构建以雷帕霉素为主预防肝癌肝移植术后肿瘤复发的综合防治体系

摘要/Abstract

摘要： 肝移植是肝癌,尤其是晚期肝癌的最有效的根治性手段,随着移植器官获取与移植手术的标准化发展,近5年我国肝癌肝移植的数量已远超美国。但是,术后复发与转移仍是限制远期疗效的关键问题。以钙调磷酸酶抑制剂为主的免疫抑制剂方案被认为是肝癌肝移植术后肿瘤复发的独立危险;避免激素与钙调磷酸酶抑制剂类药物长期的高暴露,早期雷帕霉素转化治疗是目前推荐的免疫抑制方案,然而,并未能改善3~5年的远期生存获益或获益较小,如何制定全面系统性、个性化的肝癌复发综合防治体系,最大优化雷帕霉素的有益生存效应,延缓肝癌的复发,是亟需解决的问题,本文旨在以肝癌、肝移植、靶向治疗、生物免疫治疗的最新成果为基础,探讨建立肝癌肝移植术后肿瘤复发综合防治体系的必要性。

关键词: 原发性肝癌, 肝移植, 雷帕霉素, 肝癌复发, 靶向治疗

Abstract: Liver transplantation (LT) represents one of the most effective radical therapy for hepatocellular carcinoma (HCC), particularly for advanced HCC. With the standardized development of organ acquisition and transplantation, the number of LT for HCC in China has far exceeded that of the United States in the past five years. However, postoperative recurrence and metastasis remains the key issues to improve the long-term prognosis. Meanwhile, immunosuppressive regimens based on calcineurin inhibitors are considered to be an independent risk factor of tumor recurrence after LT for HCC, early rapamycin conversion therapy is currently recommended for immunosuppression in recommended so as to avoid long-term high exposure to hormones and calcineurin inhibitors. Nevertheless, this option failed to improve the long-term survival of 3 to 5 years or the benefit was limited. Therefore, it is important and urgent to establish a personalized comprehensive prevention and treatment system to maximize the survival benefit of rapamycin and delay the recurrence of HCC. Based on the recent progress of HCC treatment including LT, targeted therapy and biological immunotherapy, our study aims to explore the necessity of establishing a comprehensive prevention and treatment system of tumor recurrence after LT.

Key words: Primary liver cancer, Liver transplantation, Rapamycin, Tumor recurrence, Targeted therapy

贺强, 周林. 构建以雷帕霉素为主预防肝癌肝移植术后肿瘤复发的综合防治体系[J]. 肝癌电子杂志, 2021, 8(3): 1-7.

He Qiang, Zhou Lin. To establish a comprehensive prevention and treatment system based on rapamycin for cancer recurrence after liver transplantation[J]. Electronic Journal of Liver Tumor, 2021, 8(3): 1-7.

参考文献

[1] SIEGEL RL, MILLER KD, JEMAL A.Cancer statistics, 2020[J]. CA Cancer J Clin, 2020,70(1):7-30.
[2] FORNER A, REIG M, BRUIX J.Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127): 1301-1314.
[3] 中国医师协会器官移植医师分会肝移植学组,中华医学会器官移植学分会肝移植学组.西罗莫司在肝癌肝移植中应用的中国专家共识(2020版)[J].中华消化外科杂志,2020,19(6):589-597.
[4] BRUIX J, REIG M, SHERMAN M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma[J]. Gastroenterology, 2016, 150(4): 835-853.
[5] INCE V, ARA C, YILMAZ S.Malatya and Other Criteria for Liver Transplantation in Hepatocellular Carcinoma[J]. Journal of gastrointestinal cancer, 2020, 51(4): 1118-1121.
[6] SAPISOCHIN G, GOLDARACENA N, LAURENCE J M, et al.The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study[J]. Hepatology, 2016, 64(6): 2077-2088.
[7] XU X, LU D, LING Q, et al.Liver transplantation for hepatocellular carcinoma beyond the Milan criteria[J]. Gut, 2016, 65(6): 1035-1041.
[8] BHOORI S, MAZZAFERRO V.Current challenges in liver transplantation for hepatocellular carcinoma[J]. Best Pract Res Clin Gastroenterol, 2014, 28(5): 867-879.
[9] 中国医师协会器官移植医师分会, 中华医学会器官移植学分会. 中国肝癌肝移植临床实践指南(2018版)[J]. 中华消化外科杂志, 2019, 18(1): 1-7.
[10] RODRíGUEZ-PERáLVAREZ M, TSOCHATZIS E, NAVEAS M C, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma[J]. J Hepatol, 2013, 59(6): 1193-1199.
[11] RODRíGUEZ-PERáLVAREZ M, DE LA MATA M, BURROUGHS A K. Liver transplantation: immunosuppression and oncology[J]. Curr Opin Organ Transplant, 2014, 19(3): 253-260.
[12] GRIGG S E, SARRI G L, GOW P J, et al.Systematic review with meta-analysis: sirolimus- or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma[J]. Aliment Pharmacol Ther, 2019, 49(10): 1260-1273.
[13] HARPER S J, GELSON W, HARPER I G, et al.Switching to sirolimus-based immune suppression after liver transplantation is safe and effective: a single-center experience[J]. Transplantation, 2011, 91(1): 128-132.
[14] 宋继勇,杜国盛,朱志东,等. 胸腺法新在肝移植术后严重肺部感染患者中的应用研究[J]. 器官移植,2015,(2):98-101.
[15] ZHOU L, PAN L C, ZHENG Y G, et al.Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience[J]. Oncol Lett, 2018, 16(4): 4407-4417.
[16] GEISSLER E K, SCHNITZBAUER A A, ZüLKE C, et al. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial[J]. Transplantation, 2016, 100(1): 116-125.
[17] FINN R, QIN S, IKEDA M, et al.Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma[J]. N Eng J Med, 2020, 382(20): 1894-1905.
[18] SEHGAL S N, BAKER H, VéZINA C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization[J]. J Antibiot (Tokyo), 1975, 28(10): 727-732.
[19] MARTEL R R, KLICIUS J, GALET S.Inhibition of the immune response by rapamycin, a new antifungal antibiotic[J]. Can J Physiol Pharmacol, 1977, 55(1): 48-51.
[20] MEISER BM, WANG J, MORRIS RE.Progress in Immunology[M]. Springer, Berlin, Heidelberg,1989:1195-1198.
[21] LAWRENCE J, NHO R.The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis[J]. Int J Mol Sci, 2018, 19(3):778.
[22] SARBASSOV D D, ALI S M, SENGUPTA S, et al.Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB[J]. Mol Cell, 2006, 22(2): 159-168.
[23] WANG C, CIGLIANO A, JIANG L, et al.4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice[J]. Hepatology, 2015, 61(1): 200-213.
[24] SALMOND R J, ZAMOYSKA R.How does the mammalian target of rapamycin (mTOR) influence CD8 T cell differentiation?[J]. Cell Cycle, 2010, 9(15): 2952-2957.
[25] YOO Y J, KIM H, PARK S R, et al.An overview of rapamycin: from discovery to future perspectives[J]. J Ind Microbiol Biotechnol, 2017, 44(4-5): 537-553.
[26] SAHIN F. mTOR and P70 S6 Kinase Expression in Primary Liver Neoplasms[J]. Clin Cancer Res, 2004, 10(24): 8421-8425.
[27] SIEGHART W, FUEREDER T, SCHMID K, et al.Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation[J]. Transplantation, 2007, 83(4): 425-432.
[28] SEMELA D, PIGUET A C, KOLEV M, et al.Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma[J]. J Hepatol, 2007, 46(5): 840-848.
[29] MATTER M S, DECAENS T, ANDERSEN J B, et al.Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends[J]. J Hepatol, 2014, 60(4): 855-865.
[30] KIM S H, LEE J E, YANG S H, et al.Induction of cytokines and growth factors by rapamycin in the microenvironment of brain metastases of lung cancer[J]. Oncol Lett, 2013, 5(3): 953-958.
[31] WU L, FENG Z, CUI S, et al.Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury[J]. PLoS One, 2013, 8(5): e63799.
[32] VIVARELLI M, CUCCHETTI A, PISCAGLIA F, et al.Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: Key role of immunosuppression[J]. Liver Transpl, 2005, 11(5):497-503.
[33] 谢琴芬,郑树森. 肝癌患者肝移植后的免疫抑制剂应用[J]. 中华器官移植杂志,2013,34(9):573-575.
[34] KWONG A, KIM W, LAKE J, et al. OPTN/SRTR2018 Annual Data Report: Liver[J]. Am J Transplant, 2020, 20 Suppl s1: 193-299.
[35] VIVARELLI M, CUCCHETTI A, PISCAGLIA F, et al.Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression[J]. Liver Transpl, 2005, 11(5): 497-503.
[36] VIVARELLI M, CUCCHETTI A, LA BARBA G, et al.Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence[J]. Ann Surg, 2008, 248(5): 857-862.
[37] DUVOUX C, ROUDOT-THORAVAL F, DECAENS T, et al.Liver Transplantation for Hepatocellular Carcinoma: A Model Including α-Fetoprotein Improves the Performance of Milan Criteria - ScienceDirect[J]. Gastroenterology, 2012, 143(4): 986-994.
[38] HARNOIS D M.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis[J]. Yearbook of Medicine, 2009,10(1):35-43.
[39] TOSO C, MERANI S, BIGAM D L, et al.Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma[J]. Hepatology, 2010, 51(4): 1237-1243.
[40] LING S, FENG T, ZHAN Q, et al.Sirolimus-based immunosuppression improves outcomes in liver transplantation recipients with hepatocellular carcinoma beyond the Hangzhou criteria[J]. Ann Transl Med, 2020, 8(4): 80.
[41] MENON K V, HAKEEM A R, HEATON N D.Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma[J]. Aliment Pharmacol Ther, 2013, 37(4): 411-419.
[42] LIANG W, WANG D, LING X, et al.Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis[J]. Liver Transpl, 2012, 18(1): 62-69.
[43] YANIK E L, CHINNAKOTLA S, GUSTAFSON S K, et al.Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma[J]. Liver Transpl, 2016, 22(5): 627-634.
[44] GUERRERO M, FERRíN G, RODRíGUEZ-PERáLVAREZ M, et al. mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence[J]. Int J Mol Sci, 2019, 20(2):336
[45] SCHNITZBAUER A A, FILMANN N, ADAM R, et al.mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors[J]. Ann Surg, 2020, 272(5): 855-862.
[46] XU S L, ZHANG Y C, WANG G Y, et al.Survival analysis of sirolimus-based immunosuppression in liver transplantation in patients with hepatocellular carcinoma[J]. Clin Res Hepatol Gastroenterol, 2016, 40(6): 674-681.
[47] RODRíGUEZ-PERáLVAREZ M, GUERRERO-MISAS M, THORBURN D, et al. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis [J]. Cochrane Database Syst Rev, 2017, 3(3): Cd011639.
[48] KUDO M, FINN R S, QIN S, et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173.
[49] HUYNH H, NGO V C, KOONG H N, et al.Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma[J]. J Cell Mol Med, 2009, 13(8b): 2673-2683.
[50] GOMEZ-MARTIN C, BUSTAMANTE J, CASTROAGUDIN J F, et al.Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation[J]. Liver Transpl, 2012, 18(1): 45-52.
[51] 李势辉,汪根树. 肝癌肝移植术后复发靶向预防和治疗的新希望:索拉非尼[J]. 器官移植,2014,3:145-148.
[52] YANG Z, WANG S, TIAN X Y, et al.Impact of treatment modalities on patients with recurrent hepatocellular carcinoma after liver transplantation: Preliminary experience[J]. Hepatobiliary Pancreat Dis Int, 2020, 19(4): 365-370.
[53] LI H, LI X, LIU S, et al.Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1[J]. Hepatology, 2017, 66(6): 1920-1933.
[54] EL-KHOUEIRY A B, SANGRO B, YAU T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502.
[55] FINN R, RYOO B Y, MERLE P, et al.Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2019, 37(S15): 4004.
[56] MARK TERRY.Bristol-Myers Squibb's Opdivo Fails to Show Superiority to Bayer's Nexavar in Liver Cancer[N]. Biospace.com, Ju, Jun 24, 2019.
[57] REN Z, FAN J, XU J, et al. LBA2 Sintilimab plus bevacizumab biosimilar vs sorafenib as first-line treatment for advanced hepatocellular carcinoma (ORIENT-32)2[J]. Ann Oncol, 2020,31(S6)S1241.
[58] PARK J, CHEN M, COLOMBO M, et al.Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study[J]. Liver Int, 2015, 35(9): 2155-2166.
[59] KITTAI A, OLDHAM H, CETNAR J, et al.Immune Checkpoint Inhibitors in Organ Transplant Patients[J]. J Immunother, 2017, 40(7): 277-281.