Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. J Clin Oncol

University of California, Berkeley, Berkeley, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2006; 24(3):419-30. DOI: 10.1200/JCO.2005.03.6392
Source: PubMed
ABSTRACT
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.
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.
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).
Astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy when combined with chemotherapy. These results require confirmation with rigorously controlled trials.

Full-text

Available from: Michael Mcculloch
Astragalus-Based Chinese Herbs and Platinum-Based
Chemotherapy for Advanced Non–Small-Cell Lung Cancer:
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, and John M. Colford Jr
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 (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 chemo-
therapy when combined with chemotherapy. These results require confirmation with rigorously
controlled trials.
J Clin Oncol 24:419-430. © 2006 by American Society of Clinical Oncology
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
Al
-
though lung cancer deaths in men have declined
substantially (from 92 in 100,000 in 1995, to 84 in
100,000 in 2001), death ratesin 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 oc
-
currences 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 chemother-
apy reduces the risk of death at 2 years by only
13%
3
; adjuvant chemoradiotherapy reduces that
risk by 14%
4
; adjuvant radiotherapy alone con
-
versely increases that risk by 21%.
5,6
The addition
of platinum-based drugs to standard chemother-
apy protocols increased 12-month survival by 5%
and tumor response by 62%, but with significantly
increased hematologic toxicity, nephrotoxicity, and
From the University of California,
Berkeley School of Public Health, Divi-
sion of Epidemiology, Berkeley; San
Francisco Oncology Associates; Insti-
tute 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.
Submitted July 29, 2005; accepted
October 12, 2005.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to John
Colford, MD, PhD, University of Califor-
nia, Berkeley, 140 Warren Hall, MC
7360, Berkeley, CA 94720; e-mail:
jcolford@
berkeley.edu.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2403-419/$20.00
DOI: 10.1200/JCO.2005.03.6392
JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
VOLUME 24 NUMBER 3 JANUARY 20 2006
419
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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 carbo-
platin/paclitaxel chemotherapy in a phase III randomized, con-
trolled 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 chemo-
therapy 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 cytokines
10
(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 pub-
lished 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 treat-
ment 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; 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.) inde-
pendently 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 to-
gether for this meta-analysis those studies using platinum-based chemother-
apy 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 al
7
and the Cochrane Collaboration’s Non–Small-Cell Lung Cancer Collab-
orative 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
Data Extraction
Two reviewers (M.M. and C.S.) 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 medi-
cine 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.
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
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.
McCulloch et al
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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 propor-
tion in the platinum-based chemotherapy group. Thus, RR less than 1 favors
Table 1. Results
Endpoint
No. of
Studies
No. of
Patients RR 95% CI P Publication Bias (P) Heterogeneity (P)
6-month survival
All studies combined 7 529 0.58 0.48 to 0.71 .000
.29 .65
Various Astragalus combinations 5 308 0.61 0.49 to 0.78 .000
.85
Jin Fu Kang 2 221 0.61 0.28 to 1.34 .22 .14
12-month survival
All studies combined 12 940 0.67 0.52 to 0.87 .002
.40 .000
Astragalus single-agent 1 60 0.62 0.43 to 0.88 .009
Various Astragalus combinations 9 659 0.67 0.49 to 0.90 .008
.000
Jin Fu Kang 2 221 0.91 0.20 to 4.01 .90 .005
24-month survival
All studies combined 9 768 0.73 0.62 to 0.86 .000
.056 .000
Astragalus single-agent 1 60 0.75 0.58 to 0.97 .026
Various Astragalus combinations 6 487 0.80 0.66 to 0.96 .016
.009
Jin Fu Kang 2 221 0.58 0.49 to 0.68 .000
.39
36-month survival
All studies combined 6 556 0.85 0.77 to 0.94 .002
.38 .091
Astragalus single-agent 1 60 0.89 0.74 to 1.08 .23
Various Astragalus combinations 4 352 0.86 0.73 to 0.998 .047
.048
Jin Fu Kang 1 144 0.79 0.67 to 0.92 .003
Tumor response
All studies combined 30 2472 1.34 1.24 to 1.46 .000
.27 .84
Ai Di injection 7 478 1.19 0.99 to 1.44 .068 1.00
Astragalus single-agent 2 156 1.57 0.85 to 2.93 .15 .11
Various Astragalus combinations 18 1427 1.34 1.21 to 1.47 .000
.74
Jin Fu Kang 3 411 1.76 1.23 to 2.53 .002
.84
Improved or stable performance status
All studies combined 12 1095 1.36 1.21 to 1.54 .000
.23 .001
Ai Di injection 4 257 1.28 1.12 to 1.46 .000
.58
Astragalus single-agent 1 60 1.22 0.98 to 1.52 .08
Various Astragalus combinations 5 445 1.32 1.16 to 1.49 .000
.30
Jin Fu Kang 2 333 1.68 0.82 to 3.44 .15 .000
Reduction in grade III or IV WBC toxicity
All studies combined 9 808 0.39 0.24 to 0.63 .000
.35 .82
Ai Di injection 2 158 0.37 0.12 to 1.10 .072 .87
Various Astragalus combinations 6 460 0.39 0.22 to 0.69 .001
.50
Jin Fu Kang 1 190 0.45 0.084 to 2.40 .35
Reduction in grade III or IV platelet toxicity
All studies combined 6 777 0.36 0.11 to 1.21 .10 .25 0.78
Ai Di injection 1 60 0.33 0.01 to 7.87 .50
Various Astragalus combinations 3 392 0.50 0.09 to 2.82 .43 0.89
Astragalus single-agent 1 135 0.063 0.004 to 1.08 .056
Jin Fu Kang 1 190 0.90 0.06 to 14.18 .94
Reduction in grade III or IV hemoglobin toxicity
All studies combined 5 500 0.26 0.13 to 0.49 .000
.92 .95
Ai Di injection 1 60 0.33 0.04 to 3.03 .33
Various Astragalus combinations 3 250 0.27 0.13 to 0.54 .000
.97
Jin Fu Kang 1 190 0.08 0.005 to 1.46 .089
Abbreviation: RR, risk ratio.
Significant finding for efficacy.
Chinese Herbs and Platinum for NSCLC
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the combination regimen. This is the same approach taken by D’Addario et
al
7
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 re-
sponse as the number of patients experiencing any response (complete re-
sponse 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 proba-
bility 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 re-
sponse 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
Fig 2. (A) Six-month survival with
Astragalus-based herbs and platinum-based
chemotherapy versus platinum-based che-
motherapy alone. (B) Twelve-month survival
with Astragalus-based herbs and platinum-
based chemotherapy versus platinum-based
chemotherapy alone.
McCulloch et al
422
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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 chemo-
therapy 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,
Fig 3. (A) Twenty-four-month survival with
Astragalus-based herbs and platinum-based
chemotherapy versus platinum-based che-
motherapy alone. (B) Thirty-six-month sur-
vival with Astragalus-based herbs and
platinum-based chemotherapy versus
platinum-based chemotherapy alone.
Chinese Herbs and Platinum for NSCLC
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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 occur-
rence 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 Laird
22
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 iden-
tifies publication bias.
25
RESULTS
Studies Retrieved
Our systematic search identified 1,305 potentially relevant ab-
stracts, of which 92 were identified as requiring full-text article re-
trieval. 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
Fig 4. Tumor response with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.
McCulloch et al
424
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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 combina-
tions 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
Among studies reporting median survival, none included confi-
dence 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,
Fig 5. Stable/improved Karnofsky performance status with Astragalus-based herbs and platinum-based chemotherapy versus platinum-based chemotherapy alone.
Chinese Herbs and Platinum for NSCLC
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Table 2. Study Characteristics
Study
No. of
Patients Protocol* Ingredients Stage†
Jadad Quality
Scale
Cao
54
76 CAP/NP Astragalus
combination
Adenophora verticillata, Ophiopogonis japonicis,
Schisandra chinensis, Astragalus
membranaceus, Oldenlandia diffusa, Eriobotrya
japonica, Fritillaria cirrhosa, Arisaema amurense
III/IV 1
Cheng
29
43 CAP Astragalus combination Codonopsis pilosula, Astragalus membranaceus,
Atractylodis macrocephala, Poria cocos, Pinellia
ternata, Citrus reticulata, Dioscoreae opposita,
Oldenlandia diffusa, Houttuynia cordata, Patrina
villosa, Scutellaria barbata, Agrimonia pilosa,
Ziziphus jujube
III/IV 1
Chen
41
60 FDH Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoii
III/IV 1
Chu
48
128 EAP Radiation Astragalus
combination
Astragalus, Panax ginseng, Atractylodis
macrocephala, Psoralea corylifolia, Asparagus
cochinchinensis, Ophiopogonis japonicis,
Scrophularia ningpoensis, Rehmannia glutinosa,
Sparganium stoloniferum, Curcuma zeodoraria,
Manis pentadactyla, Ostrea gigis shell,
Trichosanthes kirilowii, Arisaema amurense,
Scutellaria barbata, Oldenlandia diffusa
III/IV 1
Fan
50
112 CAP Astragalus combination Codonopsis pilosulae, Atractylodis macrocephala,
Glycyrrhiza uralensis, Astragalus, Ligustricum
lucidum, Poria cocos, Salvia miltiorrhiza, Prunus
persica
III/IV 1
Fei CB, 2003
52
68 MVP Astragalus combination Astragalus, Codonopsis pilosulae, Rehmannia
glutinosae, Asparagus cochinchinensis,
Ophiopogonis japonicis, Scrophulariae
ningpoensis, Cimicifuga foetida, Houttuynia
cordata, Smilax glabra, Aloe vera
III/IV 1
Gao
44
96 MVP/CAP Astragal. Astragalus III/IV 1
Gao
38
67 GCN Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 1
Jia YJ, 2004
53
68 MVP/NP Astragalus
combination
Curcuma longa, Curcuma aromatica, Snake,
Prunellae vulgaris, Concha ostrea, Oldenlandia
diffusa, Astragalus, Panax qinquefolium
III/IV 1
Jin
33
90 MVP Astragalus combination Astragalus, Polygonatum chinense, Ligustricum
lucidum, Ganoderma lucidum, Salvia chinensis,
Paris polyphylla, Drynaria fortunei, Citrus
reticulate
III/IV 0
Li
47
114 CE/CAP Astragalus
combination
Astragalus, Polygonatum chinense, Panax
ginseng, Agrimonia pilosa, Houttuynia cordata,
Rheum palmatum, Polyporus umbellatus,
Lobelia chinensis, Oldenlandia diffusa,
Arisaema amurense, Coix lachryma, Prunus
persica, Trichosanthes kirilowii, Prunella
vulgaris
III/IV 1
Li
55
90 CE/CAP Astragalus
combination
Astragalus, Adenophora verticillata, Lilium
brownii, Ophiopogonis japonicis, Coix lachryma,
Scutellaria barbata, Akebia trifoliata, Selaginella
doederleinii, Agrimoniae pilosa, Polistes
japonicus, Fritillaria thunbergii, Houttuynia
cordata, Pinellia ternate, Glycyrrhizae
III/IV 1
Liu
31
77 MAP Jin Fu Kang Astragalus, Adenophora verticillata, Ophiopogonis
japonicis, Ligustricum lucidum, Selaginella
doederleinii, Paris polyphylla
2
Liu
56
190 CAP/MVP Jin Fu Kang Astragalus, Adenophora verticillata, Ophiopogonis
japonicis, Ligustricum lucidum, Selaginella
doederleinii, Paris polyphylla
II, III or IV 4
Liu
32
144 MAP Jin Fu Kang Astragalus, Adenophora verticillata, Ophiopogonis
japonicis, Ligustricum lucidum, Selaginella
doederleinii, Paris polyphylla
2
Liu
49
65 EAP/CAP Astragalus
combination
Astragalus, Pseudostellaria heterophylla,
Adenophora verticillata, Atractylodis
macrocephala, Rehmannia glutinosae, Coix
lachryma, Poria cocos, Curcuma zeodoaria,
Saliva miltiorrhiza, Panax notoginseng, Citrus
aurantium, Cremastra variabilis, Prunus
armeniaca
III/IV 1
(continued on following page)
McCulloch et al
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Table 2. Study Characteristics (continued)
Study
No. of
Patients Protocol* Ingredients Stage†
Jadad Quality
Scale
Liu SS, 2004
36
78 CAP/MVP/CE Astragalus
combination
Pseudostellaria heterophylla, Astragalus,
Atractylodis macrocephala, Poria cocos,
Ophiopogonis japonicis, Oldenlandia diffusa,
Scutellaria barbata, Taraxicum mongolicum, Paris
polyphylla, Fritillaria thunbergii, Ligustricum
lucidum, Buthus martensi, Scolopendra
subspinipes, Hirudo nipponica, Coix lachryma,
Glycyrrhizae uralensis
1
Lu
39
73 NP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 1
Sui
30
80 MVP Astragalus combination Lilium brownii, Rehmannia glutinosa, Scrophularia
ningpoensis, Angelicae sinensis, Ophiopogonis
japonicis, Paeonia lactiflora, Adenophora
verticillata, Astragalus, Ligustricum lucidum, Paris
polyphylla, Oldenlandia diffusa, Houttuynia
cordata, Fritillaria cirrhosa, Cremastra variabilis
(with individualized additions)
II, III or IV 0
Sun
45
74 CE-CAP/MVP/TC Astragalus
combination
Ganoderma lucidum, Pseudostellaria heterophylla,
Coix lachryma, Atractylodis macrocephala,
Astragalus, Lycium chinense, Curcuma zeodoaria,
Scolopendra subspinipes, Smilax glabra,
III/IV 1
Wang
37
32 NP/MVP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 1
Wang
43
98 NP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 1
Wang
27
93 MOP Astragalus
combination
Adenophora verticillata, Asparagus cochinchinensis,
Ophiopogonis japonicis, Pseudostellaria
heterophylla, Astragalus, Curcuma zeodoaria,
Atractylodis macrocephala, C. aromatica, Paeonia
rubra, Paeonia lactiflora, Oldenlandia diffusa,
Scutellaria barbata
1
Wang
26
58 Cisplatin Astragalus
combination
Astragalus, Panax ginseng, Lilium brownii,
Adenophora verticillata, Ophiopogonis japonici,
Fritillaria cirrhosa, Morus alba, Trichosanthes
kirilowii, Scutellariae baicalensis, Paris polyphylla,
Scutellaria barbata, Solanum nigrum, Lepidium
apetalum, Atractylodis macrocephalae, Poria
cocos, Phaseolus carcaratus, Ziziphus jujube
III/IV 1
Wang
46
58 CAP/MVP Astragalus
combination
Panax ginseng, Astragalus, Asparagus
cochinchinensis, Ophiopogonis japonicis,
Adenophora verticillata, Angelicae sinensis,
Dioscoreae opposita, Dendrobium nobile,
Polygonatum chinense, Schisandra chinensis,
Ziziphus spinosa, Glycyrrhizae uralensis, Citrus
reticulate
III/IV 1
Weng
28
34 CAP Astragalus combination Codonopsis pilosulae, Astragalus, Atractylodis
macrocephala, Poria cocos, Pinellia ternata, Citrus
reticulata, Dioscorea opposita, Oldenlandia
diffusa, Houttuynia cordata, Patrina villosa,
Scutellaria barbata, Agrimonia pilosa, Ziziphus
jujube
1
Yu
34
92 MAP radiation Astragalus
combination
Astragalus, Pseudostellaria heterophylla, Poria
cocos, Amomum xanthioides, Salvia miltiorrhiza,
Paeonia rubra, Spathalobus suberectus,
Schisandra chinensis, Glycyrrhizae uralensis (with
individualized additions)
III/IV 0
Zhang
40
50 NP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 0
Zhang
42
98 NP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 0
Zhang
57
60 EP Ai Di injection Panax ginseng, Astragalus, Eleutherococcus
senticosus, Mylabirs cichoi
III/IV 0
Zhou
51
63 CAP Astragalus combination Panax ginseng, Atractylodis macrocephala, Poria
cocos, Astragalus, Polygonatum chinense,
Ophiopogonis japonicis, Cordyceps chinensis,
Lycium chinense, Ephedra sinica, Prunus
armeniaca, Trionyx sinensis, Prunellae vulgaris,
Oldenlandia diffusa, Scutellaria barbata, P.
notoginseng
III/IV 1
(continued on following page)
Chinese Herbs and Platinum for NSCLC
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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
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; Table 1 and Fig 5).
32,56
Reduction in Chemotherapy Toxicity
We found no significant results for specific herbal formulas in
reducing severe WBC, platelet, or hemoglobin toxicity.
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
These findings are subject to several limitations. Our meta-analysis
results suggest that combining platinum-based chemotherapy with
Chinese herbal medicine in the treatment of non–small-cell lung
cancer may increase survival, tumor response, and performance sta-
tus, as well as reduce chemotherapy toxicity, when compared with
treatment with platinum-based chemotherapy alone; however, be-
cause the studies we found were of poor quality, we are unable to
make firm conclusions and confirmation must await investigation
in future trials.
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 comput-
ers 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 de-
scribe 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 ran-
domized trials, more than 40% of trials published in 2004 in
Western medical journals either failed to use adequate random-
ization 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 han-
dled 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 identi-
fication 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 chemother-
apy and Astragalus, such interactions are possible, and should be
investigated further.
The Institute of Medicine, Washington, D.C., recently con-
cluded 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
Table 2. Study Characteristics (continued)
Study
No. of
Patients Protocol* Ingredients Stage†
Jadad Quality
Scale
Zhou
35
91 Cisplatin Astragalus
combination
Adenophora verticillata, Ophiopogonis japonicis,
Pseudostellaria heterophylla, Paris polyphylla,
Astragalus, Scutellaria barbata, Curcuma zeodoaria,
Atractylodis macrocephala, Paeonia rubra, Paeonia
lactiflora, Oryza sativa, Hordeum vulgare, Massa
fermenta, Crataegus pinnatifida, Cremastra variabilis,
Curcuma aromatica, Citrus reticulata
III/IV 1
Zou
12
60 MAP Astragalus Astragalus III/IV 1
Total 2,815
Abbreviations: CAP, cyclophosphamide, doxorubicin, cisplatin; NP, vinorelbine, cisplatin; FDH, hydroxy camptothecin, fluorouracil, leucovorin, cisplatin; EAP,
etoposide, doxorubicin, cisplatin; MVP, mitomycin-C, vindesine, cisplatin; TC, paclitaxel, carboplatin; GCN, gemcitabine, cisplatin, vinorelbine; CE, cisplatin,
etoposide; MAP, mitomycin, doxorubicin, cisplatin; EP, etoposide, cisplatin; MOP, mitomycin, vincristine, cisplatin.
In studies that included stage II patients, all patients received systemic therapy, and no patients received surgery.
†In studies in which patients received radiation in addition to chemotherapy, all patients in both groups received radiation and chemotherapy. The only difference
between the two groups was whether they received Astragalus-based herbal medicine.
McCulloch et al
428
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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 medi-
cine may increase effectiveness (by improving survival, tumor re-
sponse, and performance status) and reduce toxicity of standard
platinum-based chemotherapy for advanced non–small-cell lung can-
cer. However, confirmation of these conclusions in rigorously con-
trolled, randomized trials is required before more firm conclusions
about this therapy can be drawn.
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■■■
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
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
McCulloch et al
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    • "Another chemotherapy drug, Gemcitabine , may cause uncomfortable symptoms, such as dizziness, vomiting, leukopenia, thrombocytopenia, and kidney toxicity [59] . Traditional Chinese herbal medicines are beginning to emerge as anti-cancer drugs [35][36][37][38]. At present, approximately two-thirds of cancer patients are at the mid-to late-stage of their diagnosis because of diagnostic technique restrictions and reduced surgical opportunities [2,[15][16][17][18][19][20][21][22][23]. "
    [Show abstract] [Hide abstract] ABSTRACT: Traditional lung cancer treatments involve chemical or radiation therapies after surgical tumor removal; however, these procedures often kill normal cells as well. Recent studies indicate that chemotherapies, when combined with Traditional Chinese Medicines, may offer a new way to treat cancer. In vitro tests measuring the induction of autophagy and/or apoptosis were used to examine the cytotoxicity of SBPE, commonly used for lung inflammation on A549 cell line. The results indicated that intercellular levels of p62 and Atg12 were increased, LC3-I was cleaved into LC3-II, and autophagy was induced with SBPE only. After 24 hours, the apoptotic mechanism was induced. If the Cisplatin was added after cells reached the autophagy state, we observed synergistic effects of the two could achieve sufficient death of lung cancer cells. Therefore, the Cisplatin dosage used to induce apoptosis could be reduced by half, and the amount of time needed to achieve the inhibitory concentration of 50% was also half that of the original. In addition to inducing autophagy within a shortened period of time, the SBPE and chemotherapy drug combination therapy was able to achieve the objective of rapid low-dosage cancer cell elimination. Besides, SBPE was applied with Gemcitabine or Paclitaxel, and found that the combination treatment indeed achieve improved lung cancer cell killing effects. However, SBPE may also be less toxic to normal cells.
    Full-text · Article · May 2016 · PLoS ONE
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    • "Astragalus is one of the main components of SFI, and it has been proven to be capable of enhancing immunologic function. McCulloCh, et al[35] performed a systemic review to evaluate the efficacy of astragalus-based Chinese drugs in curing advanced NSCLC, and the results suggested that astragalus-based medicine may increase effectiveness when combined with chemotherapy, which is in consistent with the present study, although SFI was not included in their study. Moreover, Jean et al.[36] further reported that herbal treatment could benefit 4751 NSCLC patients from 65 RCTs with significantly improved survival at 12, 24 and 36 months. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To evaluate the effect of ShenQi FuZheng Injection (SFI) on cellular immunity and clinical efficacy in patients with advanced non small cell lung cancer(NSCLC) when combined with chemotherapy. Methods: Electronic databases including EMBASE, PUBMED, the conference proceedings of the American Society of Clinical Oncology (ASCO), Cochrane, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biological Medical disc(CBM) were searched, until July, 2015. The randomized controlled clinical studies reporting results of efficacy and immune function were collected according to the inclusion criteria. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and Revman 5 software was used for data analysis. Results: Fifteen studies including 1006 cases of advanced NSCLC were included based on the inclusion criteria. The results of meta-analysis showed that there were significant differences in percentages of CD3+ cells (SMD = 13.48; 95%CI: 8.11-18.85; p<0.01), CD4+ cells (SMD = 10.78; 95%CI, 6.38-15.18; p<0.01), NK [WMD = 8.59, 95% CI(3.97, 13.21), p = 0.003], and ratio of CD4+/ CD8+ (SMD = 0.32; 95%: 0.28-0.36; p<0.01) between SFI combination group and control group, whereas the difference was not significant in CD8+ (SMD = -1.44; 95%CI, -4.53-1.65; p = 0.36). Funnel plot, Begg's rank correlation test and Egger's linear regression analysis indicated that there was significant publication bias across studies. Conclusion: SFI is effective to improve the efficacy of chemotherpay and function of cellular immunity in NSCLC patients, however, high quality RCTs are needed to further confirm the findings.
    Full-text · Article · Mar 2016 · PLoS ONE
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    • "The survival rate remains very poor and the treatment cost is very high despite various methods for NSCLC treatment, including surgical resection, chemotherapy, radiotherapy, and small molecular target therapy [2]. Except for upper treatment strategies, traditional Chinese prescriptions are also widely used for NSCLC treatment in clinical medicine in China because of their efficient therapeutic effect and low cost [3, 4]. Prescriptions used for lung cancer therapy in China include " Jie-Geng Decoction, " " Gan-Cao-Gan-Jiang Decoction, " and " Bai- He-Gu-Jin Decoction, " which mainly contain Glycyrrhiza uralensis Fisch [5, 6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Licorice (Gancao in Chinese) has been used worldwide as a botanical source in medicine and as a sweetening agent in food products for thousands of years. Triterpene saponins and flavonoids are its main ingredients that exhibit a variety of biological activities, including hepatoprotective, antiulcer, anti-inflammatory, antiviral and anticancer effects among others. This review attempts to summarize the current knowledge on the anticancer properties and mechanisms of the compounds isolated from licorice and obtain new insights for further research and development of licorice. A broad spectrum of in vitro and in vivo studies have recently demonstrated that the mixed extracts and purified compounds from licorice exhibit evident anticancer properties by inhibition of proliferation, induction of cell cycle arrest, apoptosis, autophagy, differentiation, suppression of metastasis, angiogenesis, and sensitization of chemotherapy or radiotherapy. A combined treatment of licorice compounds and clinical chemotherapy drugs remarkably enhances anticancer effects and reduces the side effects of chemotherapeutics. Furthermore, glycyrrhizic acid and glycyrrhetinic acid in licorice have been indicated to present obvious liver-targeting effects in targeted drug delivery systems for hepatocellular carcinoma treatment.
    Full-text · Article · Dec 2015 · Planta Medica
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