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

MICHAEL MCCULLOCH, CAYLIE SEE, XIAO-JUAN SHU, MICHAEL BROFFMAN, ALAN KRAMER, WEI-YU FAN, JIN GAO, WHITNEY LIEB, KANE SHIEH, & JOHN M COLFORD JR

This Pine Street Foundation research paper was first published in the January 20th, 2006, issue of the Journal of Clinical Oncology (Volume 24, Number 3). Contact us for the full study.

ABSTRACT
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 reported reduced risk of death at 12 months. Thirty studies reported improved tumor response data. In subgroup analyses, Jin Fu Kang (a type of Astragalus-based herbal formula) in two studies reduced risk of death at 24 months and in three studies increased tumor response. Ai Di injection (another type of Astragalus-based herbal formula) stabilized or improved Karnofsky performance.

Conclusion. Astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy for non-small-cell lung cancer. These results require confirmation with rigorously controlled trials.

INTRODUCTION
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 to 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% confidence interval [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 is frequently 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
Study Identification
We conducted a systematic search of the following databases: CBM China BioMedical Bibliographic Database (1978 to August 2004), TCMLARS (1984 to August 2004), MEDLINE (1966 to August 2004), EMBASE (1974 to August 2004), Cochrane Library (1988 to August 2004), and Cochrane Central Register of Controlled Trials (1966 to August 2004). 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 (MM and CS) 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.13

Data Extraction
Two reviewers (MM and CS) independently extracted data on patient characteristics, treatment details, clinical outcomes, and study quality.14,15 We searched for data on survival outcomes of any type (total survival, cause specific survival, and disease-free survival, with either crude data or adjusted measures), objective tumor response, reduction in chemotherapy toxicity, and improved or stabilized performance status. To evaluate Chinese herbal medicine in total as a therapeutic system, we first grouped together for meta-analysis the data from all studies meeting our inclusion criteria. Then, to evaluate the efficacy of specific herbal formulas, when we found more than one study using the exact same herbal formula, we grouped together for meta-analysis the data from those specific studies.

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 non-platinum-based chemotherapy.

Objective Tumor Response. The probability of tumor response was calculated as the number of patients experiencing any response (complete response plus partial response) divided by the total number in each treatment group. The RR of tumor response was calculated as the probability of tumor response in the combination group, divided by this proportion in the chemotherapy group; RR more than 1 favors the combination regimen.

Performance Status. RR more than 1 favors the combination regimen.

RESULTS
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.

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).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).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).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 .998),27,33,35,36 and one using formula Jin Fu Kang (RR=0.79; 95% CI, 0.67 to 0.92).32 Among studies reporting median survival, none included confidence intervals, P values, or variance. We were therefore unable to perform a meta-analysis of median survival.

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).31,32,56

Performance Status
We identified 12 studies representing a total of 1,095 patients that reported performance status data (RR=1.36; 95% CI, 1.21 to 1.54): four using specific formula Ai Di injection (RR=1.28; 95%CI, 1.12 to 1.46),37,38,43,57 one using single-agent Astragalus (RR=1.22; 95% CI, 0.98 to 1.52),12 five using various Astragalus-based combinations (RR=1.32; 95% CI, 1.16 to 1.49),36,48,50,51,53 and two using formula Jin Fu Kang (RR=1.68; 95% CI, 0.82 to 3.44).32,56

DISCUSSION
These findings are subject to several limitations. Our meta-analysis results suggest that combining platinum-based chemotherapy with Astragalus-based Chinese herbal medicine in the treatment of non-small-cell lung cancer may increase survival, tumor response, and performance status, when compared to treatment with platinum-based chemotherapy alone.

However, confirmation of these conclusions in rigorously controlled, randomized trials is required before more firm conclusions about this therapy can be drawn.

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