Efficacy and cost-effectiveness of thymalfasin for hepatocellular carcinoma after liver resection_West China Medical Journal

Authors：

WANG Xinyuan ¹ , WEN Feng ¹ , ZHU Yongqiang ² , LING Yunbiao ³ ,  LI Qiu ¹

1. Department of Abdominal Tumor, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of General Surgery, Chengdu Military General Hospital, Chengdu, Sichuan 610041, P. R. China;
3. Department of Liver Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P. R. China;

Corresponding?author：

LI Qiu, Email: 329718382@qq.com

Keywords：

Thymalfasin; Hepatocellular carcinoma; Adjuvant therapy; Recurrence-free survival; Overall survival; Cost-effectiveness; Sensitive analyses

DOI：

10.7507/1002-0179.201811022

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ObjectiveTo evaluate the efficacy and cost-effectiveness of thymalfasin (Tα1) as an adjuvant therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after surgery.MethodsPatients with HBV-related HCC who underwent hepatectomy from February 2007 to December 2015 in West China Hospital of Sichuan University, Chengdu Military General Hospital, or the Third Affiliated Hospital of Sun Yat-sen University were retrospectively collected and divided into the Tα1 group and the observation group. Log-rank test and Kaplan-Meier curve were used to assess the overall survival, recurrence-free survival, and safety of patients. A Markov model was used to calculate the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) of the Tα1 group compared with the observation group. Cost data was from the hospital information system of the three hospitals. Utility scores mainly came from published data. Sensitivity analyses were applied to explore the impact of essential variables.ResultsA total of 208 patients with HCC after liver resection were enrolled, among them 48 received Tα1 treatment (the Tα1 group) and 160 were only followed up (the observation group). There was no significant difference between the two groups in the baseline characteristics. The median overall survival of the Tα1 group and the observation group was 102.0 months [95% confidence interval (CI) (74.8, 129.2) months] and 81.6 months [95%CI (65.7, 97.6) months], respectively, and the difference was statisitically significant (P=0.047); the median recurrence-free survival was 66.7 months [95%CI (17.3, 116.1) months] and 37.4 months [95%CI (28.7, 46.2) months], respectively, and the difference was statistically significant (P=0.044). There were no grade Ⅲ-Ⅳ adverse events and no treatment-related death occurred. The ICER of Tα1 group was ￥108 050.02/QALY, which was less than the willingness to pay (￥177 785.25/QALY).ConclusionsTα1, as an adjuvant therapy for HBV-related HCC patients, can improve the prognosis of the patients, and the cost is within the acceptable level in our country, so this strategy is likely to be a cost-effective option compared with the observation group.

Citation： WANG Xinyuan, WEN Feng, ZHU Yongqiang, LING Yunbiao, LI Qiu. Efficacy and cost-effectiveness of thymalfasin for hepatocellular carcinoma after liver resection. West China Medical Journal, 2018, 33(12): 1471-1478. doi: 10.7507/1002-0179.201811022 Copy

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2.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
3.	Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010, 127(12): 2893-2917.
4.	Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology, 2011, 53(3): 1020-1022.
5.	Ming L, Thorgeirsson SS, Gail MH, et al. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology, 2002, 36(5): 1214-1220.
6.	Sohn W, Paik YH, Lee MW, et al. Predisposing factors for recurrence of HBV-related small hepatocellular carcinoma after percutaneous radiofrequency ablation. Scand J Gastroenterol, 2014, 49(3): 373-380.
7.	Sasaki K, Shindoh J, Nishioka Y, et al. Impact of viral etiology on postoperative De Novo recurrence after hepatectomy for hepatocellular carcinoma in cirrhotic patients. J Gastrointest Surg, 2017, 21(3): 487-495.
8.	Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol, 2006, 45(4): 529-538.
9.	Yang T, Lu JH, Zhai J, et al. High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study. Eur J Surg Oncol, 2012, 38(8): 683-691.
10.	Yu SJ, Kim YJ. Hepatitis B viral load affects prognosis of hepatocellular carcinoma. World J Gastroenterol, 2014, 20(34): 12039-12044.
11.	Meng W, Bai B, Bai Z, et al. The immunosuppression role of alpha-fetoprotein in human hepatocellular carcinoma. Discov Med, 2016, 21(118): 489-494.
12.	Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2015, 16(13): 1344-1354.
13.	Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet, 2012, 379(9822): 1245-1255.
14.	Goldstein AL, Guha A, Zatz MM, et al. Purification and biological activity of thymosin, a hormone of the thymus gland. Proc Natl Acad Sci USA, 1972, 69(7): 1800-1803.
15.	Fan YZ, Chang H, Yu Y, et al. Thymosin alpha1 suppresses proliferation and induces apoptosis in human leukemia cell lines. Peptides, 2006, 27(9): 2165-2173.
16.	Moretti S, Oikonomou V, Garaci E, et al. Thymosin alpha 1: burying secrets in the thymus. Expert Opin Biol Ther, 2015, 15(1): S51-S58.
17.	Serafino A, Pierimarchi P, Pica F, et al. Thymosin alpha1 as a stimulatory agent of innate cell-mediated immune response. Ann N Y Acad Sci, 2012, 1270: 13-20.
18.	Gish RG, Gordon SC, Nelson D, et al. A randomized controlled trial of thymalfasin plus transarterial chemoembolization for unresectable hepatocellular carcinoma. Hepatol Int, 2009, 3(3): 480-489.
19.	Jeng WJ, Lin CC, Chen WT, et al. Adjuvant therapy for hepatocellular carcinoma after curative treatment. Dig Dis, 2014, 32(6): 747-754.
20.	Kim BK, Jy P, Kim DY, et al. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int, 2008, 28(3): 393-401.
21.	Cheng SQ, Wu MC, Chen H, et al. Antiviral therapy using lamivudine and thymosin α1 for hepatocellular carcinoma coexisting with chronic hepatitis B infection. Hepato-gastroenterology, 2006, 53(68): 249-252.
22.	He C, Peng W, Li C, et al. Thymalfasin, a promising adjuvant therapy in small hepatocellular carcinoma after liver resection. Medicine, 2017, 96(16): e6606.
23.	Watanabe H, Okada M, Kaji Y, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1). Gan To Kagaku Ryoho, 2009, 36(13): 2495-2501.
24.	National Cancer Institute. Common terminology criteria for adverse events v. 3.0 and v. 4.0 (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
25.	Sonnenberg F, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making, 1993, 13(4): 322-338.
26.	Purmonen T, Martikainen JA, Soini EJ, et al. Economic evaluation of sunitinib malate in second-line treatment of metastatic renal cell carcinoma in Finland. Clin Ther, 2008, 30(2): 382-392.
27.	《中國藥物經濟學評價指南》課題組, 劉國恩, 胡善聯, 等. 中國藥物經濟學評價指南 (2011 版). 中國藥物經濟學, 2011(3): 6-48.
28.	Cucchetti A, Piscaglia F, Cescon M, et al. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol, 2013, 59(2): 300-307.
29.	Suh CH, Kim KW, Park SH, et al. Performing gadoxetic acid-enhanced MRI after CT for guiding curative treatment of early-stage hepatocellular carcinoma: a cost-effectiveness analysis. AJR Am J Roentgenol, 2018, 210(2): W63-W69.
30.	Murray CJ, Evans DB, Acharya A, et al. Development of WHO guidelines on generalized cost-effectiveness analysis. Health Econ, 2000, 9(3): 235-251.
31.	Tangka FK, Trogdon JG, Richardson LC, et al. Cancer treatment cost in the United States has the burden shifted over time?. Cancer, 2010, 116(14): 3477-3484.
32.	Zhang P, Yang Y, Wen F, et al. Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib. J Gastroenterol Hepatol, 2016, 31(12): 1978-1985.
33.	Ko CJ, Chien SY, Chou CT, et al. Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection. Can J Gastroenterol, 2011, 25(9): 485-491.
34.	Hosaka T, Ikeda K, Kobayashi M, et al. Predictive factors of advanced recurrence after curative resection of small hepatocellular carcinoma. Liver Int, 2009, 29(5): 736-742.
35.	Hung H. Treatment modalities for hepatocellular carcinoma. Curr Cancer Drug Targets, 2005, 5(2): 131-138.
36.	宋繼勇, 杜國盛, 朱志東, 等. 胸腺法新在腫瘤患者肝移植術后應用的安全性研究. 中華損傷與修復雜志: 電子版, 2014, 9(2): 166-168.
37.	邱濟海, 楊亦德. 胸腺法新聯合恩替卡韋治療慢性乙型肝炎效果觀察. 中國鄉村醫藥, 2018, 25(2): 24-25.
38.	李濤, 李政文, 文華長. 高劑量胸腺五肽在原發性肝癌栓塞治療中的應用和安全性研究. 中華腫瘤雜志, 2007, 29(12): 941-942.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
3. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010, 127(12): 2893-2917.
4. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology, 2011, 53(3): 1020-1022.
5. Ming L, Thorgeirsson SS, Gail MH, et al. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology, 2002, 36(5): 1214-1220.
6. Sohn W, Paik YH, Lee MW, et al. Predisposing factors for recurrence of HBV-related small hepatocellular carcinoma after percutaneous radiofrequency ablation. Scand J Gastroenterol, 2014, 49(3): 373-380.
7. Sasaki K, Shindoh J, Nishioka Y, et al. Impact of viral etiology on postoperative De Novo recurrence after hepatectomy for hepatocellular carcinoma in cirrhotic patients. J Gastrointest Surg, 2017, 21(3): 487-495.
8. Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol, 2006, 45(4): 529-538.
9. Yang T, Lu JH, Zhai J, et al. High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: a prospective cohort study. Eur J Surg Oncol, 2012, 38(8): 683-691.
10. Yu SJ, Kim YJ. Hepatitis B viral load affects prognosis of hepatocellular carcinoma. World J Gastroenterol, 2014, 20(34): 12039-12044.
11. Meng W, Bai B, Bai Z, et al. The immunosuppression role of alpha-fetoprotein in human hepatocellular carcinoma. Discov Med, 2016, 21(118): 489-494.
12. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2015, 16(13): 1344-1354.
13. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet, 2012, 379(9822): 1245-1255.
14. Goldstein AL, Guha A, Zatz MM, et al. Purification and biological activity of thymosin, a hormone of the thymus gland. Proc Natl Acad Sci USA, 1972, 69(7): 1800-1803.
15. Fan YZ, Chang H, Yu Y, et al. Thymosin alpha1 suppresses proliferation and induces apoptosis in human leukemia cell lines. Peptides, 2006, 27(9): 2165-2173.
16. Moretti S, Oikonomou V, Garaci E, et al. Thymosin alpha 1: burying secrets in the thymus. Expert Opin Biol Ther, 2015, 15(1): S51-S58.
17. Serafino A, Pierimarchi P, Pica F, et al. Thymosin alpha1 as a stimulatory agent of innate cell-mediated immune response. Ann N Y Acad Sci, 2012, 1270: 13-20.
18. Gish RG, Gordon SC, Nelson D, et al. A randomized controlled trial of thymalfasin plus transarterial chemoembolization for unresectable hepatocellular carcinoma. Hepatol Int, 2009, 3(3): 480-489.
19. Jeng WJ, Lin CC, Chen WT, et al. Adjuvant therapy for hepatocellular carcinoma after curative treatment. Dig Dis, 2014, 32(6): 747-754.
20. Kim BK, Jy P, Kim DY, et al. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int, 2008, 28(3): 393-401.
21. Cheng SQ, Wu MC, Chen H, et al. Antiviral therapy using lamivudine and thymosin α1 for hepatocellular carcinoma coexisting with chronic hepatitis B infection. Hepato-gastroenterology, 2006, 53(68): 249-252.
22. He C, Peng W, Li C, et al. Thymalfasin, a promising adjuvant therapy in small hepatocellular carcinoma after liver resection. Medicine, 2017, 96(16): e6606.
23. Watanabe H, Okada M, Kaji Y, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1). Gan To Kagaku Ryoho, 2009, 36(13): 2495-2501.
24. National Cancer Institute. Common terminology criteria for adverse events v. 3.0 and v. 4.0 (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
25. Sonnenberg F, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making, 1993, 13(4): 322-338.
26. Purmonen T, Martikainen JA, Soini EJ, et al. Economic evaluation of sunitinib malate in second-line treatment of metastatic renal cell carcinoma in Finland. Clin Ther, 2008, 30(2): 382-392.
27. 《中國藥物經濟學評價指南》課題組, 劉國恩, 胡善聯, 等. 中國藥物經濟學評價指南 (2011 版). 中國藥物經濟學, 2011(3): 6-48.
28. Cucchetti A, Piscaglia F, Cescon M, et al. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol, 2013, 59(2): 300-307.
29. Suh CH, Kim KW, Park SH, et al. Performing gadoxetic acid-enhanced MRI after CT for guiding curative treatment of early-stage hepatocellular carcinoma: a cost-effectiveness analysis. AJR Am J Roentgenol, 2018, 210(2): W63-W69.
30. Murray CJ, Evans DB, Acharya A, et al. Development of WHO guidelines on generalized cost-effectiveness analysis. Health Econ, 2000, 9(3): 235-251.
31. Tangka FK, Trogdon JG, Richardson LC, et al. Cancer treatment cost in the United States has the burden shifted over time?. Cancer, 2010, 116(14): 3477-3484.
32. Zhang P, Yang Y, Wen F, et al. Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib. J Gastroenterol Hepatol, 2016, 31(12): 1978-1985.
33. Ko CJ, Chien SY, Chou CT, et al. Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection. Can J Gastroenterol, 2011, 25(9): 485-491.
34. Hosaka T, Ikeda K, Kobayashi M, et al. Predictive factors of advanced recurrence after curative resection of small hepatocellular carcinoma. Liver Int, 2009, 29(5): 736-742.
35. Hung H. Treatment modalities for hepatocellular carcinoma. Curr Cancer Drug Targets, 2005, 5(2): 131-138.
36. 宋繼勇, 杜國盛, 朱志東, 等. 胸腺法新在腫瘤患者肝移植術后應用的安全性研究. 中華損傷與修復雜志: 電子版, 2014, 9(2): 166-168.
37. 邱濟海, 楊亦德. 胸腺法新聯合恩替卡韋治療慢性乙型肝炎效果觀察. 中國鄉村醫藥, 2018, 25(2): 24-25.
38. 李濤, 李政文, 文華長. 高劑量胸腺五肽在原發性肝癌栓塞治療中的應用和安全性研究. 中華腫瘤雜志, 2007, 29(12): 941-942.

West China Medical Journal

Efficacy and cost-effectiveness of thymalfasin for hepatocellular carcinoma after liver resection

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