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Original article
Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial
  1. Qian Chen1,
  2. Chang Shu2,3,4,
  3. Arian D Laurence5,
  4. Yan Chen3,6,7,
  5. Bao-Gang Peng8,
  6. Zuo-Jun Zhen9,
  7. Jian-Qiang Cai10,
  8. Yi-Tao Ding11,
  9. Le-Qun Li12,
  10. Yu-Bao Zhang13,
  11. Qi-Chang Zheng14,
  12. Ge-Liang Xu15,
  13. Bo Li16,
  14. Wei-Ping Zhou17,
  15. Shou-Wang Cai18,
  16. Xi-Yan Wang19,
  17. Hao Wen20,
  18. Xin-Yu Peng21,
  19. Xue-Wen Zhang22,
  20. Chao-Liu Dai23,
  21. Ping Bie24,
  22. Bao-Cai Xing25,
  23. Zhi-Ren Fu26,
  24. Lian-Xin Liu27,
  25. Yi Mu28,
  26. Ling Zhang29,
  27. Qi-Shun Zhang30,
  28. Bin Jiang31,
  29. Hai-Xin Qian32,
  30. Yi-Jun Wang33,
  31. Jing-Feng Liu34,
  32. Xi-Hu Qin35,
  33. Qiang Li36,
  34. Ping Yin2,
  35. Zhi-Wei Zhang3,6,7,
  36. Xiao-Ping Chen3,6,7
  1. 1Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China
  2. 2Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health, School of Public Health, Tongji Medical College, HUST, Wuhan, China
  3. 3Hepatic Surgery Centre at Tongji Hospital, Tongji Medical College, HUST, Wuhan, China
  4. 4Surgery administrator office at Tongji Hospital, Tongji Medical College, Hust, Wuhan, China
  5. 5Hematology Department, The Newcastle upon Tyne Hospitals NHS Foundation Trust at Freeman Hospital, Newcastle, UK
  6. 6Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
  7. 7Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China
  8. 8Surgery Department, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
  9. 9Surgery Department, First People’s Hospital, Foshan, China
  10. 10Surgery Department, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China
  11. 11Surgery Department, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
  12. 12Surgery Department, Cancer Hospital Affiliated to Guangxi Medical University, Nanning, China
  13. 13Surgery Department, Third Affiliated Hospital of Harbin Medical University, Harbin, China
  14. 14Surgery Department, Wuhan Union Hospital of HUST, Wuhan, China
  15. 15Surgery Department, Shengli Hospital Affiliated to Anhui Medical University, Hefei, China
  16. 16Surgery Department, West China Hospital of Sichuan University, Chengdu, China
  17. 17Surgery Department, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
  18. 18Surgery Department, Chinese PLA General Hospital of Medical School of Chinese PLA, Beijing, China
  19. 19Surgery Department, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi, China
  20. 20Surgery Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
  21. 21Surgery Department, First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, China
  22. 22Surgery Department, China and Japan Union Hospital of Jilin Hospital, Changchun, China
  23. 23Surgery Department, Shengjing Hospital of China Medial University, Shenyang, China
  24. 24Surgery Department, Southwest University Hospital, Chongqing, China
  25. 25Surgery Department, Beijing Cancer Hospital, Beijing, China
  26. 26Surgery Department, Shanghai Changzheng Hospital, Shanghai, China
  27. 27Surgery Department, First Affiliated Hospital of Harbin Medical University, Harbin, China
  28. 28Surgery Department, Beijing Ditan Hospital Affiliated to Capital Medical University, Beijing, China
  29. 29Surgery Department, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, China
  30. 30Surgery Department, Guangxi Liuzhou Worker’s Hospital, Liuzhou, China
  31. 31Surgery Department, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan, China
  32. 32Surgery Department, First Affiliated Hospital of Suzhou Medical University, Suzhou, China
  33. 33Surgery Department, Tianjin No.3 Hospital, Tianjin, China
  34. 34Surgery Branch at the Hospital of Infectious and Contagious Diseases Affiliated to Fujian Medical University, Fuzhou, China
  35. 35Surgery Department, Third People’s Hospital of Changzhou, Changzhou, China
  36. 36Surgery Department, Tianjin Medical University Cancer Institute and Hospital (TMUCIH), Tianjin, China
  1. Correspondence to Dr Ping Yin, Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health, School of Public Health, Tongji Medical College, HUST, Wuhan, 430030, RR China ; pingyin2000{at}126.com, Dr Zhi-Wei Zhang, Hepatic Surgery Centre at Tongji Hospital of Tongji Medical College of HUST, Jie Fang Avenue 1095, Wuhan 430030, PR China; zwzhang{at}tjh.tjmu.edu.cn and Professor Xiao-Ping Chen, Tongji Hospital of Tongji Medical College of HUST, Jie Fang Avenue 1095, Wuhan 430030, PR China; chenxpchenxp{at}163.com

Abstract

Objective There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.

Design and results A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI −12.59 to −2.50; p=0.0018), respectively.

Conclusions This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.

Trial registration NCT01770431; Post-results.

  • hepatocellular carcinoma
  • adjuvant treatment

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Footnotes

  • QC and CS contributed equally.

  • Contributors Z-WZ and X-PC were involved in the development of study protocol, study design, data review and interpretation as joint lead investigators of Huaier clinical trial, and both acted as co-lead authors of the Huaier clinical trial report. CS and Z-WZ were both responsible for the provision of patients and data acquisition. QC, ADL and X-PC were responsible for the review of statistical tables, interpretation of data and review of the report for medical consistency against the study database. ADL, YC, B-GP, Z-JZ, J-QC, Y-TD, L-QL, Y-BZ, Q-CZ, G-LX, BL, W-PZ, S-WC, X-YW, HW, X-YP, X-WZ, C-LD, PB, B-CX, Z-RF, L-XL, YM, LZ, Q-SZ, BJ, H-XQ, Y-JW, J-FL, X-HQ and QL were the study physician advisers and contributed to data interpretation. CS and PY were the study statisticians and contributed to data analysis. QC wrote the manuscript. All authors provided critical review of the manuscript and approved the final version for publication.

  • Funding The study was funded by the Major and Special Program of Hepatic Surgery Clinical Study Center of Hubei Province, China (2014BKB089 and 2013BCB026), the National Natural Science Foundation of China (81471612, 81372495, and 81573262), the Fundamental Research Funds for the Central Universities, HUST (No. 2016YXZD042) and the Twelfth Five-Year Plan for Major and Special Program of the National Science and Technology (2012–2015).

  • Disclaimer The funders had no role in the study design, data gathering, analysis, interpretation or writing of the report. The corresponding author had full access to all of the study data, and all authors had access upon request. The corresponding authors had final responsibility to submit the manuscript for publication.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by Ethics Committee of Tongji Hospital, Tongji Medical College, HUST and all other participating centres. The trial conformed to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice (GCP) as well as obeyed local laws.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The abstract has been corrected.

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