Search JIM Advanced Search

Journal of Chinese Integrative Medicine ›› 2013, Vol. 11 ›› Issue (2): 90-100.doi: 10.3736/jintegrmed2013021

• Research Article • Previous Articles     Next Articles

Traditional herbal medicine in preventing recurrence after resection of small hepatocellular carcinoma: A multicenter randomized controlled trial

Xiao-feng Zhaia, Zhe Chena, Bai Lia, Feng Shenb, Jia Fanc, Wei-ping Zhoub, Yun-ke Yangd, Jing Xue, Xiao Qine, Le-qun Lif, Chang-quan Linga()   

  1. a. Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai 200433, China
    b. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
    c. Liver Cancer Institute, Fudan University, Shanghai 200032, China
    d. Department of Traditional Chinese Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
    e. Department of Hepatic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021,  Guangxi Zhuang Autonomous Region, China
    f. Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
  • Received:2013-02-08 Accepted:2013-02-27 Online:2013-03-10 Published:2013-03-15

Background

Disease recurrence is a main challenge in treatment of hepatocellular carcinoma (HCC). There is no generally accepted method for preventing recurrence of HCC after resection.


Objective

To compare the efficacy of a traditional herbal medicine (THM) regimen and transarterial chemoembolization (TACE) in preventing recurrence in post-resection patients with small HCC.



Design, setting, participants and interventions

This is a multicenter, open-label, randomized, controlled study, which was undertaken in five centers of China. A total of 379 patients who met the eligibility criteria and underwent randomization were enrolled in this trial. One hundred and eighty-eight patients were assigned to the THM group and received Cinobufacini injection and Jiedu Granule, and the other 191 patients were assigned to the TACE group and received one single course of TACE.


Main outcome measures

Primary outcome measures were the annual recurrence rate and the time to recurrence. Incidence of adverse events was regarded as the secondary outcome measure.


Results

Among the 364 patients who were included in the intention-to-treat analysis, 67 patients of the THM group and 87 of the TACE group had recurrence, with a hazard ratio of 0.695 (P = 0.048). Median recurrence-free survival of the patients in the THM and TACE groups was 46.89 and 34.49 months, respectively. Recurrence rates at 1, 2 and 3 years were 17.7%, 33.0% and 43.5% for the THM group, and 28.8%, 42.5% and 54.0% for the TACE group, respectively (P = 0.026). Multivariate analysis indicated that the THM regimen had a big advantage for prolonging the recurrence-free survival. Adverse events were mild and abnormality of laboratory indices of the two groups were similar.


Conclusion

In comparison with TACE therapy, the THM regimen was associated with diminished risk of recurrence of small-sized HCC after resection, with comparable adverse events.


Trial registration identifier

This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-07000033.

Key words: Hepatocellular carcinoma, Recurrence, Traditional Chinese medicine, Transarterial chemoembolization, Randomized controlled trial

Figure 1

Enrollment, randomization, and follow-up of the patientsTHM: traditional herbal medicine; TACE: transarterial chemoembolization."

"

Figure 2

Kaplan-Meier estimates of probability of recurrence after resection, according to different study groups.The hazard ratio for recurrence in the THM group as compared with the TACE group was 0.695 (95% CI: 0.484 to 0.997). THM: traditional herbal medicine; TACE: transarterial chemoembolization; CI: confidence interval."

"

"

Figure 3

Hazard ratio and 95% CI for recurrence in the group given THM regimen as compared with the TACE group, according to prognostic factors CI: confidence interval; HR: hazard ratio; MI: microvascular invasion; AST: aspartate aminotransferase; AFP: α-fetoprotein."

[1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics[J]. CA Cancer J Clin, 2011,61(2):69-90
doi: 10.3322/caac.v61:2
[2] Ferlay J, shin HR, Bray F, Forman D, Mathers C, Parkin DM . GLOBOCAN 2008: Cancer incidence and mortality worldwide: IARC CancerBase No.10. Lyon: International Agency for Research on Cancer. 2010. (2010-01-05)[ 2011-01-15]. .
[3] Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, Varotti G, Cetta F, Cavallari A . Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence[J]. Ann Surg, 2003,237(4):536-543
[4] Bruix J Sherman M; Practice Guidelines Committee , American Association for the Study of Liver Diseases.Management of hepatocellular carcinoma[J]. Hepatology, 2005,42(5):1208-1236
doi: 10.1002/hep.v42:5
[5] Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, Sugawara Y, Minagawa M, Takayama T, Kawasaki S, Makuuchi M . Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy[J]. J Hepatol, 2003,38(2):200-207
[6] Jiang K, Huang ZQ, Li WH, Zhou NX, Huang XQ, Zhang WZ, Liu R . Study for the clinical and pathological factors influencing the early postoperative recurrence of the small hepatocellular carcinoma[J]. Lin Chuang Yu Shi Yan Bing Li Xue Za Zhi, 2003,19(3):258-262
[7] Poon RT, Fan ST, Lo CM, Liu CL, Wong J . Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation[J]. Ann Surg, 2002,235(3):373-382
doi: 10.1097/00000658-200203000-00009
[8] Llovet JM, Bruix J . Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival[J]. Hepatology, 2003,37(2):429-442
doi: 10.1053/jhep.2003.50047
[9] Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T . Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial[J]. Lancet, 2000,356(9232):802-807
doi: 10.1016/S0140-6736(00)02654-4
[10] Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J . A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma[J]. Ann Surg, 2007,245(6):831-842
doi: 10.1097/01.sla.0000245829.00977.45
[11] Schwartz JD, Schwartz M, Mandeli J, Sung M . Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials[J]. Lancet Oncol, 2002,3(10):593-603
doi: 10.1016/S1470-2045(02)00873-2
[12] Samuel M, Chow PK, Chan Shih-Yen E, Machin D, Soo KC .Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma[J].Cochrane Database Syst Rev, 2009,( 1):CD001199
[13] Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, Margulies A, Browall M, Magri M, Selvekerova S, Madsen E, Milovics L, Bruyns I, Gudmundsdottir G, Hummerston S, Ahmad AM, Platin N, Kearney N, Patiraki E . Use of complementary and alternative medicine in cancer patients: a European survey[J]. Ann Oncol, 2005,16(4):655-663
doi: 10.1093/annonc/mdi110
[14] Gupta D, Lis CG, Birdsall TC, Grutsch JF . The use of dietary supplements in a community hospital comprehensive cancer center: implications for conventional cancer care[J]. Support Care Cancer, 2005,13(11):912-919
doi: 10.1007/s00520-005-0820-9
[15] Wu MC . Traditional Chinese medicine in prevention and treatment of liver cancer: function, status and existed problems[J]. J Chin Integr Med, 2003,1(3):163-164
doi: 10.3736/jcim
[16] Deng G, Cassileth BR , Yeung KS.Complementary therapies for cancer-related symptoms[J].J Support Oncol, 2004, 2(5):419-426; discussion 427-419
[17] Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J, Lin HS . Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial[J]. Anticancer Res, 2004,24(1):303-309
[18] Qi F, Li A, Zhao L, Xu H, Inagaki Y, Wang D, Cui X, Gao B, Kokudo N, Nakata M, Tang W . Cinobufacini, an aqueous extract from Bufo bufo gargarizans Cantor, induces apoptosis through a mitochondria-mediated pathway in human hepatocellular carcinoma cells[J]. J Ethnopharmacol, 2010,128(3):654-661
doi: 10.1016/j.jep.2010.02.022
[19] Xin HL, Yue XQ, Xu YF, Wu YC, Zhang YN, Wang YZ, Ling CQ . Two new polyoxygenated triterpenoids from Actinidia valvata[J]. Helvetica Chimica Acta, 2008,91(3):575-580
doi: 10.1002/(ISSN)1522-2675
[20] Shim JS, Kim JH, Lee J, Kim SN, Kwon HJ . Anti-angiogenic activity of a homoisoflavanone from Cremastra appendiculata[J]. Planta Med, 2004,70(2):171-173
doi: 10.1055/s-2004-815496
[21] Liu CP, Wang XS, Fang JN . Chemical studies on two acidic polysaccharides from Salvia chinensis[J]. Zhong Cao Yao, 2004,35(1):8-12
[22] Meng Z, Yang P, Shen Y, Bei W, Zhang Y, Ge Y, Newman RA, Cohen L, Liu L, Thornton B, Chang DZ, Liao Z, Kurzrock R . Pilot study of huachansu in patients with hepatocellular carcinoma, nonsmall-cell lung cancer, or pancreatic cancer[J]. Cancer, 2009,115(22):5309-5318
doi: 10.1002/cncr.24602
[23] Yu Y, Lang Q, Chen Z, Li B, Yu C, Zhu D, Zhai X, Ling C . The efficacy for unresectable hepatocellular carcinoma may be improved by transcatheter arterial chemoembolization in combination with a traditional Chinese herbal medicine formula: a retrospective study[J]. Cancer, 2009,115(22):5132-5138
doi: 10.1002/cncr.24567
[24] Chen Z, Li B, Yue X, Zhu D, Yu C, Wu M, Ling C . A retrospective controlled analysis of outcomes of using integrated therapy of traditional Chinese and modern medicines for primary liver cancer of middle and late stages[J]. J Altern Complement Med, 2006,12(10):941-942
doi: 10.1089/acm.2006.12.941
[25] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE , McFadden ET, Carbone PP.Toxicity and response criteria of the Eastern Cooperative Oncology Group[J]. Am J Clin Oncol, 1982,5(6):649-655
doi: 10.1097/00000421-198212000-00014
[26] Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gotzsche PC, Lang T; CONSORT GROUP ( Consolidated Standards of Reporting Trials).The revised CONSORT statement for reporting randomized trials: explanation and elaboration[J]. Ann Intern Med, 2001,134(8):663-694
doi: 10.7326/0003-4819-134-8-200104170-00012
[27] Kumada T, Nakano S, Takeda I, Sugiyama K, Osada T, Kiriyama S, Sone Y, Toyoda H, Shimada S, Takahashi M, Sassa T . Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma[J]. Hepatology, 1997,25(1):87-92
doi: 10.1002/(ISSN)1527-3350
[28] Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CECAE) V 3.0. DCTD, NCI, NIH, DHHS. 3, 31, 2003. (2006-08-09)[ 2010-07-15]. .
[29] ICH Harmonised Tripartite Guideline . Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group[J]. Stat Med, 1999,18(15):1905-1942
[30] Strategy for model selection . In: Collett D.Modelling survival data in medical research[M]. London: Chapman & Hall, 1994, 78-86
[31] Wei ZH, Pu J, Ma YF , Wang jC, Lu GM, Wei BN.Clinical research on the recrudesce and prognosis of liver cancer with TACE[J]. Youjiang Yi Xue, 2011,39(4):403-405
[32] Su YH, Yin XC, Xie JM, Gao B, Ling CQ . Inhibition effects of three kinds of bufotoxins on human SMMC-7721 and BEL-7402 hepatoma cells lines[J]. Di Er Jun Yi Da Xue Xue Bao, 2003,24(4):393-395
[33] Han KQ, Gu W, Su YH, Huang XQ, Wang X, Ling CQ . Anti-tumor effects of bufalin on the orthotopic transplantation tumor model of hepatocellular carcinoma in mice[J]. Zhonghua Shi Yan Wai Ke Za Zhi, 2004,21(12):1436-1438
[34] Cui X, Inagaki Y, Xu H, Wang D, Qi F, Kokudo N, Fang D, Tang W . Anti-hepatitis B virus activities of cinobufacini and its active components bufalin and cinobufagin in HepG2. 2.15 cells[J]. Biol Pharm Bull, 2010,33(10):1728-1732
doi: 10.1248/bpb.33.1728
[35] Llovet JM, Bruix J . Novel advancements in the management of hepatocellular carcinoma in 2008[J]. J Hepatol, 2008,48(Suppl 1):S20-S37
[36] Ling CQ . Problems in cancer treatment and major research of integrative medicine[J]. J Chin Integr Med, 2003,1(3):168-170
doi: 10.3736/jcim
[1] Xia-qiu Wu, Wendy Satmary, Jin Peng, Ka-kit Hui. Women's preconception health patterns in traditional Chinese medicine as a predictor of fertility outcomes. Journal of Integrative Medicine, 2020, 18(3): 222-228.
[2] Kai-yue Tang, Shi-lin Du, Qian-lei Wang, Yi-fan Zhang, Hai-yan Song. Traditional chinese medicine targeting cancer stem cells as an alternative treatment for hepatocellular carcinoma. Journal of Integrative Medicine, 2020, 18(3): 196-202.
[3] Chang-quan Ling. Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-CoV-2). Journal of Integrative Medicine, 2020, 18(2): 87-88.
[4] Sherman Gu, Arthur Yin Fan. Controversial conclusions from two randomized controlled trials for acupuncture's effects on polycystic ovary syndrome or in vitro fertilization support. Journal of Integrative Medicine, 2020, 18(2): 89-91.
[5] Xue-qing Yu, Shu-guang Yang, Yang Xie, Jian-sheng Li. Traditional Chinese medicine in the treatment of idiopathic pulmonary fibrosis based on syndrome differentiation: Study protocol of exploratory trial. Journal of Integrative Medicine, 2020, 18(2): 163-168.
[6] Gerli E.G. Herr, Fábio Goulart da Silva, Francisco José Cidral-Filho, Fabricia Petronilho, Lucinéia Gainski Danielski, Mariana Pereira de Souza Goldim, Afonso Shiguemi Inoue Salgado, Franciane Bobinski, Daniel Fernandes Martins, Eliane R. Winkelmann. Effects of the use of bioceramic wraps in patients with lower limb venous ulcers: A randomized double-blind placebo-controlled trial. Journal of Integrative Medicine, 2020, 18(1): 27-.
[7] Wen Qiang Lee, Jeremy Teoh, Pei Zheng Kenneth Lee, Zhi Xiong Gerard Low, Xueling Sim, Foong Fong Mary Chong, Norbert Ludwig Wagner. Factors influencing communication of traditional Chinese medicine use between patients and doctors: a multisite cross-sectional study. Journal of Integrative Medicine, 2019, 17(6): 396-403.
[8] Mikhail Teppone. Medicine has always been “Modern” and “Scientific” from ancient times to the present day. Journal of Integrative Medicine, 2019, 17(4): 229-237.
[9] Charles Dalcanale Tesser, Ari Ojeda Ocampo Moré, Melissa Costa Santos, Emiliana Domingues Cunha da Silva, Fátima Terezinha Pelachini Farias, Lúcio José Botelho. Auriculotherapy in primary health care: A large-scale educational experience in Brazil. Journal of Integrative Medicine, 2019, 17(4): 302-309.
[10] Ya-ru Huangfu, Wei Peng, Bao-jun Guo, Zhi-fu Shen, Li Li, Shi-wei, Liu, Hui Zheng, You-ping Hu. Effects of acupuncture in treating insomnia due to spleen-stomach disharmony syndrome and its influence on intestinal microbiome: Study protocol for a randomized controlled trial. Journal of Integrative Medicine, 2019, 17(3): 161-167.
[11] Pádraic J.Dunne, Julie Lynch, Lucia Prihodova, Caoimhe O'Leary, Atiyeh Ghoreyshi, Sharee A. Basdeo, Donal J.Cox, Rachel Breen, Ali Sheikhi, Áine Carroll, Cathal Walsh, Geraldine McMahon, Barry White. Burnout in the emergency department: Randomized controlled trial of an attention-based training program. Journal of Integrative Medicine, 2019, 17(3): 173-180.
[12] Xin-yu Yue, Zhuo-qi Feng, Xi-yi Yu, Jia-min Hu, Xiao-Jing He, Shi Shu. Fire-needle acupuncture for upper limb spastic paralysis after stroke: Study protocol for a randomized controlled trial. Journal of Integrative Medicine, 2019, 17(3): 167-172.
[13] Rachael Farrington, Ian F.Musgrave, Roger W.Byard. Evidence for the efficacy and safety of herbal weight loss preparations. Journal of Integrative Medicine, 2019, 17(2): 87-92.
[14] Fung-Kei Cheng. An overview of the contribution of acupuncture to thyroid disorders. Journal of Integrative Medicine, 2018, 16(6): 375-383.
[15] J.M. Oliver-Baxter, H.S. Whitford, D.A. Turnbull, M.J. Bond. Effects of vitamin supplementation on inflammatory markers and psychological wellbeing among distressed women: A randomized controlled trial. Journal of Integrative Medicine, 2018, 16(5): 322-328.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] Zhao-guo Li. Discussion on English translation of commonly used sentences in traditional Chinese medicine: part one. Journal of Chinese Integrative Medicine, 2008, 6(1): 107-110
[2] Yi-ting He, Qing-lin Zha, Jian-ping Yu, Yong Tan, Cheng Lu, Ai-ping Lv. Principal factor analysis of symptoms of rheumatoid arthritis and their correlations with efficacy of traditional Chinese medicine and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 32-36
[3] Dong Yang, Yong-ping Du, Qing Shen, Wei Chen, Yan Yu, Guang-lei Chen. Expression of alpha-smooth muscle actin in renal tubulointerstitium in patients with kidney collateral stasis. Journal of Chinese Integrative Medicine, 2008, 6(1): 41-44
[4] Xue-mei Liu, Qi-fu Huang, Yun-ling Zhang, Jin-li Lou, Hong-sheng Liu, Hong Zheng. Effects of Tribulus terrestris L. saponion on apoptosis of cortical neurons induced by hypoxia-reoxygenation in rats. Journal of Chinese Integrative Medicine, 2008, 6(1): 45-50
[5] Zhi-chun Jin. Problems in establishing clinical guideline for integrated traditional Chinese and Western medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 5-8
[6] Hai-feng Wei, Bai-liu Ya, Ling Zhao, Cui-fei Ye, Li Zhang, Lin Li. Evaluation of tongue manifestation of blood stasis syndrome and its relationship with blood rheological disorder in a rat model of transient brain ischemia. Journal of Chinese Integrative Medicine, 2008, 6(1): 73-76
[7] Xi Lin, Jian-ping Liu. Tai chi for treating rheumatoid arthritis. Journal of Chinese Integrative Medicine, 2008, 6(1): 82
[8] Guo-hong Yuan, Xiao-jing Pang, He-chao Ma. Synergic effects of Danggui Buxue Decoction in reducing toxicity of cytoxan in tumor-bearing mice. Journal of Chinese Integrative Medicine, 2008, 6(1): 83-88
[9] Ning-qun Wang, Liang-duo Jiang, Zong-xing Li. Research progress in asthma-related quality of life. Journal of Chinese Integrative Medicine, 2008, 6(1): 93-97
[10] Daniel Weber, Janelle M Wheat, Geoffrey M Currie. Inflammation and cancer: Tumor initiation, progression and metastasis,and Chinese botanical medicines. Journal of Chinese Integrative Medicine, 2010, 8(11): 1006-1013