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Elemene, One Ingredient of a Chinese Herb, Against Malignant Tumors: A Literature-based Meta-analysis

Xu HB, Zheng LP, Li L, Xu LZ, Fu J. Cancer Invest. 2013 Feb;31(2):156-66. doi: 10.3109/07357907.2012.756108. Epub 2013 Jan 3.

In China, compounds that extracted from herbal medicine frequently are combined with chemotherapy in the treatment of cancer. Of particular interest is the elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), isolated from the Chinese medicinal herb Curcuma wenyujin, which exhibits antitumor activity in vitro and in vivo (Guo, 1983; Tang et al, 2010). Elemene injection, a wide spectrum antitumor drug with the main ingredient of β-elemene, has been manufactured by DaLian JinGang Pharmacy Ltd. of China since 1995 after the State Administration of Pharmacy of China and Ministry of Health People’s Republic of China approved it as a medical treatment in clinical practice.

Since elemene injection was introduced in the middle of 1990s, a large number of clinical trials were published in many Chinese academic publications and has showed the effective of elemene injection in the treatment of leukemia and carcinomas of the lung, liver, stomach, brain, and other tissues. A published meta-analysis of 17 low-bias randomized controlled trials (RCTs) involving 935 participants reviewed the effects of elemene injection in the treatment of lung cancer (Zhao et al, 2005)).

However, the results had reported that elemene plus chemotherapy failed to show favorable effects than chemotherapy alone in the treatment of lung cancer except elemene plus EP regimen (etoposide + cisplatin). Currently, no systematic review was available and comprehensive to evaluate the effects of elemene as adjunct therapy for cancer therapy.

Our meta-analysis data are limited to suggest that some of the short-term efficacies are significantly improved by chemotherapy combined with elemene. The adding of elemene has shown to be significantly beneficial in ORR and CB. This is probably because elemene enhanced the inhibitory effect of chemotherapy through a mitochondria dependent apoptosis pathway on the growth of tumor cells in vitro (Hao et al 2002; Li et al, 2005; Li et al, 2009). Another possible mechanism includes an influence on the heat shock proteins. It has been shown that elemene upregulated heat shock protein 70 and increased the apoptosis of tumor cells (Wu et al, 1999; Jin et al, 1999). The third hypothesis is that elemene improves the function of immune cells. Elemene inhibited the growth of tumor and enhanced cellular immune functions via cytokine production (IL-2 or IL-12) and increase of natural killer cell activity in tumor-bearing mice (Chen et al, 1998; Yao et al, 2000; Chen et al, 2007).

None of these theories are, however, currently fully established. On the other hand, this review does not show any significant improvement of survival for cancer patients after chemotherapy combined with elemene. This is possibly because sole chemotherapy can normally lead to a survival period up to 6 months or more.

Our findings are subject to some limitations. Only three of these studies described the method of randomization used (Chen et al, 2008; Li et al, 2004; Gu et al, 2011). None of the other studies provided any details of the randomization method used. Even more problematic was the lack of discussion in any study about whether the investigators knew which patients were randomly assigned to receive elemene. A previous study also evaluated and reported the poor methodological quality of 127 RCTs that used elemene injections as an intervention in cancer therapy (Xiao et al, 2006). Therefore, we are unable to make firm conclusions, and confirmation must await investigation in future trials.

However, failure to describe randomization procedures fully is not limited to Chinese medical journals. Hewitt et al. (Hewitt et al, 2005) reported that more than 40% of trials published in 2004 in Western medical journals either failed to use adequate randomization methods or failed to report the method for concealment of allocation. Furthermore, He et al. (2005) reported that the methodological quality of 579 RCTs published in 2009 in foreign journals was generally poor, 75% failed to use adequate randomization methods, and 74% failed to report adequate allocation concealment.

Moreover, no studies in our meta-analysis reported how they handled patients who were lost to follow up, the percentage of patients lost to follow up, and whether those patients were censored in the analysis. Although there exists the possibility of censoring, which could bias our findings, our analysis would tend toward underestimation of any effects of this potential bias. These findings may be limited by the low quality of published studies identified in our systematic searching.

However, there was no between-study heterogeneity in the evidence for tumor response, as well as in the evidence for survival. Complementary and alternative medicines should be rigorous testing (Marwick, 2005). An efficient method for identifying compounds or combinations of compounds with potential antitumor activity and clinical efficacy may be to critically evaluate the evidence from clinical studies published in China. Although such studies have been reported to be of low quality, nevertheless, they may contain credible evidence pointing the direction toward herbal medicines worthy of additional study. Because clinical trials are so expensive and difficult, these findings can help to pick the most promising agents for study. We hope that systematic review and meta-analysis such as this one will help specify where further improvements in the design and reporting of research conducted and published in China are needed. In conclusion, we found evidence that elemene might increase effectiveness (by increasing tumor response) and reduce chemotherapy-related toxicity for cancer therapy.

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