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Astragalus-Based Chinese Herbs and Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Meta-Analysis of Randomized Trials

From the University of California, Berkeley School of Public Health, Division of Epidemiology, Berkeley; San Francisco Oncology Associates; Institute of Biophysics, Chinese Academy of Sciences, San Francisco, CA; Pine Street Foundation, San Anselmo; and Institute of Information, China Academy of Traditional Chinese Medicine, Beijing, China

Address reprint requests to John Colford, MD, PhD, University of California, Berkeley, 140 Warren Hall, MC 7360, Berkeley, CA 94720; e-mail: jcolford{at}berkeley.edu

	ABSTRACT

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Purpose: Systemic treatments for advanced non–small-cell lung cancer have low efficacy and high toxicity. Some Chinese herbal medicines have been reported to increase chemotherapy efficacy and reduce toxicity. In particular, Astragalus has been shown to have immunologic benefits by stimulating macrophage and natural killer cell activity and inhibiting T-helper cell type 2 cytokines. Many published studies have assessed the use of Astragalus and other Chinese herbal medicines in combination with chemotherapy. We sought to evaluate evidence from randomized trials that Astragalus-based Chinese herbal medicine combined with platinum-based chemotherapy (versus platinum-based chemotherapy alone) improves survival, increases tumor response, improves performance status, or reduces chemotherapy toxicity.

Methods: We searched CBM, MEDLINE, TCMLARS, EMBASE, Cochrane Library, and CCRCT databases for studies in any language. We grouped studies using the same herbal combinations for random-effects meta-analysis.

Results: Of 1,305 potentially relevant publications, 34 randomized studies representing 2,815 patients met inclusion criteria. Twelve studies (n = 940 patients) reported reduced risk of death at 12 months (risk ratio [RR] = 0.67; 95% CI, 0.52 to 0.87). Thirty studies (n = 2,472) reported improved tumor response data (RR = 1.34; 95% CI, 1.24 to 1.46). In subgroup analyses, Jin Fu Kang in two studies (n = 221 patients) reduced risk of death at 24 months (RR = 0.58; 95% CI, 0.49 to 0.68) and in three studies (n = 411) increased tumor response (RR = 1.76; 95% CI, 1.23 to 2.53). Ai Di injection (four studies; n = 257) stabilized or improved Karnofsky performance status (RR = 1.28; 95% CI, 1.12 to 1.46).

Conclusion: Astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy when combined with chemotherapy. These results require confirmation with rigorously controlled trials.

	INTRODUCTION

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Lung cancer is the leading cause of cancer death in the United States, accounting for 27% and 31% of all cancer deaths in women and men, respectively.¹ Although lung cancer deaths in men have declined substantially (from 92 in 100,000 in 1995, to 84 in 100,000 in 2001), death rates in women only recently began to stabilize in 1995 (at approximately 42 in 100,000 between 1995 and 2001) after increasing for two decades between 4% and 6% per year.² Lung cancer is now the leading cause of cancer death in women.¹ Seventy-five percent of all lung cancer occurrences are non–small-cell lung cancer.

Despite treatment advances, new systemic therapies for advanced non–small-cell lung cancer developed in the last few decades continue to have both low efficacy and high toxicity. Meta-analyses have shown that, compared with treatment with surgery alone, adjuvant treatment with chemotherapy reduces the risk of death at 2 years by only 13%³; adjuvant chemoradiotherapy reduces that risk by 14%⁴; adjuvant radiotherapy alone conversely increases that risk by 21%.^5,6 The addition of platinum-based drugs to standard chemotherapy protocols increased 12-month survival by 5% and tumor response by 62%, but with significantly increased hematologic toxicity, nephrotoxicity, and nausea and vomiting.⁷ The 12-month survival for platinum-based regimens has been found in meta-analysis to be 34% (95% CI, 33% to 36%).⁷ More recently, the addition of the epidermal growth factor receptor tyrosine kinase–inhibitor drug, gefitinib, to carboplatin/paclitaxel chemotherapy in a phase III randomized, controlled trial demonstrated no additional benefit in survival or time to progression.⁸ These poor outcomes in survival, tumor response, quality of life, and toxicity for patients with advanced non–small-cell lung cancer emphasize the need for additional improvements in approaches to treatment.

In China, herbal medicine frequently is combined with chemotherapy in the treatment of lung cancer. Of particular interest is the herb Astragalus membranaceus (Fisch.), which may potentiate host immune function by stimulating macrophage and natural killer cell activity,⁹ and enhance immune recognition of lung cancer cells by inhibiting production of T-helper cell type 2 cytokines¹⁰ (T-helper cell subsets implicated in the development of immunological tolerance to tumor progression).¹¹ In a recent clinical trial, single-agent Astragalus herbal treatment in combination with platinum-based chemotherapy, compared with platinum-based chemotherapy alone, has been shown to significantly reduce risk of death at 12 months (risk ratio [RR] = 0.62; 95% CI, 0.43 to 0.89) and 24 months (RR = 0.75; 95% CI, 0.58 to 0.97).¹² In clinical practice and in most published trials, however, Astragalus rarely is used as single-agent therapy; it usually is combined with other herbal medicines.

This meta-analysis was motivated by the large number of published trials of Astragalus-based Chinese herbal medicines combined with platinum-based chemotherapy, and the continuing problems with low efficacy and high toxicity in standard chemotherapy treatment of advanced non–small-cell lung cancer. Our a priori hypotheses were that adding Astragalus-based Chinese herbal medicine to platinum-based chemotherapy, compared with treatment with platinum-based chemotherapy alone, could prolong survival, increase tumor response, stabilize or improve performance status, and reduce chemotherapy toxicity.

	METHODS

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Study Identification
We conducted a systematic search of the following databases: CBM China BioMedical Bibliographic Database (1978 to August 2004; www.imicams.ac.cn/cbm), TCMLARS (1984 to August 2004; www.cintcm.com), PubMed (1966 to August 2004; www.pubmed.gov), EMBASE (1974 to August 2004; http://embase.com/), Cochrane Library (1988 to August 2004; http://cochrane.org), and Cochrane Central Register of Controlled Trials (1966 to August 2004; http://cochrane.org). We used an extensive list of search terms (the full search strategy is available on request from the authors). The search was designed to find initially all trials involving non–small-cell lung cancer, chemotherapy, Chinese herbal medicine, and randomized controlled trials (and multiple synonyms for each term). We also searched for references from within the bibliographies of all eligible studies. No restrictions were placed on the publication language. Two reviewers (M.M. and C.S.) independently identified studies and translated abstracts and relevant data portions of eligible studies.

Study Eligibility
We screened titles and abstracts and retained those that were described as randomized, recruited patients with advanced non–small-cell lung cancer, provided the treatment group with Chinese herbal medicines containing the herb Astragalus in combination with standard platinum-based chemotherapy, provided the control group with platinum-based chemotherapy alone, and reported data on at least one of our outcomes of interest (survival, tumor response, performance status, or toxicity) with sufficient detail to permit calculation of the risk ratios of each outcome and 95% CIs. We obtained full-text copies of all abstracts or titles that potentially met our inclusion criteria and conducted a thorough screening of those articles obtained to confirm they met our inclusion criteria.

All inclusion and exclusion criteria and the categorization of outcomes were made before any meta-analysis of the data. Our decision to group together for this meta-analysis those studies using platinum-based chemotherapy was based on the fact that this therapy is currently a standard treatment for advanced non–small-cell lung cancer. Following the example set by D’Addario et al⁷ and the Cochrane Collaboration’s Non–Small-Cell Lung Cancer Collaborative Group,³ platinum-based chemotherapy was grouped together as a therapeutic class when assessing efficacy of treatment for non–small-cell lung cancer. Each stage of the planning, design, analysis, and reporting of this meta-analysis was conducted in accordance with the QUOROM Statement guidelines (Fig 1). ¹³

View larger version (37K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Quorom Statement flow diagram. Because most studies reported more than one outcome, the total of the individual outcomes listed in the lowermost box will be greater than 34. RCTs, randomized controlled trials.

Study Quality
We used the Jadad scale, a validated 5-point scale developed to evaluate the quality of the reporting of randomized trials in meta-analysis.^16,17 The scale assigns a score of 0 or 1 for each of the following study quality criteria: whether the study was described as randomized, whether the authors reported the method of randomization, whether the use of blinding was reported, whether the method for concealment of allocation was reported, and whether the authors accounted for patient withdrawals and drop-outs. Thus, a perfect study would receive a score of 5, and the lowest quality study according to this scale would receive a score of 0.

Analysis of Outcomes
Survival. Given that all of the studies identified in our systematic search reported crude survival data as the number of patients in each treatment group who died by 6, 12, 24, or 36 months, we calculated the probability of failure (death) as the number of patients who had died by each time point divided by the total number of patients enrolled at the start of the trial for each treatment group. This approach is intentionally conservative: if some patients dropped out of the study, retaining them in the denominator as we have done would lower the estimate of effectiveness. This is analogous to an intention-to-treat analysis.¹⁸ The risk ratios of treatment failure (death) at each time point was calculated as the proportion who died in the Astragalus-based herbal medicine plus platinum-based chemotherapy treatment group, divided by this proportion in the platinum-based chemotherapy group. Thus, RR less than 1 favors the combination regimen. This is the same approach taken by D’Addario et al⁷ in a meta-analysis of 12-month survival rates in the treatment of advanced non–small-cell lung cancer patients with platinum-based versus nonplatinum-based chemotherapy.

Objective tumor response. Given that most of the studies identified in our systematic search reported tumor response at conclusion of treatment using the 4-point WHO scale,¹⁹ we calculated the probability of tumor response as the number of patients experiencing any response (complete response plus partial response) divided by the total number of patients in each treatment group (complete response plus partial response plus no change plus progressive disease). The RR of tumor response was calculated as the probability of tumor response in the Astragalus-based herbal medicine plus platinum-based chemotherapy treatment group, divided by this proportion in the platinum-based chemotherapy group. Thus, RR more than 1 favors the combination regimen. This is the approach for meta-analysis of tumor response recommended by Sutton et al.¹⁴

Performance status. Many of the studies identified in our systematic search reported performance status using the Karnofsky performance scale,²⁰ with most using a 10-point change as the cutoff for improved or worse performance status, and a few others using a 20-point change as the cutoff. We therefore calculated the probability of improved or stable performance status as the proportion of improved or stable performance status: (> 10-point increase plus no change) divided by the total (> 10-point increase, plus no change, plus > 10-point decrease). The RR of improved or stable performance status was calculated as the proportion of improved or stable performance status in the Astragalus-based herbal medicine plus platinum-based chemotherapy treatment group, divided by this proportion in the platinum-based chemotherapy group. Thus, RR more than 1 favors the combination regimen.

Reduction in chemotherapy toxicity. Given that most of the studies identified in our systematic search reported occurrence of chemotherapy-related toxicity using the 5-point WHO scale,¹⁹ we calculated the probability of occurrence of toxicity as the number of patients experiencing any severe toxicity (WHO grade 3 or 4) divided by the total number of patients in each treatment group (WHO grades 0 + 1 + 2 + 3 + 4). The RR of reduction in toxicity was calculated as the proportion of severe toxicity in the Astragalus-based herbal medicine plus platinum-based chemotherapy treatment group, divided by this proportion in the platinum-based chemotherapy group. Thus, RR less than 1 favors the combination regimen. This is the same approach taken recently by Delbaldo et al,²¹ who reported the odds ratio for the occurrence of grade 3 or 4 toxicity in a meta-analysis of single-agent versus two-agent chemotherapy for non–small-cell lung cancer.

Meta-Analysis, Between-Study Heterogeneity, and Publication Bias
We used the random-effects model of DerSimonian and Laird²² to estimate the summary RR for each of the four outcomes: risk of death (at 6, 12, 24, and 36 months), tumor response, performance status, and severe chemotherapy toxicity. We used the ² statistic to assess between-study heterogeneity.^23,24 To assess publication bias, we used the Begg test, which examines the association between the effect estimates of individual studies and their variances; significant correlation between these two factors identifies publication bias.²⁵

	RESULTS

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Studies Retrieved
Our systematic search identified 1,305 potentially relevant abstracts, of which 92 were identified as requiring full-text article retrieval. Close screening of these 92 studies excluded 58 because no patients received Astragalus (n = 33), patients randomly assigned to herbal therapy in some cases received herbal medicine not actually containing the specific herb Astragalus (n = 6), the article did not describe a controlled trial (n = 3), no platinum drugs were included in chemotherapy (n = 3), there were no usable end points (n = 9), or the article was a duplicate of another study (n = 4). This resulted in 34 studies accepted for meta-analysis (Fig 1).

Survival
We identified seven studies reporting a total of 529 patients that reported reduced risk of death at 6 months for Astragalus combinations versus chemotherapy alone (RR = 0.58; 95% CI, 0.48 to 0.71): five using various Astragalus-based combinations (RR = 0.61; 95% CI, 0.49 to 0.78)^26-30 and two using a specific herbal formula, Jin Fu Kang (RR = 0.61; 95% CI, 0.28 to 1.34; Table 1 and Fig 2). ^31,32 We identified 12 studies with a total of 940 patients that reported reduced risk of death at 12-months (RR = 0.67; 95% CI, 0.52 to 0.87): one using single-agent Astragalus (RR = 0.62; 95% CI, 0.43 to 0.88),¹² nine using various Astragalus-based combinations (RR = 0.67; 95% CI, 0.49 to 0.90),^26-30,33-36 and two using formula Jin Fu Kang (RR = 0.91; 95% CI, 0.20 to 4.01; Table 1 and Fig 2).^31,32 We identified nine studies with a total of 768 patients that reported reduced risk of death at 24 months (RR = 0.73; 95% CI, 0.62 to 0.86): one using single-agent Astragalus (RR = 0.75; 95% CI, 0.58 to 0.97),¹² six using various Astragalus-based combinations (RR = 0.80; 95% CI, 0.66 to 0.96),^27,29,33-36 and two using formula Jin Fu Kang (RR = 0.58; 95% CI, 0.49 to 0.68; Table 1 and Fig 3). ^31,32 We identified six studies with a total of 556 patients that reported reduced risk of death at 36 months (RR = 0.85; 95% CI, 0.77 to 0.94): one using single-agent Astragalus (RR = 0.89; 95% CI, 0.74 to 1.08),¹² four using various Astragalus-based combinations (RR = 0.86; 95% CI, 0.73 to 0.998),^27,33,35,36 and one using formula Jin Fu Kang (RR = 0.79; 95% CI, 0.67 to 0.92; Table 1 and Fig 3).³²

View larger version (28K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Six-month survival with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone. (B) Twelve-month survival with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.

View larger version (24K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Twenty-four-month survival with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone. (B) Thirty-six-month survival with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.

Tumor Response
We identified 30 studies representing a total of 2,472 patients that reported tumor response data (RR = 1.34; 95% CI, 1.24 to 1.46): seven using specific formula Ai Di injection (RR = 1.19; 95% CI, 0.99 to 1.44),^37-43 two using single-agent Astragalus (RR = 1.57; 95% CI, 0.85 to 2.93),^12,44 18 using various Astragalus-based combinations (RR = 1.34; 95% CI, 1.21 to 1.47),^{27-30,34-36,45-55} and three using formula Jin Fu Kang (RR = 1.76; 95% CI, 1.23 to 2.53; Table 1 and Fig 4). ^31,32,56

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Tumor response with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Stable/improved Karnofsky performance status with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.

Publication Bias and Study Quality
We did not find evidence for publication bias according to the Begg test (Table 1). Most studies had a quality score of only 0 or 1 on the Jadad scale. Only three studies had a score of 2 or higher (Table 2). ^31,32,56

	DISCUSSION

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Only one of these studies,⁵⁶ using the formula Jin Fu Kang, described the method of randomization used. None of the other studies provided any details of the randomization method used, an unfortunate oversight given the availability of low-cost computers and free random number–generating software. Even more problematic was the lack of discussion in any study about whether the investigators knew which patients were randomly assigned to receive Astragalus-based herbal medicine. However, failure to describe randomization procedures fully is not limited to Chinese medical journals. Surprisingly, nearly 10 years since publication of the Consolidated Standards of Reporting Trials statement,⁵⁸ which was intended to improve the quality of reporting in randomized trials, 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.⁵⁹

Current standards in the quality of reporting in studies that analyze survival time require that the authors specify 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.⁵⁹ No studies reported this information. Although there exists the possibility of censoring, which could bias our survival 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. In addition, there was between-study heterogeneity in the evidence for improved survival at 6, 12, and 24 months, as well as in the evidence for improved performance status.

Additional research is needed to further understand the specific immunologic and cytotoxic mechanisms by which Astragalus may function as an adjunct to chemotherapy for the treatment of advanced non–small-cell lung cancer. Such work would also assist in the identification of which specific herbal combinations most strongly and reliably enhance the action of Astragalus. Although we did not locate any published evidence of interaction between platinum chemotherapy and Astragalus, such interactions are possible, and should be investigated further.

The Institute of Medicine, Washington, D.C., recently concluded that complementary and alternative medicines should face rigorous testing.⁶⁰ 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 many 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.

Other systematic reviews of published studies from Chinese journals have identified specific journals with better study quality, and also found trends in improvement of study quality over time.⁶¹ It is hoped that systematic reviews and meta-analyses such as this one will help specify where further improvements in the design and reporting of research conducted and published in China are needed.

We found evidence that Astragalus-based Chinese herbal medicine may increase effectiveness (by improving survival, tumor response, and performance status) and reduce toxicity of standard platinum-based chemotherapy for advanced non–small-cell lung cancer. However, confirmation of these conclusions in rigorously controlled, randomized trials is required before more firm conclusions about this therapy can be drawn.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Michael McCulloch, Michael Broffman, John M. Colford Jr Administrative support: Michael Broffman, Wei-yu Fan, Jin Gao, John M. Colford Jr Provision of study materials or patients: Michael McCulloch, Xiao-juan Shu, Wei-yu Fan, Jin Gao Collection and assembly of data: Michael McCulloch, Caylie See, Xiao-juan Shu, Wei-yu Fan, Jin Gao, Whitney Lieb, Kane Shieh Data analysis and interpretation: Michael McCulloch, Caylie See, Xiao-juan Shu, Alan Kramer, John M. Colford Jr Manuscript writing: Michael McCulloch, Michael Broffman, Alan Kramer, John M. Colford Jr Final approval of manuscript: Michael McCulloch, Caylie See, Xiao-juan Shu, Michael Broffman, Alan Kramer, Wei-yu Fan, Jin Gao, Whitney Lieb, Kane Shieh, John M. Colford Jr

 

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted July 29, 2005; accepted October 12, 2005.

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