Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma

Primary 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 controversy 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" (referred to as the consensus hereafter, full-length version of the consensus can be seen in Supplementary File, https://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: In liver transplant recipients who have exceeded the criteria for HCC and those who 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 PFS and overall survival. Secondary efficacy indicators can be the main pathological response, 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)), TIL subsets, and the NLR in peripheral blood may be related to the efficacy of ICIs. High expression of immune checkpoint molecules (such as PD-LI) 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 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.