence and metastasis. Currently, there is no standardized guidelines or widespread consensus on the application of ICIs in LT for HCC among both domestic and international medical communities. To achieve effective and safe application of ICIs for patients with HCC before and after LT, in August 2023, Organ Transplantation Banch of the Chinese Medical Association convened national experts to jointly formulate the “Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma” (full-length version of the consensus can be seen in Supplementary File, http://links.lww.com/CM9/C97).

Application of ICIs in the Preoperative Treatment of LT for HCC

Indications for the application of ICIs before LT for HCC

Recommendation 1: Pre-LT ICIs for HCC are mainly suitable for patients with mid- or advanced-stage HCC, without distant metastasis, and with good liver function and physical fitness scores. Fully informing patients and obtaining informed consent before treatment are necessary because of the lack of high-level evidence for ICIs in the pre-treatment of LT for HCC.

Contraindications for using ICIs before LT for HCC

Recommendation 2: Before ICI treatment, careful evaluation of contraindications should be performed. Caution should be exercised in patients with the following situations: (1) with autoimmune diseases, (2) with gastric varicose veins accompanied by bleeding or high risk of bleeding, (3) with idiopathic pulmonary fibrosis or pneumonia, (4) with major cardiovascular disease or unstable arrhythmias, and (5) with moderate-to-severe ascites or severe infections. Above-mentioned opinions are mainly based on clinical experience in mid- to advanced-stage HCC.

Pre-transplant ICIs for patients with HCC

Recommendation 3: Based on published case reports and clinical experience, ICI monotherapy can be safely used before transplantation.

Pre-transplant ICI combination treatment regimen for HCC

Recommendation 4: The combination of ICIs and multiple treatments (e.g., transcatheter arterial chemoembolization [TACE], radiofrequency ablation, radiotherapy, and targeted therapy) can achieve better therapeutic effects than monotherapy, but the appropriate combination treatment regimen needs to be selected according to individual conditions.

Recommendation 5: The current first-line treatment regimens for ICIs combination therapy should include atezolizumab combined with bevacizumab, sintilimab combined with bevacizumab analogs, and apatinib combined with camrelizumab. If first-line treatment regimens are ineffective, second-line and third-line regimens may be considered.

Evaluation of therapeutic effect of ICI application before LT in patients with HCC

Recommendation 6: Dynamic enhanced magnetic resonance imaging (MRI) or computed tomography (CT) should be used as imaging examinations in combination with tumor markers, such as alpha-fetoprotein and protein induced by vitamin K absenceor antagonist-II (PIVKA-II), for evaluating the efficacy. The modified response evaluation criteria in solid tumors (mRECIST) can be used for imaging evaluation. Follow-up imaging should be performed every 6–8 weeks for the first 6 months after starting ICI treatment and may be combined with tumor markers for follow-up every 9–12 weeks.

Recommendation 7: Liver transplant recipients who have exceeded the criteria for HCC but successfully downstage to the Hangzhou criteria can achieve a similar prognosis to that in those who initially meet the criteria.

Interval between discontinuation of ICIs and transplantation before LT for HCC

Recommendation 8: In the case of good tumor control, the preoperative discontinuation time should be 30 days or longer.

Indications for the application of ICIs for tumor recurrence after LT for HCC

Recommendation 9: ICIs may be used as salvage therapy for patients with recurrent liver cancer after LT when the recurrent tumor continues to progress after receiving several different types of treatment regimens.

Contraindications for the use of ICIs in recurrence and metastasis after LT for HCC

Recommendation 10: In patients with tumor recurrence after LT, contraindications for the use of ICIs can be the same as those for preoperative contraindications, with a special contraindication that recipients are recommended to undergo a liver tissue biopsy before ICI treatment. Those with positive PD-L1 expression should be contraindicated for PD-1/PD-L1 inhibitors. Being in the acute rejection phase is also a contraindication for the use of ICIs.

The necessity of prophylactic therapy after LT for HCC

Recommendation 11: Because of the risk of triggering rejection reactions, using ICIs as a treatment for preventing tumor recurrence post-LT is not recommended.

Treatment strategies of ICIs for recurrence and metastasis of HCC after LT

Recommendation 12: Use of ICIs for recurrent and metastatic HCC after LT should mostly be used as salvage therapy, with monotherapy ICIs as the main approach. Systemic combination options should include combination with bevacizumab and combination with tyrosine kinase inhibitors (TKIs) such as lenvatinib, and dual immunotherapy is not recommended.

Recommendation 13: In recurrent and metastatic HCC after LT, ICIs can be combined with local treatment options, such as radiofrequency ablation, TACE, hepatic arterial infusion chemotherapy, and radiation therapy. However, there is currently limited relevant literature and research on combination treatments, leading to insufficient evidence.

Evaluation of therapeutic effects of ICI treatment for recurrence and metastasis of HCC after LT

Recommendation 14: The main efficacy indicators for immune checkpoint therapy for recurrence and metastasis of HCC after LT can be progression-free survival (PFS) and overall survival. Secondary efficacy indicators can be the main pathological response, objective response rate (ORR), and time to tumor progression.

Potential biomarkers for the benefits of ICI treatment in the recurrence and metastasis of HCC after LT

Recommendation 15: For indicating the benefits of ICI treatment in HCC, biomarkers in tumor genomics (e.g., mismatch repair defects, microsatellite instability (MSI) and tumor mutational burden (TMB)), tumor-infiltrating lymphocyte (TIL) subsets, and the neutrophil lymphocyte ratio (NLR) in peripheral blood may be related to the efficacy of ICIs. High expression of immune checkpoint molecules (such as PD-L1) in tumor tissue is also a potential biomarker for a benefit of ICI treatment.

Adjustment of the anti-rejection regimen during ICI treatment for recurrence and metastasis of HCC after LT

Recommendation 16: An immunosuppressive regimen based on tacrolimus or sirolimus is recommended during treatment with ICIs. Since the incidence of rejection with single-agent immunosuppressive regimens is higher than that with combination immunosuppressive regimens, tacrolimus combined sirolimus was recommended.

Management of Adverse Effects of ICIs in LT Recipients for HCC

Common adverse events and management

Recommendation 17: The predominant adverse effects induced by ICIs are related to the skin and gastrointestinal system. Vigilance is particularly necessary in the event of major organ adverse reactions, such as those affecting the liver, lungs, and heart. Mild adverse reactions call for a temporary pause in ICI treatment and symptomatic support, while reactions of grade 2 and above frequently require discontinuation of ICIs. Additionally, if deemed necessary, corticosteroids and immunosuppressive drugs should be added.

Diagnosis and management principles of rejection induced by ICIs treatment after LT

Recommendation 18: It is crucial to conduct early monitoring of rejection following the use of ICIs in liver transplant recipients, as the clinical manifestations may not have distinct features and therefore require differentiation from immune-related hepatitis. Graft biopsy serves as the gold standard for diagnosis.

Recommendation 19: The first step in managing rejection secondary to ICIs is to immediately discontinue the use of ICIs. Mild acute rejection may be treated with combined medication to enhance immunosuppression, including increasing calcineurin inhibitors (CNIs) doses. Meanwhile, moderate-to-severe acute rejection may require intravenous methylprednisolone shock therapy. In cases of severe rejection unresponsive to hormone shock therapy, antilymphocyte globulin, antithymocyte globulin, or anti-CD3 monoclonal antibodies can be considered. For combined humoral rejection, options include intravenous immunoglobulin or plasma exchange. In situations of irreversible rejection, re-transplantation should be considered, in conjunction with transplant eligibility criteria.

Incidence, prognosis, and high-risk group warning of rejection following ICI treatment after LT for HCC

Recommendation 20: The prognosis for rejection after ICIs treatment following liver transplantation for HCC is generally poor. Short interval time post-transplantation and reduced doses of immunosuppressive drugs are significant risk factors for subsequent rejection.

Preventive strategies for rejection in HCC patients undergoing LT and receiving ICIs treatment

Recommendation 21: A personalized immunosuppressive induction and maintenance strategy should be developed considering the downstaging efficacy, the specific type and duration of ICIs treatment, interval for discontinuing ICIs, PD-L1 expression level in the graft, recovery of liver function, and serum concentration of immunosuppressant.

Role of the Multidisciplinary Team (MDT) in ICI Application for HCC Before and After LT

Recommendation 22: In the application of ICIs before and after LT for HCC, an MDT team should be fully involved in the patient’s evaluation, medication regimen, efficacy appraisal, and adverse reaction monitoring and prevention. The MDT model can provide patients with more scientific, reasonable, and comprehensive treatment regimens, and increase their treatment benefits.

Chief experts

Shusen Zheng, Xiao Xu, Hong Zheng, Jian Zhou, Qian Lu

Funding

This concensus was funded by the National Key Research and Development Program of China (Nos. 2021YFA1100500 and 2023YFC2505900), National Natural Science Foundation of China (Nos. 81873874, 82071797, and 82241225), and Beijing Natural Science Foundation (No. 7222096).

Conflicts of interest

None.

Supplementary Material

How to cite this article: Wang ZX, Yang JY, Li GM. Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma. Chin Med J 2024;137:2143–2145. doi: 10.1097/CM9.0000000000003237
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