The clinical application of everolimus after liver transplantation for hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Qianying ,  WANG Weixing

Department of General Surgery, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan 430060, P. R. China;

Corresponding author：

WANG Weixing, Email: sate.llite@163.com

Keywords：

everolimus; hepatocellular carcinoma; liver transplantation

DOI：

10.7507/1007-9424.201909060

Video：

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Objective To elucidate the mechanism of evolimus (EVR) and its application, efficacy and common adverse reactions in hepatocellular carcinoma (HCC) patients after liver transplantation.Method Relevant literatures in recent years were searched through websites such as Wanfang, CNKI and PubMed, and the results were read, analyzed and summarized.Results Currently, there are a wide variety of immunosuppressive agents for HCC patients after liver transplantation, and immunosuppressive treatment options are also diverse and there is no unified standard. Today is more widely used clinically used for transplantation immune inhibitors of calcineurin inhibitors (CNIs), but because of its renal toxicity and side effects and recurrence of HCC risk increases, CNIs in HCC patients after liver transplantation using gradually is restricted, and mammalian target of rapamycin (mTOR) inhibitors are valued, gradually into clinical immunosuppression after liver transplantation for treatment provides a new way of thinking. As an mTOR inhibitor, EVR is gradually being applied to HCC patients after liver transplantation.Conclusion As an mTOR inhibitor only approved for use in HCC patients after liver transplantation in recent years, relevant literature studies have shown that EVR plays an important role in improving the success rate of transplantation, protecting renal function and inhibiting HCC recurrence.

Citation： HE Qianying, WANG Weixing. The clinical application of everolimus after liver transplantation for hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(6): 759-762. doi: 10.7507/1007-9424.201909060 Copy

1.	Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol, 2017, 34(2): 153-159.
2.	Meirelles Júnior RF, Salvalaggio P, Rezende MB, et al. Liver transplantation: history, outcomes and perspectives. Einstein (Sao Paulo), 2015, 13(1): 149-152.
3.	Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
4.	Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med, 2003, 349(10): 931-940.
5.	Giakoustidis AE, Giakoustidis DE. Immunosuppression strategies in liver transplantation patient; patients with hepatocellular carcinoma. Immunotherapy, 2017, 9(2): 197-206.
6.	Carenco C, Assenat E, Faure S, et al. Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship. Am J Transpl, 2015, 15(3): 678-686.
7.	Cucchiari D, Ríos J, Molina-Andujar A, et al. Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice. J Nephrol, 2019 Dec 18.[Epub ahead of print].
8.	Choudhary NS, Saigal S, Sonavane A, et al. A Case of sirolimus-induced interstitial lung disease after liver transplantation. J Clin Exp Hepatol, 2019, 9(4): 539-540.
9.	Dumortier J, Dharancy S, Calmus Y, et al. Use of everolimus in liver transplantation: The French experience. Transplant Rev (Orlando), 2016, 30(3): 161-170.
10.	Hasskarl J. Everolimus. Recent Results Cancer Res, 2018, 211: 101-123.
11.	Hsieh A C, Liu Y, Edlind M P, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 2012, 485(7396): 55-61.
12.	Golob-Schwarzl N, Krassnig S, Toeglhofer AM, et al. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer, 2017, 83: 56-70.
13.	宋晓红, 刘明明, 仉红刚. mTOR信号通路与相关疾病的研究进展. 微循环学杂志, 2018, 28(3): 64-70.
14.	乔振宇, 王健, 吕晓业, 等. 依维莫司和MK-2206联合用药协同抑制肝癌细胞增殖. 中国药理学与毒理学杂志, 2017, 31(8): 793-799.
15.	Klawitter J, Nashan B, Christians U. Everolimus and sirolimus in transplantation-related but different. Expert Opin Drug Saf, 2015, 14(7): 1055-1070.
16.	Crowe A, Bruelisauer A, Duerr L, et al. Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos, 1999, 27(5): 627-632.
17.	Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet, 2001, 40(8): 573-585.
18.	Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet, 2004, 43(2): 83-95.
19.	Fischer L, Saliba F, Kaiser GM, et al. Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study. Transplantation, 2015, 99(7): 1455-1462.
20.	Cholongitas E, Goulis I, Theocharidou E, et al. Everolimus-based immunosuppression in liver transplant recipients: a single-centre experience. Hepatol Int, 2014, 8(1): 137-145.
21.	俞亮, 张栋, 潘飞, 等. 肝移植术后应用依维莫司的Meta分析. 中华肝胆外科杂志, 2016, 22(7): 454-459.
22.	Cillo U, Saracino L, Vitale A, et al. Very early introduction of everolimus in de novo liver transplantation: results of a multicenter, prospective, randomized trial. Liver Transpl, 2019, 25(2): 242-251.
23.	Kamar N, Allard J, Ribes D, et al. Assessment of glomerular and tubular functions in renal transplant patients receiving cyclosporine A in combination with either sirolimus or everolimus. Clin Nephrol, 2005, 63(2): 80-86.
24.	Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol, 2013, 59(6): 1193-1199.
25.	Duvoux C, Toso C. mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation? Transplantat Rev, 2015, 29(3): 168-174.
26.	Piguet AC, Saar B, Hlushchuk R, et al. Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma. Mol Cancer Ther, 2011, 10(6): 1007-1017.
27.	Saliba F, Dharancy S, Lorho R, et al. Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis. Liver Transpl, 2011, 17(8): 905-913.
28.	Motzer RJ, Barrios CH, Kim TM, et al. Phase Ⅱ randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(25): 2765-2772.
29.	Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Cancer, 2010, 116(18): 4256-4265.
30.	Arena C, Troiano G, Zhurakivska K, et al. Stomatitis and everolimus: a review of current literature on 8 201 patients. Onco Targets Ther, 2019, 12: 9669-9683.
31.	王娟, 张甜甜, 张朝阳, 等. 依维莫司相关间质性肺病研究进展. 现代肿瘤医学, 2019, 27(20): 3743-3745.
32.	Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. Plos One, 2017, 12(8): e180939.
33.	Fazio N, Buzzoni R, Delle Fave G, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci, 2018, 109(1): 174-181.
34.	Wasilewicz MP, Moczydlowska D, Janik M, et al. Immuno-suppressive treatment with everolimus in patients after liver transplant: 4 years of single-center experience. Pol Arch Intern Med, 2019, 129(10): 686-691.

1. Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol, 2017, 34(2): 153-159.
2. Meirelles Júnior RF, Salvalaggio P, Rezende MB, et al. Liver transplantation: history, outcomes and perspectives. Einstein (Sao Paulo), 2015, 13(1): 149-152.
3. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136(5): E359-E386.
4. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med, 2003, 349(10): 931-940.
5. Giakoustidis AE, Giakoustidis DE. Immunosuppression strategies in liver transplantation patient; patients with hepatocellular carcinoma. Immunotherapy, 2017, 9(2): 197-206.
6. Carenco C, Assenat E, Faure S, et al. Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship. Am J Transpl, 2015, 15(3): 678-686.
7. Cucchiari D, Ríos J, Molina-Andujar A, et al. Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice. J Nephrol, 2019 Dec 18.[Epub ahead of print].
8. Choudhary NS, Saigal S, Sonavane A, et al. A Case of sirolimus-induced interstitial lung disease after liver transplantation. J Clin Exp Hepatol, 2019, 9(4): 539-540.
9. Dumortier J, Dharancy S, Calmus Y, et al. Use of everolimus in liver transplantation: The French experience. Transplant Rev (Orlando), 2016, 30(3): 161-170.
10. Hasskarl J. Everolimus. Recent Results Cancer Res, 2018, 211: 101-123.
11. Hsieh A C, Liu Y, Edlind M P, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 2012, 485(7396): 55-61.
12. Golob-Schwarzl N, Krassnig S, Toeglhofer AM, et al. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer, 2017, 83: 56-70.
13. 宋晓红, 刘明明, 仉红刚. mTOR信号通路与相关疾病的研究进展. 微循环学杂志, 2018, 28(3): 64-70.
14. 乔振宇, 王健, 吕晓业, 等. 依维莫司和MK-2206联合用药协同抑制肝癌细胞增殖. 中国药理学与毒理学杂志, 2017, 31(8): 793-799.
15. Klawitter J, Nashan B, Christians U. Everolimus and sirolimus in transplantation-related but different. Expert Opin Drug Saf, 2015, 14(7): 1055-1070.
16. Crowe A, Bruelisauer A, Duerr L, et al. Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos, 1999, 27(5): 627-632.
17. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet, 2001, 40(8): 573-585.
18. Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet, 2004, 43(2): 83-95.
19. Fischer L, Saliba F, Kaiser GM, et al. Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study. Transplantation, 2015, 99(7): 1455-1462.
20. Cholongitas E, Goulis I, Theocharidou E, et al. Everolimus-based immunosuppression in liver transplant recipients: a single-centre experience. Hepatol Int, 2014, 8(1): 137-145.
21. 俞亮, 张栋, 潘飞, 等. 肝移植术后应用依维莫司的Meta分析. 中华肝胆外科杂志, 2016, 22(7): 454-459.
22. Cillo U, Saracino L, Vitale A, et al. Very early introduction of everolimus in de novo liver transplantation: results of a multicenter, prospective, randomized trial. Liver Transpl, 2019, 25(2): 242-251.
23. Kamar N, Allard J, Ribes D, et al. Assessment of glomerular and tubular functions in renal transplant patients receiving cyclosporine A in combination with either sirolimus or everolimus. Clin Nephrol, 2005, 63(2): 80-86.
24. Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol, 2013, 59(6): 1193-1199.
25. Duvoux C, Toso C. mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation? Transplantat Rev, 2015, 29(3): 168-174.
26. Piguet AC, Saar B, Hlushchuk R, et al. Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma. Mol Cancer Ther, 2011, 10(6): 1007-1017.
27. Saliba F, Dharancy S, Lorho R, et al. Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis. Liver Transpl, 2011, 17(8): 905-913.
28. Motzer RJ, Barrios CH, Kim TM, et al. Phase Ⅱ randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(25): 2765-2772.
29. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Cancer, 2010, 116(18): 4256-4265.
30. Arena C, Troiano G, Zhurakivska K, et al. Stomatitis and everolimus: a review of current literature on 8 201 patients. Onco Targets Ther, 2019, 12: 9669-9683.
31. 王娟, 张甜甜, 张朝阳, 等. 依维莫司相关间质性肺病研究进展. 现代肿瘤医学, 2019, 27(20): 3743-3745.
32. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. Plos One, 2017, 12(8): e180939.
33. Fazio N, Buzzoni R, Delle Fave G, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci, 2018, 109(1): 174-181.
34. Wasilewicz MP, Moczydlowska D, Janik M, et al. Immuno-suppressive treatment with everolimus in patients after liver transplant: 4 years of single-center experience. Pol Arch Intern Med, 2019, 129(10): 686-691.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The clinical application of everolimus after liver transplantation for hepatocellular carcinoma

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