Chinese Herbal Medicine and Chemotherapy in the Treatment of Primary Liver Cancer: A Meta-analysis of Randomized Controlled Trials

By Xiaojuan Shu, MPH (Candidate), Michael McCulloch, LAc, MPH, Hang Xiao, MPH, PhD, Michael Broffman, LAc, and Jin Gao, MD, PhD

This paper was first published in the September 2005 issue of Integrative Cancer Therapies (Volume 4, Number 3).

Primary liver cancer (hepatocellular carcinoma or HCC) is the fifth leading cause of cancer worldwide, with increasing incidence.1 The incidence ranges from 1 to 4 cases per 100,000 population in Western Europe and North America to 50 to 150 cases per 100,000 population in parts of Asia and Africa, where HCC is responsible for a large proportion of cancer deaths.2 Its treatment remains a controversial issue, despite the progress that has been made during the past decades, as most HCC patients are diagnosed at late stages and receive only palliative treatments not intended to extend survival.1 Untreated patients with advanced disease have a 1-year survival rate of 29%, a 2-year survival rate of 16%, and a 3-year survival rate of 8%.3

Arterial embolization, chemoembolization, and arterial chemotherapy are the major procedures in chemotherapy used to treat HCC. These procedures, however, are associated with their own potentially life threatening toxicities and complications, and previous studies have shown only slightly improved survival or no survival advantages.5-7 Meta-analysis of randomized controlled trials of treatment with chemoembolization or embolization has shown only a modest advantage in 2-year survival for patients with unresectable HCC, compared with conservative management.8 The same meta-analysis revealed that tamoxifen provided no advantage in 1-year survival.8

Since the prognosis with existing therapy is so poor, we sought to evaluate the clinical evidence for effectiveness of Chinese herbal medicine in combination with systemic chemotherapy for the treatment of HCC.

In China, herbal medicine is frequently combined with chemotherapy in the treatment of liver cancer, usually in formulas that combine various Chinese herbs into one treatment strategy. In this meta-analysis, we sought to assess the effectiveness of this therapy for HCC by analyzing data from studies that compared treatment with Chinese herbal medicine combined with chemotherapy to treatment with chemotherapy alone.

METHODS
Systematic Search
We performed a retrieval of studies in all languages through systematic searching of the databases TCMLARS, PubMed, and EMBASE using the keywords liver cancer, chemotherapy, Chinese medicine, and randomized controlled trials. We also searched the bibliographies of review papers and published randomized controlled trials identified in our systematic search.

Criteria for Inclusion
To be included in this meta-analysis, a study had to fulfill the following criteria: (1) only patients with HCC were included, (2) studies were described as randomized or had the design elements of quasi-randomized studies (studies did not mention adoption of randomization but reported there was no statistical difference between two groups), (3) HCC patients were given either Chinese herbal medicine therapy in combination with chemotherapy in the treatment group or chemotherapy alone in the control group, and (4) authors provided necessary data on the number of responders and non-responders for the end points of tumor response and survival sufficient to calculate relative risks (RRs) and 95% confidence intervals (CIs).

Criteria for Exclusion
Randomized controlled trials were excluded if they (1) were not described as randomized or quasi-randomized, (2) did not provide information concerning survival or tumor response, (3) included patients with cholangiocellular carcinomas or liver metastases of primary cancers other than liver, (4) did not contain an experimental arm treated with Chinese medicine combined with chemotherapy and a control arm treated with chemotherapy alone, or (5) were duplicate publications of other studies previously identified in our systematic search. Decisions on whether to include or exclude trials and how to group studies for analysis by end points reported were made before conducting the meta-analysis.

Criteria for Combinability
Since there is no successful standard treatment for HCC, there are few published trials using exactly the same chemotherapy treatments and the same Chinese herbal formulas. As has been done in previous meta-analyses of chemotherapy for HCC, we combined studies in which patients in the treatment group were treated with the new therapy being evaluated and those in the control group were treated with standard chemotherapy alone.7-9 We also sought to separately meta-analyze any subgroups of studies that all used the same herbal combination.

RESULTS
Selection of Trials
After an initial screening of titles and abstracts, 385 potentially relevant clinical trials of HCC were identified. We then performed a second screening of these 385 studies and retained 126 published full papers, which were randomized controlled trials assessing Chinese herbal medicine in the treatment of HCC. After further evaluation, we excluded 9 studies because of non-randomization, 13 studies because they lacked relevant end points, 24 studies because other cancers were included, 51 studies because they were missing either a qualified experimental groupor control group, and 3 studies because they were duplicate publications of other studies previously identified in our systematic search. This yielded a total of 24 randomized controlled trials and 2 quasi–randomized controlled trials totaling 2079 patients.

Treatment Effectiveness
Chemotherapy combined with Chinese herbal medicine, compared with chemotherapy alone, significantly improved survival at 12 months (survival was increased by 55%), 24 months (survival was increased by 115%), and 36 months (survival was increased by 176%). Tumor response to treatment was also significantly improved (tumor response improved by 39%). The data analyzed were not reliable enough to make any conclusions about survival at 6 months.

Two of the studies we analyzed used the exact same Chinese herbal formula (Hua Chan Su), so we conducted a separate meta-analysis to see what survival benefit, if any, might exist.16,17 The result of this analysis similarly showed survival benefits of Hua Chan Su at 12 months (survival increased by 76%). It should be noted that Hua Chan Su contains bufotoxin, a digoxin-like substance that must be provided in carefully measured dosages to avoid toxicity.

CONCLUSIONS
Our meta-analysis data suggest promising evidence that Chinese herbal medicine in the treatment of HCC may have potential therapeutic value. Herbal medicine combined with chemotherapy for the treatment of HCC can improve survival at 12, 24, and 36 months when compared to chemotherapy alone. There is additional evidence that 6-month survival may also be improved, but more data is needed to make more definitive conclusions. Tumor response was also improved by the addition of Chinese herbal medicine to chemotherapy. In a separate meta-analysis of the only two studies using the exact same herbal medicine, Hua Chan Su, we found that 12-month survival was also increased.16,17

Limitations
» Publication Bias. In the data for meta-analysis of survival at 6 and 12 months for all herbal formulas combined, we found evidence for publication bias – the phenomenon by which research that does not produce positive results is simply not published and thus not searchable for our meta-analysis. We also found evidence for publication bias in the data for meta-analysis of tumor response.

» Research Techniques Used in Chinese Studies. Published studies from China were found to be more highly condensed than typical articles published in the Western literature, with key details of study design omitted, especially details concerning blinding of subjects and clinicians. In addition, since most studies did not describe subject withdrawals or dropouts, it is not possible to adjust the analysis for censoring, and therefore pooled estimates of survival should be interpreted with caution; because of these limitations, we are unable to make more definitive conclusions from our data. It should be noted, however, that inadequate reporting of specific details of randomization is also found in many Western medical journals. In 2004, eight years after publication of the CONSORT Statement (intended to improve the quality of reporting of results in randomized controlled trials), more than 40% of trials published in Western medical journals failed to use adequate randomization methods or failed to report the method for concealment of allocation.18 In 1994, this figure was as high as 70% to 80%.19

» Standardized Herbal Formulas. Since there is no standard Chinese formula for the treatment of HCC, it is hard to identify the active components in the treatments. Further investigation is needed on effects of Chinese herbal medicine on HCC, on the identity of active components of Chinese herbal medicine, and on the therapeutic mechanisms underlying possible survival benefits of combining Chinese herbal medicine with chemotherapy for HCC.

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References:
1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907-1917.
2. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19:271-285.
3. Llovet JM, Bustamante J, Castells A. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29:62-67.
4. Chan ES, Chow PK, Tai B, Machin D, Soo K. Neoadjuvant and adjuvant therapy for operable hepatocellular carcinoma. Cochrane Database Syst Rev. 2000(2):CD001199.
5. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol. 2004;7:431-441.
6. De Maio E, Fiore F, Daniele B, et al. Transcatheter arterial procedures in the treatment of patients with hepatocellular carcinoma: a review of literature. Crit Rev Oncol Hematol. 2003;46:285-295.
7. Geschwind JF, Ramsey DE, Choti MA, Thuluvath PJ, Huncharek MS. Chemoembolization of hepatocellular carcinoma: results of a metaanalysis. Am J Clin Oncol. 2003;26:344-349.
8. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429-442.
9. Mathurin P, Raynard B, Dharancy S, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247-1261.
10. Berlin JA. Does blinding of readers affect the results of metaanalyses? University of Pennsylvania Meta-analysis Blinding Study Group. Lancet. 1997;350:185-186.
11. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. Vol offset publication no. 40. Geneva, Switzerland: World Health Organization; 1979.
12. Kountouras J, Zavos C, Chatzopoulos D, Zavos N, Boura P,
Safioleas M. Locoregional immunochemotherapy in primary and metastatic liver disease: meta-analysis and review of literature. Hepatogastroenterology. 2003;50:1506-1510.
13. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.
14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.
15. Clark HD,Wells GA, Huet C, et al. Assessing the quality of randomized trials: reliability of the Jadad scale. Control Clin Trials. 1999;20:448-452.
16. Sun ZJ, Pan CE,Wang GJ. Clinical observation of Hua Chan Su combined with TACE in the treatment of hepatocellular carcinoma. Zhong Liu Fang Zhi Yan Jiu. 2002;29:67-68.
17. Wu HM, Zhu DZ, Ling CQ, Chen Z. Clinical observation of hepatic artery intubation with Hua Chan Su infusion chemotherapy in treatment of liver cancer. Liaoning Journal of Traditional Chinese Medicine. 2000;27:127-128.
18. Hewitt C, Hahn S, Torgerson DJ, Watson J, Bland JM. Adequacy and reporting of allocation concealment: review of recent trials published in four general medical journals. BMJ. 2005;330:1057-1058.
19. Williams DH, Davis CE. Reporting of assignment methods in clinical trials. Control Clin Trials. 1994;15:294-298.
20. Cao MR, Tang HL. Observation of the effectiveness of Ai Di Zhu She Ye combined with hepatic artery infusion chemotherapy in the treatment of mid- and late-stage hepatocellular carcinoma. Zhong Guo Zhong Xi Yi Jie He Za Zhi. 2003;23:713-714.
21. Chen C, Zhou JG, Huang HC, Ruan SH, Zhang QS. Hepatic artery lipiodol infusion chemotherapy combined with Pei Yuan Gu Ben Kang Ai Jiao Nang in the treatment of 42 cases of mid- and late-stage hepatocellular carcinoma. Zhong Xi Yi Jie He Gan Bing Za Zhi. 2001;11:183-184.
22. Feng J. Chinese medicine and interventional therapy in the treatment of 35 cases of hepatocellular carcinoma. Guang Xi Zhong Yi Xue Yuan Xue Bao. 2002;5:51-52.
23. Gao P. Clinical study of Gan Ai Jian Ji combined with hepatic artery infusion chemoembolization in the treatment of hepatocellular carcinoma. Zhongguo Yi Yao Xue Bao. 2004;19:28-30.
24. Jia YS,Wu SQ, Qin ZQ, Lu LQ. Clinical analysis of Ya Dan Zi oil combined with interventional chemotherapy in treatment of primary hepatocellular carcinoma. Zhong Guo Zhong Yao Za Zhi. 2003;28:683-684.
25. Li J, Sun GZ, Pu BK, Chen CH, Song L. Clinical study of Gan Kang Chong Ji combined with hepatic artery interventional chemotherapy in the treatment of hepatocellular carcinoma. Yi Xue Li Lun Yu Shi Jian. 1998;11:341-343.
26. Li JC. Clinical study of Chinese medicine differential diagnosis combined with interventional therapy in the treatment of hepatocellular carcinoma. Guang Dong Yi Xue. 2001;22:263-264.
27. LiW, Li XL. Clinical study of Fu Zheng Yi Liu Tang in reducing toxicity and increasing effectiveness of chemotherapy in midand late-stage primary hepatocellular carcinomachemotherapy. Zhong Guo Zhong Yi Yao Xin Xi Za Zhi. 2001;8:52-53.
28. Liu XL, Zhu XQ. Clinical study in Yanshu in the treatment of hepatocellular carcinoma. Journal of Ningxia Medical College. 2002;24:105-106.
29. Shao ZX, Chen ZG, Yin XE, et al. Clinical observation of hepatic artery infusion chemotherapy combined with Chinese medicine Gan Ai I and II in the treatment of mid- and latestage
hepatocellular carcinoma. Zhong Guo Zhong Xi Yi Jie He Za Zhi. 2001;21:168-170.
30. Tian HQ, Liang GW, Tao Y, Huang ZQ, Yu SY, Ye WY. Clinical study of Chinese medicine combined with interventional therapy in the treatment of hepatocellular carcinoma. Henan Zhong Yi Yao Xue Kan. 2001;16:47-48.
31. Wang HZ. Clinical study of immune and Chinese medicine in post-treatment of liver cancer with infusion chemotherapy. Zhong Guo Zhong Xi Yi Jie He Za Zhi. 1998;18:411-413.
32. Wang ZX,Wu XH, Chen SQ. Fu Zheng Hua Ji Jie Du Fang and hepatic artery infusion chemotherapy in treatment of primary hepatocellular carcinoma. Henan Traditional Chinese Medicine. 2001;21:48-49.
33. Wu JX. Observation of long-term effectiveness of Yi Guan Jian Jia Wei combined with TACE in the treatment of hepatocellular carcinoma. Zhejiang Zhong Xi Yi Jie He Za Zhi. 1999;9:100-101.
34. Wu WG, Guo WJ, Lin JH. Ping Xiao capsule combined with hepatic artery infusion in the treatment of 25 cases of primary hepatocellular carcinoma. Zhong Xi Yi Jie He Gan Bing Za Zhi. 2001;11:50-51.
35. Wu XD, Wang YD, Liu SM, Wu ZS, Ye AN. Observation of Hu Gan Ruan Jian Fang in increasing effectiveness and reducing toxicity of hepatic artery chemoembolization in stage II and III hepatocellular carcinoma. Zhong Xi Yi Jie He Gan Bing Za Zhi. 2002;12:43-44.
36. Xie XR, Li JK, Zhan GQ. Ruan Gan Jian combined with chemotherapy in the treatment of 42 cases of mid- and late-stage hepatocellular carcinoma. Zhong Xi Yi Jie He Gan Bing Za Zhi. 2004;14:110-111.
37. Yu Y. Observations of the effect of hepatic artery chemoembolization combined with Chinese medicine in the treatment of mid- and late-stage hepatocellular carcinoma. Xian Dai Zhen Duan Yu Zhi Liao. 2002;13:1-3.
38. Zhang QZ, Zhang CL. Hepatic artery intubation embedding drug pump combined with Chinese medicine in the treatment of 30 cases of mid- and late-stage primary hepatocellular carcinoma. Practical Journal of Integrating Chinese With Modern Medicine. 1998;11:242.
39. Zhang SY, Geng NZ, Liu YE, JiangW, Jiang LF. Clinical study of hepatic artery infusion chemotherapy combined with AC-III Zhu She Ye in the treatment of hepatocellular carcinoma. Information on Traditional Chinese Medicine. 1996(4):29-31.
40. Zhang YH. Clinical study of anti-tumor effect of Bu Gan Ruan Jian Tang. Hubei Zhong Yi Za Zhi. 1998;20(1):21-22.
41. Zhou BG, Sun JZ, Jing SH, Fan YZ, Huang YN. Observation of combined Chinese and Western medicine in the treatment of 26 cases of mid- and late-stage hepatocellular carcinoma. Xin Zhong Yi. 2002;34:37-38.
42. Zhou XY, Wu XD, Zuo X, Ge R, Xue YB. Clinical research of TACE combined with Chinese medicine in the treatment of 118 cases of mid- and late-stage hepatocellular carcinoma. Jiangsu Zhong Yi Yao. 2002;23:15-17.
43. Zhou YF, Jiao ZH, Song MM, et al. Fu Zheng Xiao Liu He Ji combined with chemotherapy in the treatment of 15 cases of primary hepatocellular carcinoma. Shandong Zhong Yi Yao Da Xue Xue Bao. 1999;23:123-125.

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