Platinum-based chemotherapy is one of the standard treatments for non-small-cell lung cancer (NSCLC), while its high toxicity and limited clinical effects raise big concerns. Shenfu injection (SFI) has been commonly used as an adjutant chemotherapy drug for NSCLC in China. We ascertained the beneficial and adverse effects of SFI in combination with platinum-based chemotherapy for advanced NSCLC by using meta-analysis methods. The randomized controlled trials (RCTs) involving advanced NSCLC treatment with SFI plus platinum-based chemotherapy versus chemotherapy alone were searched on 6 medical databases up to February 2017. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and RevMan 5.3 software was employed for data analysis. 23 RCTs including 1574 patients met our inclusion criteria. We evaluated the following outcome measures: objective tumor response (ORR), disease control rate (DCR), Karnofsky performance score (KPS), adverse effects, and indicators of cellular immune function. The meta-analysis indicated that SFI plus platinum-based chemotherapy may benefit the patients with NSCLC on attenuated synergies of chemotherapy. These findings need to be confirmed by further rigorously designed high-quality and large-scale RCTs.
Lung cancer is the leading cause of cancer-related mortality and is responsible for 1.38 million deaths each year [
NSCLC is the most common form of lung cancer, accounting for approximately 85% of all cases [
In China, traditional Chinese medicines (TCMs), as complementary and alternative medicines in patients with advanced NSCLC, play vital and positive roles in controlling tumor metastasis and decreasing toxicity as an adjunctive therapy, improving the cancer patients’ immunity, the quality of life, and progression-free survival as a maintenance therapy, and providing a compelling therapeutic option as monotherapy [
The following major Chinese or English language electronic databases including the PubMed, EMBASE, China National Knowledge Infrastructure Database (CNKI), the Cochrane Library, WanFang Database, and China Biological Medicine Database (CBM) were searched up to February 2017. Two reviewers (Ailing Cao and Hailang He) independently searched articles in electronic databases using the search strategy (Neoplasm [Mesh] OR Lung Neoplasm [Mesh] OR Pulmonary Neoplasms OR Pulmonary Neoplasm OR Lung Cancer OR Thoracic Neoplasm OR Pulmonary Cancer OR Lung Carcinoma OR Pulmonary Carcinoma OR NSCLC OR Non-small Cell Lung Cancer) AND (Shenfu OR Shenfu injection). All retrievals were implemented by the Mesh and free word.
Included studies must meet the following criteria: the disease was diagnosed and confirmed with NSCLC by histopathological or cytological diagnostic criteria. The stage of NSCLC TNM was advanced stage (III-IV). Type of study was randomized controlled trial (RCT). The patients of each study were divided into two arms. The intervention of one arm was platinum-based chemotherapy alone, whereas the intervention in the other arm was platinum-based chemotherapy plus SFI. Moreover, the reported data must have at least one of following outcomes: (1) objective tumor response (ORR); (2) disease control rate (DCR); (3) Karnofsky performance score (KPS); (4) grade 3 or 4 white blood cell, platelet, hemoglobin, and vomiting toxicity; (5) relevant indicators of cellular immune function: percentages of total T lymphocytes (CD3+), helper T lymphocytes (CD4+), and helper T lymphocytes (CD4+)/cytotoxic T lymphocytes (CD8+). The reported data also needed to have sufficient details to permit the calculation of the risk ratios and its 95% CIs for each outcome.
Relevant clinical trials were manually removed if any of the following factors was identified: (1) the studies that included patients with other malignancy; (2) the interventions that were combined with other Chinese herbs or other TCM therapies; (3) duplicated articles; (4) the design scheme of the research was not clear, or the data was not complete.
Outcome measures included primary and secondary indices. ORR and DCR were primary outcomes. KPS, adverse effects of white blood cell, platelet, hemoglobin, and vomiting toxicity and the percentages of CD3+, CD4+, and CD4+/CD8+ were regarded as the secondary indices of evaluation. ORR, formulated by the WHO scale [
Two investigators (Ailing Cao and Hailang He) reviewed the eligible studies and extracted the data independently. This course had to be cross-checked in order to ensure accuracy and reliability. Any discrepancy was resolved by consultation of the 3rd reviewer (Xianmei Zhou). The required information was collected from each article: (1) basic information such as language, year of publication, and name of the first author; (2) number of participants, sex, age, physical status, and TNM stage information in each group; (3) details of interventions and outcomes from each studies. The methodological quality of the included RCTs was assessed independently by two reviewers (Ailing Cao and Hailang He) based on the criteria in the Cochrane evaluation handbook of RCTs 5.1.0 [
The RevMan 5.3 software (Cochrane Collaboration) was used to perform the meta-analysis. The weighted mean differences (WMD) and relative risk (RR) with 95% confidence were calculated to compare continuous and dichotomous variables, respectively. If the heterogeneity existed in pooled studies (
In this study, sensitivity analysis was employed to verify the robust and reliable results from our study. We conducted the analysis by deleting the poor studies with relatively high overall risk of bias.
The initial database search identified 270 potentially relevant possible studies by using our search strategies from electronic database searching. A total of 62 records were identified after removing duplicates and screening the titles and abstracts. 39 trials were excluded with the following reasons: animal experiment
Flow diagram of the literature search process.
Table
Baseline characteristics of included studies.
Study |
|
Physical | Stage | Interventions | Outcomes | |
---|---|---|---|---|---|---|
|
|
|||||
Liang et al., 2016 [ |
39/39 | KPS ≥ 60 | III-IV | DP + SFI (80 ml/d, d1–d10) | DP | ⑦ |
Wang et al., 2016 [ |
96/96 | PS ≤ 2 | IIIb-IV | GP + SFI (100 ml/d, d1–d15) | GP | ①②③④⑤ |
Zhang, 2015 [ |
64/64 | NR | III-IV | GP + SFI (60 ml/d, d1–d21) | GP | ①⑦ |
Xie et al., 2015 [ |
40/40 | PS ≤ 2 | III-IV | TP + SFI (80 ml/d, d1–d7) | TP | ②④⑤ |
Bai et al., 2014 [ |
39/39 | KPS ≥ 60 | III-IV | DP + SFI (80 ml/d, d1–d10) | DP | ①②③④⑤⑥ |
Li, 2014 [ |
30/30 | PS ≤ 2 | III-IV | NP + SFI (50 ml/d, d1–d10) | NP | ①⑥ |
Chen and Zhao, 2013 [ |
40/36 | KPS ≥ 60 | IIIb-IV | GP + SFI (30 ml/d, d1–d14) | GP | ②④⑤ |
Gao et al., 2008 [ |
43/43 | KPS ≥ 60 | III-IV | GP + SFI (60 ml/d, d1–d10) | GP | ①②③④⑤⑥ |
Hu, 2011 [ |
19/19 | PS ≤ 2 | III-IV | GP + SFI (60 ml/d, d1–d9) | GP | ②③④ |
Jiang et al., 2011 [ |
38/38 | KPS ≥ 60 | III-IV | NP + SFI (60 ml/d, d1–d10) | NP | ⑦ |
Liu and Huang, 2011 [ |
30/30 | KPS ≥ 70 | III-IV | NP + SFI (60 ml/d, d1–d14) | NP | ⑥ |
Lu et al., 2011 [ |
30/30 | KPS ≥ 60 | III-IV | NP + SFI (60 ml/d, d1–d10) | NP | ①②④⑤⑦ |
Liu and Zhang, 2010 [ |
18/19 | PS ≤ 2 | IIIb-IV | TP + SFI (60 ml/d, d1–d14) | TP | ①②③④⑤ |
Chen, 2010 [ |
24/23 | NR | III-IV | NP + SFI (50 ml/d, d1–d10) | NP | ①②③④⑤ |
Xie et al., 2010 [ |
25/25 | KPS ≥ 60 | III-IV | NP + SFI (50 ml/d, 1–d10) | NP | ②③④⑤ |
Zhang et al., 2009 [ |
31/28 | KPS ≥ 60 | IIIb-IV | GC + SFI (60 ml/d, d1–d10) | GC | ①②③④⑤⑦ |
Liu, 2008 [ |
21/20 | KPS ≥ 60 | III-IV | GP + SFI (50 ml/d, d1–d10) | GP | ②③④⑤ |
Li et al., 2008 [ |
26/28 | KPS ≥ 70 | IIIb-IV | TC + SFI (100 ml/d, d1–d7) | TC | ① |
Tang et al., 2008 [ |
18/19 | KPS ≥ 60 | IIIb-IV | NP + SFI (60 ml/d, d1–d7) | NP | ①⑤⑥ |
Liu et al., 2008 [ |
35/35 | PS ≤ 2 | IIIb-IV | TP + SFI (40–60 ml/d, d1–d10) | TP | ⑦ |
Gong and Luo, 2008 [ |
30/30 | KPS ≥ 50 | IIIb-IV | NP + SFI (50 ml/d, d1–d14) | NP | ①②③④ |
Lu et al., 2005 [ |
36/29 | KPS ≥ 60 | IIIb-IV | TP + SFI (50 ml/d, d1–d14) | TP | ②③④ |
Liu et al., 2004 [ |
21/21 | KPS ≥ 60 | IIIb-IV | NP + SFI (50 ml/d, d1–d14) | NP | ①②④ |
All of the included trials mentioned randomization, but only 16 [
13 trials [
DCR could be definitively extracted from twelve reports [
In 23 trials, 5 trials [
The incidence of white blood cell toxicity was reported in 15 trials [
11 studies [
Trials [
There were 12 trials [
In all included studies, 6 trials [
Funnel plots and Egger’s test were performed to identify potential publication bias among the included studies. The funnel plots were asymmetric in the studies about objective tumor response and disease control rate (Figures
The results of the fixed-effects and random-effects model had good consistency. After deleting the low quality studies with relatively high overall risk of bias, the results were still similar to the results before they were excluded (Table
Sensitivity analysis of this study.
Outcomes | |
RR or WMD (95% CI) | |
Excluded the studies | |
RR or WMD (95% CI) | |
---|---|---|---|---|---|---|---|
ORR | 13 | 1.33 (1.12, 1.59) | 0% | [ |
11 | 1.23 (1.02, 1.48) | 0% |
DCR | 12 | 1.17 (1.08, 1.27) | 48% | [ |
10 | 1.15 (1.05, 1.26) | 51% |
WBC | 15 | 0.29 (0.20, 0.41) | 0% | [ |
10 | 0.32 (0.22, 0.48) | 0% |
HBG | 11 | 0.28 (0.14, 0.54) | 0% | [ |
7 | 0.28 (0.13, 0.59) | 0% |
PLT | 15 | 0.31 (0.20, 0.47) | 0% | [ |
10 | 0.32 (0.20, 0.50) | 0% |
Vomiting | 12 | 0.27 (0.17, 0.43) | 0% | [ |
8 | 0.30 (0.17, 0.50) | 0% |
CD3+ | 6 | 15.09 (11.13, 19.05) | 93% | [ |
4 | 14.75 (9.33, 20.17) | 88% |
CD4+ | 6 | 10.25 (7.31, 13.20) | 87% | [ |
4 | 11.36 (5.76, 16.97) | 83% |
CD4+/CD8+ | 6 | 0.44 (0.25, 0.63) | 88% | [ |
4 | 0.38 (0.22, 0.74) | 82% |
TCMs, used in Asia for centuries, are beginning to play a role in western health care as complementary and alternative medicines. For cancer patients, they can enhance efficacy and decrease toxicity when combined with radiotherapy and chemotherapy. As a traditional Chinese medicine injection, SFI, which consists of extract of Radix Ginseng and Radix Aconiti Lateralis Preparata (prepared aconite root), has been widely used in the treatment of NSCLC. The active ingredients of SFI are mainly ginsenoside, aconitine, and ginseng polysaccharide. Modern pharmacological researches have proved that the ginsenoside Rg3 plays an important role in suppressing tumor cell proliferation, inhibiting tumor cell invasion and metastasis, and promoting the apoptosis of tumor cells [
In this study, 23 RCTs containing 1574 NSCLC patients were included, which ensured adequacy specimen for meta-analysis. Most of outcomes have good objectivity and stability. Prior to our meta-analysis [
Adverse effects often occur in patients with advanced NSCLC when chemotherapy is used. The leukopenia, anemia, thrombocytopenia, and vomiting at toxicity grade of III-IV were clearly decreased in patients with SFI-containing treatments. The results were also in accordance with previous findings [
The toxicity of chemotherapy can impair immune function and lower the quality of life for NSCLC patients. The meta-analysis suggested that SFI could improve the quality of life. However, the results were limited by smaller samples in the meta-analysis of KPS. This might lead to insufficient assessment to them. Many experiments had reported that SFI could stimulate immune cells to enhance their anticancer activity [
Although our meta-analysis demonstrates favorable outcomes in a combination of SFI and chemotherapy, several limitations in the present meta-analysis must be taken into account. Firstly, all the included trials manifested at least some methodological deficiencies leading to potential high risks of bias. The reporting of trial methods, procedures, and execution was frequently unclear, vague, and insufficient. After attempts verification by contacting the authors of the original papers through phone or e-mail, 18 trials were randomized by using random number tables to generate a sequence. We failed to get in touch with the remaining authors. None of included trials provided the detailed information on the concealment of treatment allocation and blinding. Therefore, there were potential risk of selection bias, performance bias, and detection bias in the present systematic review, which would lead to the overestimation of the clinical efficacy and attenuation of the treatment group. Secondly, all of the included studies were published in Chinese which might lead to ethical bias. Thirdly, the diversity of therapeutic dose, the small samples, and the lack of long-term follow-ups degraded the validity of the evidence of the clinical trials. Fourthly, all of the included studies applied an “A + B versus B” design where patients were randomized to accept SFI plus chemotherapy versus chemotherapy alone, without a rigorous placebo control. Such a design probably resulted in false positive results [
In summary, we find evidence that SFI combined with chemotherapy may amend tumor response, improve KPS, reduce chemotherapy toxicity, and enhance immune function when combined with chemotherapy alone in NSCLC patients. However, due to the poor quality of trials, the conclusion should be interpreted with caution. High-quality, precisely evaluated, and large sample size researches, particularly in the descriptions of methodology and study processes, are urgently needed to support the conclusion.
All authors declare that they have no conflicts of interest.
Xianmei Zhou and Hailang He conceived and designed the project. Ailing Cao performed the review. Ailing Cao and Hailang He analyzed the data and wrote the paper. Xianmei Zhou was responsible for quality control of the study. Dr. Ailing Cao and Dr. Hailang He contributed equally to this work.
This work was supported by the Project of Key Discipline for TCM Construction of Jiangsu Province, China (no. JS1302).