Efficacy and safety of Yangxiao Fukang granule (养消复康颗粒) in the treatment of stage Ⅲ hepatitis B related liver cancer: study protocol for a randomized controlled trial

doi:10.19852/j.cnki.jtcm.2025.05.018

Abstract

Abstract:

Primary liver cancer (PLC) is the third major cause of cancer related death, which seriously affects the survival period and quality of life of patients. However, there is currently no evidence to prove which treatment method is most effective. Traditional Chinese Medicine (TCM) has shown certain advantages in the treatment of PLC, especially in the side effects of Western Medicine. Therefore, we designed a clinical trial protocol for the treatment of PLC using TCM granules. Our purpose is to explore the efficacy and safety of Yangxiao Fukang granule (YXFKG, 养消复康颗粒) in the treatment of stage III hepatitis B related PLC. A total of 216 patients from three hospitals in Henan Province will be enrolled and randomly divided into a trial group and a control group in a 1∶1 ratio. The trial group will be treated with conventional western medicine plus YXFKG, while the control group will receive conventional western medicine plus a placebo for YXFKG. All patients will receive a daily dose of either YXFKG or a placebo for six months, followed by a six-month follow-up period. The main observation outcome includes 1-year survival rate, while secondary outcomes include conversion rate to remission, objective response rate, progression free survival, overall survival, quality of life score, and TCM clinical symptom score. Blood routine, urine routine, stool routine, electrocardiogram, liver and kidney function, coagulation function test, and D-dimer are safety indicators. Collect data before treatment and during the 3rd, 6th, 9th, and 12th months of treatment, and conduct statistical analysis. This study will preliminarily verify the effectiveness and safety of YXFKG in the treatment of stage III hepatitis B related PLC, which may provide a new choice for clinical treatment of PLC.

Key words: hepatitis B, liver neoplasms, treatment outcome, safety, clinical trial protocol, Yangxiao Fukang granule

LI Shanyi, GAO Qi, LI Yanjie, ZHANG Yaling, CHEN Xiaoqi. Efficacy and safety of Yangxiao Fukang granule (养消复康颗粒) in the treatment of stage Ⅲ hepatitis B related liver cancer: study protocol for a randomized controlled trial[J]. Journal of Traditional Chinese Medicine, 2025, 45(5): 1127-1134.

Figures/Tables 3

References 41.

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-49.
2.	Dasgupta P, Henshaw C, Youlden DR, Clark PJ, Aitken JF, Baade PD. Global trends in incidence rates of primary adult liver cancers: a systematic review and Meta-analysis. Front Oncol 2020; 10: 171. DOI PMID
3.	Zeng HM, Chen WQ, Zheng RS, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 2018; 6: e555-67. DOI PMID
4.	Zhou MG, Wang HD, Zeng XY, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet 2019; 394: 1145-58. DOI PMID
5.	Chen WQ, Zheng RS, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66: 115-32.
6.	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424.
7.	Sagnelli E, Macera M, Russo A, Coppola N, Sagnelli C. Epidemiological and etiological variations in hepatocellular carcinoma. Infection 2020; 48: 7-17. DOI PMID
8.	Su L, Xu JH, Liu YM, Zhang GM, GuoYT, Wang GQ. Do HBV DNA-negative HBsAg-positive patients with compensated hepatitis Bcirrhosis need antiviral therapy? Lin Chuang Gan Dan Bing Za Zhi 2023; 39: 37-42.
9.	Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 2019; 68: 916-27. DOI PMID
10.	Huang FY, Wong DK, Mak LY, Cheung TT, Seto WK, Yuen MF. Hepatitis B virus X protein promotes hepatocarcinogenesis via the activation of HMGA2/STC2 signaling to counteract oxidative stress-induced cell death. Carcinogenesis 2022; 43: 671-81.
11.	Yao MJ, Chen HN, Qian XJ, et al. Effect of PIVKA-Ⅱ and AFP levels on the prognosis of patients with HBV infection-related hepatocellular carcinoma. Zhong Guo Shi Yong Nei Ke Za Zhi 2019; 39: 640-3.
12.	Feng XM. The clinical value of alpha fetoprotein heterogeneity in hepatitis B virus associated liver cancer. Jian Yan Yi Xue Yu Lin Chuang 2018; 15: 1820-3.
13.	Bai SL, Xiang HJ, Xia Y, Li J, Yang PH, Shen Feng. Long-term outcomes and prognostic factors of surgical resection of hepatitis B virus-related solitary large hepatocellular carcinoma. Zhong Hua Xiao Hua Wai Ke Za Zhi 2017; 16: 151-8.
14.	He J, Chen WQ, Shen HB, et al. China guideline for liver cancer screening (2022, Beijing). Zhong Guo Zhong Liu 2022; 31: 587-631.
15.	Deng H, Fan XD, Wang XY, et al. Serum pentraxin 3 as a biomarker of hepatocellular carcinoma in chronic hepatitis B virus infection. Sci Rep 2020; 10: 20276. DOI PMID
16.	Huang GD, Lu HQ, Pan ML, Lyu QX. Differential expression and value of T cell subsets in peripheral blood of patients with hepatitis B and alcohol-related liver cancer. Xian Dai Zhong Liu Yi Xue 2021; 29: 1547-50.
17.	Wang MC, Xu AF, Hou QM, Wang GW. Application of AFP and AFP-L3 in evaluating post-TACE therapeutic effects of HBV-related liver cancer patients. Zhong Guo Wei Sheng Jian Yan Za Zhi 2021; 31: 50-2.
18.	Han SX, Zhang PA, Zhao YY. Study on the association between miRNA-221/222 gene polymorphism and liver function indicators with hepatitis B virus associated primary liver cancer. Zhong Xi Yi Jie He Gan Bing Za Zhi 2019; 29: 406-9.
19.	Zhao ZY, Qin Z, Zhou LL, et al. The impact of IFNL 3 genotype on interferon treatment outcome in patients chronically infected with hepatitis B virus: a Meta-analysis. Microb Pathog 2019; 134: 103598.
20.	You W, Li XC. Effect of radiofrequency ablation and surgical resection on small hepatocellular carcinoma: a Meta-analysis. Nanjing Yi Ke Da Xue Xue Bao (Zi Ran Ke Xue Ban) 2012; 32: 1179-84.
21.	Zhang LL, Niu GH, Zhang TT, Zhang C. Treating ankylosing spondylitis by invigorating kidneys and strengthening the governor vessel based on the theory of “Evil pathogen will not disturb if healthy Qi exists in the body”. Zhong Yi Lin Chuang Yan Jiu 2023; 15: 125-9.
22.	Liu HX, Lu MY, Liang X, et al. Herbal textural research on treatment of headache based on syndrome differentiation. Zhong Guo Shi Yan Fang Ji Xue Za Zhi 2023; 29: 155-62.
23.	Shao ZY, Liu X, Peng CJ, Wang LP, Xu Dong. Combination of transcatheter arterial chemoembolization and portal vein embolization for patients with hepatocellular carcinoma: a review. World J Surg Oncol 2021; 19: 293. DOI PMID
24.	Galanakis N, Kehagias E, Matthaiou N, Samonakis D, Tsetis D. Transcatheter arterial chemoembolization combined with radiofrequency or microwave ablation for hepatocellular carcinoma: a review. Hepat Oncol 2018; 5: HEP07.
25.	Lyu N, Kong Y, Pan T, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin in hepatocellular cancer with extrahepatic spread. J Vasc Interv Radiol 2019; 30 349-57.e2. DOI PMID
26.	He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol 2021; 13: 17588359211002720.
27.	Zong JJ, Qing X, Fan Z, Xu WJ. Progress in the treatment of primary liver cancer. Dong Nan Da Xue Xue Bao (Yi Xue Ban) 2021; 40: 542-7.
28.	Li XS, Chen GD. Efficacy and safety of shenqi fuzheng injection combined with transarterial chemoembolization in the treatment of patients with middle and advanced liver cancer. Zhong Wai Yi Xue Yan Jiu 2024; 22: 105-8.
29.	Li ZJ, Wang Y. Effect of compound Kushen injection in patients with hepatocellular carcinoma treated with TACE combined with RFA. Zhong Guo Zhong Xi Yi Jie He Ying Xiang Xue Za Zhi 2021; 19: 31-3.
30.	Xing Y, Zhong ZQ, Liu ZR, Zhang HY. Evaluation and plan of interventional therapy for malignant liver tumors. Zhong Guo Lin Chuang Yi Sheng Za Zhi 2022; 50: 521-3.
31.	Jin Y, Ren H, Yue Q, et al. Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma. BMC Cancer 2024; 24: 258. DOI PMID
32.	Liu W, Wang K, Bao Q, Sun Y, Xing BC. Hepatic resection provided long-term survival for patients with intermediate and advanced-stage resectable hepatocellular carcinoma. World J Surg Oncol 2016; 14: 62. DOI PMID
33.	Li L, Mo FK, Chan SL, et al. Prognostic values of EORTC QLQ-C30 and QLQ-HCC 18 index-scores in patients with hepatocellular carcinoma-clinical application of health-related quality-of-life data. BMC Cancer 2017; 17: 8.
34.	Zheng XY. Guiding principles of clinical research on new drugs of Traditional Chinese Medicine (2002 trial version). Beijing: China Medical-Pharmaceutical Science & Technology Publishing House, 2002: 211-2.
35.	Wang JL. Clinical epidemiology:design, measurement, and evaluation in clinical research. 4th ed. Shanghai: Shanghai Science and Technology Press, 2014: 64.
36.	Lyu M, Zhou H, Zhi LM, et al. Saponin Ⅰ from Shuitianqi inhibits metastasis by negatively regulating the transforming growth factor-β1/Smad7 network and epithelial-mesenchymal transition in the intrahepatic metastasis Bagg’s Albino/c mouse model. J Tradit Chin Med 2024; 44: 642-51.
37.	Fan XY, Li MZ, Chen L, et al. Transcriptome profile and its partly verification of human hepatocellular carcinoma cells exposed to Yuzhizi seed extract. J Tradit Chin Med 2022; 42: 922-31.
38.	Fan YF, Zhao HT, Zhang YN, Yani ZF, Du J, Ling CQ. Effectiveness of Jiedu granule on gut microbiota in patients with advanced hepatocellular carcinoma: a randomized controlled trial. J Tradit Chin Med 2022; 42: 988-96.
39.	Wang BC, Zhang Y, Zhang QY, et al. Reveal the mechanisms of prescriptions for liver cancer' treatment based on two illustrious senior TCM physicians. J Tradit Chin Med 2023; 43: 188-97. DOI
40.	Tong W, Yang ZY, Yang YY, et al. Effect of decoction of Fuzheng Jiedu Xiaoji formula plus chemoembolization on primary liver cancer in patients. J Tradit Chin Med 2022; 42: 446-50. DOI
41.	Niu YQ, Yang B, Wang L, et al. Advances in the mechanism of anti-hepatoma effect of Chinese Medicine. Zhong Yi Zhong Liu Xue Za Zhi 2021; 3: 88-96.

Study data collection	Intervention period			Follow-up period
Study data collection	Month 0	Month 3	Month 6	Month 9	Month 12
Collect basic medical history and physical examination
Sign informed consent form	√
Determine inclusion/exclusion criteria	√
Fill in demographic information	√
Vital signs	√	√	√	√	√
Course of disease	√
Degree of illness	√
Alpha-fetoprotein	√
CT/MRI	√	√	√	√	√
Tongue pulse changes	√	√	√	√	√
Five items of hepatitis B	√
HBV-DNA	√		√		√
Effectiveness observation
Quality of life score	√	√	√	√	√
TCM syndrome points	√	√	√	√	√
Safety indicators
Blood routine	√		√		√
Urine routine	√		√		√
Stool routine	√		√		√
Electrocardiogram	√		√		√
Liver function	√		√		√
Kidney function	√		√		√
Coagulation function test	√		√		√
D-Dimer	√		√		√
Other work
Randomization	√

Study data collection	Intervention period			Follow-up period
Study data collection	Month 0	Month 3	Month 6	Month 9	Month 12
Collect basic medical history and physical examination
Sign informed consent form	√
Determine inclusion/exclusion criteria	√
Fill in demographic information	√
Vital signs	√	√	√	√	√
Course of disease	√
Degree of illness	√
Alpha-fetoprotein	√
CT/MRI	√	√	√	√	√
Tongue pulse changes	√	√	√	√	√
Five items of hepatitis B	√
HBV-DNA	√		√		√
Effectiveness observation
Quality of life score	√	√	√	√	√
TCM syndrome points	√	√	√	√	√
Safety indicators
Blood routine	√		√		√
Urine routine	√		√		√
Stool routine	√		√		√
Electrocardiogram	√		√		√
Liver function	√		√		√
Kidney function	√		√		√
Coagulation function test	√		√		√
D-Dimer	√		√		√
Other work
Randomization	√

Syndrome	Mild (2)	Moderate (4)	Severe (6)
Hypochondriac pain	Occasional discomfort and pain in the rib cage, but biochemical and sleep disturbances are not present.	The pain is obvious, frequent and unbearable, requiring the use of painkillers.	The pain is severe, unbearable, and can interfere with daily life and sleep. Painkillers are required, and daily life and sleep are severely disrupted.
Lumps in the abdomen	There is no palpable lump under the ribs, but a special examination revealed a space occupying lesion.	A lump can be palpated under the rib, within 3 cm, with a relatively hard texture and an uneven surface.	A lump can be palpated under the ribs, with a thickness of more than 3 cm and a hard texture, and nodules can be palpated on the surface.
Fatigue	Lack of energy and fatigue, but can persist in daily light physical activities.	Mental fatigue, barely adhering to daily light physical activities.	Extremely mentally exhausted, weak limbs, unable to persist in daily activities.
Bitter taste and anorexia	In the morning, the mouth is slightly bitter. And the diet is tasteless.	Bitter in the mouth, tasteless when eaten, and poor appetite.	Bitter in the mouth, no taste or appetite.
Abdominal distention	Mild abdominal distension, relieved after eating for half an hour.	Abdominal fullness, significant bloating after eating, relieved within half an hour to one hour.	Abdominal distension is obvious, especially after eating, and cannot be relieved within 2 h.
Fever	Intermittent low fever in the afternoon. (37.2-37.9 ℃)	Continuous low fever.	Fever does not subside (38 ℃ and above).

Syndrome	Mild (2)	Moderate (4)	Severe (6)
Hypochondriac pain	Occasional discomfort and pain in the rib cage, but biochemical and sleep disturbances are not present.	The pain is obvious, frequent and unbearable, requiring the use of painkillers.	The pain is severe, unbearable, and can interfere with daily life and sleep. Painkillers are required, and daily life and sleep are severely disrupted.
Lumps in the abdomen	There is no palpable lump under the ribs, but a special examination revealed a space occupying lesion.	A lump can be palpated under the rib, within 3 cm, with a relatively hard texture and an uneven surface.	A lump can be palpated under the ribs, with a thickness of more than 3 cm and a hard texture, and nodules can be palpated on the surface.
Fatigue	Lack of energy and fatigue, but can persist in daily light physical activities.	Mental fatigue, barely adhering to daily light physical activities.	Extremely mentally exhausted, weak limbs, unable to persist in daily activities.
Bitter taste and anorexia	In the morning, the mouth is slightly bitter. And the diet is tasteless.	Bitter in the mouth, tasteless when eaten, and poor appetite.	Bitter in the mouth, no taste or appetite.
Abdominal distention	Mild abdominal distension, relieved after eating for half an hour.	Abdominal fullness, significant bloating after eating, relieved within half an hour to one hour.	Abdominal distension is obvious, especially after eating, and cannot be relieved within 2 h.
Fever	Intermittent low fever in the afternoon. (37.2-37.9 ℃)	Continuous low fever.	Fever does not subside (38 ℃ and above).

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