Therapeutic effect of rapamycin combined with sorafenib in hepatocellular carcinoma patients with tumor recurrence after liver transplantation beyond Milan criteria_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

GAO Jingya ¹ , GUO Qingjun ² , XIE Yan ² , ZHANG Li ² , TIAN Dazhi ² , LI Junjie ² ,  JIANG Wentao ²

1. Tianjin Medical University First Center Clinical College, Tianjin 300070, P.R. China;
2. Department of Liver Transplantation, Tianjin First Center Hospital; Key Laboratory for Critical Care Medicine of Ministry of Health; Tianjin Key Laboratory for Organ Transplantation; Tianjin Clinical Research Center for Organ Transplantation; Key Laboratory of Transplantation Medicine, Chinese Academy of Medical Sciences, Tianjin 300070, P.R. China;

Corresponding author：

JIANG Wentao, Email: jiangwentao1974@163.com

Keywords：

hepatocellular carcinoma; liver transplantation; recurrence; sorafenib; rapamycin

DOI：

10.7507/1007-9424.201808036

Video：

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Objective To observe efficacy of rapamycin combined with sorafenib in hepatocellular carcinoma (HCC) patients with tumor recurrence after liver transplantation beyond Milan criteria. Methods Forty-one beyond Milan criteria HCC patients who underwent the classic orthotopic liver transplantation without bypass and the tumor postoperatively recurred in the Tianjin First Center Hospital from February 1, 2012 to August 31, 2015 were collected retrospectively, then were divided into a local treatment group (n=21) and a comprehensive treatment group (n=20). The local treatment included the surgical resection, radiofrequency ablation, transcatheter arterial chemoembolization, radioactive seed implantation, etc.. The comprehensive treatment was on the basis of the local treatment plus rapamycin in combination with sorafenib. Results There were 12 patients with stable disease and 9 patients with progressive disease in the local treatment group. There were 12 patients with partial response, 10 patients with stable disease and 8 patients with progressive disease in the comprehensive group. In the local treatment group and the comprehensive treatment group, the median survival time were 9 months and 12 months, and the 1-year and 2-year survival rates after the recurrence were 14% versus 55%, 0 versus 15%, respectively. The survival of the comprehensive treatment group was significantly better than that of the local treatment group (P<0.01). Conclusion Combination of rapamycin and sorafenib in HCC patients with tumor recurrence after liver transplantation beyond Milan criteria can significantly improve survival time of patient with recurrence.

Citation： GAO Jingya, GUO Qingjun, XIE Yan, ZHANG Li, TIAN Dazhi, LI Junjie, JIANG Wentao. Therapeutic effect of rapamycin combined with sorafenib in hepatocellular carcinoma patients with tumor recurrence after liver transplantation beyond Milan criteria. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(9): 1039-1043. doi: 10.7507/1007-9424.201808036 Copy

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2.	陈万青, 李贺, 孙可欣, 等. 2014年中国恶性肿瘤发病和死亡分析. 中华肿瘤杂志, 2018, 40(1): 5-13.
3.	Wang C, Xie H, Lu D, et al. The MTHFR polymorphism affect the susceptibility of HCC and the prognosis of HCC liver transplantation. Clin Transl Oncol, 2018, 20(4): 448-456.
4.	Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 1996, 334(11): 693-699.
5.	Jung DH, Tak E, Hwang S, et al. Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence. Liver Transpl, 2018, 24(7): 932-945.
6.	Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000, 92(3): 205-216.
7.	Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys, 2000, 47(1): 13-47.
8.	Xu XS, Liu C, Qu K, et al. Liver transplantation versus liver resection for hepatocellular carcinoma: a meta-analysis. Hepatobiliary Pancreat Dis Int, 2014, 13(3): 234-241.
9.	Krenzien F, Schmelzle M, Struecker B, et al. Liver transplantation and liver resection for cirrhotic patients with hepatocellular carcinoma: comparison of long-term survivals. J Gastrointest Surg, 2018, 22(5): 840-848.
10.	Menahem B, Lubrano J, Duvoux C, et al. Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: An attempt to perform an ideal meta-analysis. Liver Transpl, 2017, 23(6): 836-844.
11.	Herrero JI, Lorenzo M, Quiroga J, et al. De Novo neoplasia after liver transplantation: an analysis of risk factors and influence on survival. Liver Transpl, 2005, 11(1): 89-97.
12.	Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun, 2018, 9(1): 191.
13.	王海清, 李磊, 杨家印. 肝癌肝移植术后的复发机制与防治策略. 中华肝脏病杂志, 2018, 26(2): 93-97.
14.	Akoad ME, Pomfret EA. Surgical resection and liver transplantation for hepatocellular carcinoma. Clin Liver Dis, 2015, 19(2): 381-399.
15.	Kozłowski P, Parfieniuk-Kowerda A, Tarasik A, et al. Occurrence and clinical characteristics of hepatocellular carcinoma in the north-eastern Poland. Przegl Epidemiol, 2017, 71(3): 405-415.
16.	陈婧. 索拉非尼治疗肝癌肝移植术后复发的疗效. 中国实用医药, 2017, 12(8): 121-123.
17.	Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2009, 10(1): 25-34.
18.	Nishida N, Kitano M, Sakurai T, et al. Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis, 2015, 33(6): 771-779.
19.	Raoul JL, Kudo M, Finn RS, et al. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat Rev, 2018, 68: 6-24.
20.	Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis. Dig Liver Dis, 2015, 47(4): 324-330.
21.	Chinnakotla S, Davis GL, Vasani S, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl, 2009, 15(12): 1834-1842.
22.	Waidmann O, Hofmann WP, Zeuzem S, et al. mTOR inhibitors and sorafenib for recurrent heptocellular carcinoma after orthotopic liver transplantation. J Hepatol, 2011, 54(2): 396-398.
23.	Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl, 2012, 18(1): 45-52.
24.	Welker MW, Bechstein WO, Zeuzem S, et al. Recurrent hepatocellular carcinoma after liver transplantation-an emerging clinical challenge. Transpl Int, 2013, 26(2): 109-118.
25.	Varghese J, Kedarisetty C, Venkataraman J, et al. Combination of TACE and sorafenib improves outcomes in BCLC stages B/C of hepatocellular carcinoma: a single centre experience. Ann Hepatol, 2017, 16(2): 247-254.

1. Sun Y, Wang Y, Li M, et al. Long-term trends of liver cancer mortality by gender in urban and rural areas in China: an age-period-cohort analysis. BMJ Open, 2018, 8(2): e020490.
2. 陈万青, 李贺, 孙可欣, 等. 2014年中国恶性肿瘤发病和死亡分析. 中华肿瘤杂志, 2018, 40(1): 5-13.
3. Wang C, Xie H, Lu D, et al. The MTHFR polymorphism affect the susceptibility of HCC and the prognosis of HCC liver transplantation. Clin Transl Oncol, 2018, 20(4): 448-456.
4. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 1996, 334(11): 693-699.
5. Jung DH, Tak E, Hwang S, et al. Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence. Liver Transpl, 2018, 24(7): 932-945.
6. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000, 92(3): 205-216.
7. Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys, 2000, 47(1): 13-47.
8. Xu XS, Liu C, Qu K, et al. Liver transplantation versus liver resection for hepatocellular carcinoma: a meta-analysis. Hepatobiliary Pancreat Dis Int, 2014, 13(3): 234-241.
9. Krenzien F, Schmelzle M, Struecker B, et al. Liver transplantation and liver resection for cirrhotic patients with hepatocellular carcinoma: comparison of long-term survivals. J Gastrointest Surg, 2018, 22(5): 840-848.
10. Menahem B, Lubrano J, Duvoux C, et al. Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: An attempt to perform an ideal meta-analysis. Liver Transpl, 2017, 23(6): 836-844.
11. Herrero JI, Lorenzo M, Quiroga J, et al. De Novo neoplasia after liver transplantation: an analysis of risk factors and influence on survival. Liver Transpl, 2005, 11(1): 89-97.
12. Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun, 2018, 9(1): 191.
13. 王海清, 李磊, 杨家印. 肝癌肝移植术后的复发机制与防治策略. 中华肝脏病杂志, 2018, 26(2): 93-97.
14. Akoad ME, Pomfret EA. Surgical resection and liver transplantation for hepatocellular carcinoma. Clin Liver Dis, 2015, 19(2): 381-399.
15. Kozłowski P, Parfieniuk-Kowerda A, Tarasik A, et al. Occurrence and clinical characteristics of hepatocellular carcinoma in the north-eastern Poland. Przegl Epidemiol, 2017, 71(3): 405-415.
16. 陈婧. 索拉非尼治疗肝癌肝移植术后复发的疗效. 中国实用医药, 2017, 12(8): 121-123.
17. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2009, 10(1): 25-34.
18. Nishida N, Kitano M, Sakurai T, et al. Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis, 2015, 33(6): 771-779.
19. Raoul JL, Kudo M, Finn RS, et al. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat Rev, 2018, 68: 6-24.
20. Mancuso A, Mazzola A, Cabibbo G, et al. Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis. Dig Liver Dis, 2015, 47(4): 324-330.
21. Chinnakotla S, Davis GL, Vasani S, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl, 2009, 15(12): 1834-1842.
22. Waidmann O, Hofmann WP, Zeuzem S, et al. mTOR inhibitors and sorafenib for recurrent heptocellular carcinoma after orthotopic liver transplantation. J Hepatol, 2011, 54(2): 396-398.
23. Gomez-Martin C, Bustamante J, Castroagudin JF, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl, 2012, 18(1): 45-52.
24. Welker MW, Bechstein WO, Zeuzem S, et al. Recurrent hepatocellular carcinoma after liver transplantation-an emerging clinical challenge. Transpl Int, 2013, 26(2): 109-118.
25. Varghese J, Kedarisetty C, Venkataraman J, et al. Combination of TACE and sorafenib improves outcomes in BCLC stages B/C of hepatocellular carcinoma: a single centre experience. Ann Hepatol, 2017, 16(2): 247-254.

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Therapeutic effect of rapamycin combined with sorafenib in hepatocellular carcinoma patients with tumor recurrence after liver transplantation beyond Milan criteria

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