Shenfu Injection Adjunct with Platinum-Based Chemotherapy...

Review ArticleShenfu Injection Adjunct with Platinum-BasedChemotherapy for the Treatment of Advanced Non-Small-CellLung Cancer: A Meta-Analysis and Systematic Review

Ailing Cao, Hailang He, Mengxin Jing, Beibei Yu, and Xianmei Zhou

Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road,Nanjing 210009, China

Correspondence should be addressed to Xianmei Zhou; [email protected]

Received 31 May 2017; Revised 21 September 2017; Accepted 11 October 2017; Published 2 November 2017

Academic Editor: Caigan Du

Copyright © 2017 Ailing Cao et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Platinum-based chemotherapy is one of the standard treatments for non-small-cell lung cancer (NSCLC), while its high toxicityand limited clinical effects raise big concerns. Shenfu injection (SFI) has been commonly used as an adjutant chemotherapy drug forNSCLC in China. We ascertained the beneficial and adverse effects of SFI in combination with platinum-based chemotherapy foradvanced NSCLC by usingmeta-analysis methods.The randomized controlled trials (RCTs) involving advanced NSCLC treatmentwith SFI plus platinum-based chemotherapy versus chemotherapy alone were searched on 6 medical databases up to February2017. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and RevMan 5.3 software was employed fordata analysis. 23 RCTs including 1574 patients met our inclusion criteria. We evaluated the following outcome measures: objectivetumor response (ORR), disease control rate (DCR), Karnofsky performance score (KPS), adverse effects, and indicators of cellularimmune function. The meta-analysis indicated that SFI plus platinum-based chemotherapy may benefit the patients with NSCLCon attenuated synergies of chemotherapy. These findings need to be confirmed by further rigorously designed high-quality andlarge-scale RCTs.

1. Introduction

Lung cancer is the leading cause of cancer-related mortalityand is responsible for 1.38 million deaths each year [1]. Its5-year survival rate remains low at 15% for patients, whichis poor when compared to other high incidence cancers [2].Reports from previous work have indicated that lung canceris the most common cancer among both men and womenthat carries tremendous social and economic burden in bothdeveloped and developing countries [3].

NSCLC is the most common form of lung cancer,accounting for approximately 85% of all cases [4]. Over 50%of patients with NSCLC have reached advanced stages atthe time of their initial diagnosis due to its high rate ofmalignancy and invasion. Hence, they are forced to acceptother standard therapies, such as chemotherapy, radiother-apy, targeted therapy, or immunotherapy for unresectabletumors [5–7]. Platinum-based chemotherapy, as an optimal

and potentially curable treatment for advanced NSCLCpatients, occupies the dominant position in the nonsurgicaltreatment and hasmade favorable efficacy for reducing tumorsize.However, despite the technological advances, the toxicityof chemotherapy is remarkable, which may lead to limitedclinical efficacy, substandard immune function, and poorquality of life for patients. Many patients have difficultycompleting the recommended number of cycles and thusmiss the opportunity to profit from chemotherapy.Therefore,it is essential to look for additional treatment strategies toimprove the clinical efficacy and alleviate toxicity duringplatinum-based chemotherapy.

In China, traditional Chinese medicines (TCMs), ascomplementary and alternative medicines in patients withadvanced NSCLC, play vital and positive roles in controllingtumor metastasis and decreasing toxicity as an adjunctivetherapy, improving the cancer patients’ immunity, the qual-ity of life, and progression-free survival as a maintenance

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017, Article ID 1068751, 12 pageshttps://doi.org/10.1155/2017/1068751

https://doi.org/10.1155/2017/1068751

2 Evidence-Based Complementary and Alternative Medicine

therapy, and providing a compelling therapeutic optionas monotherapy [8–11]. Shenfu injection (SFI), which isextracted from two different Chinese herbs, Radix Ginsengand Radix Aconiti Lateralis Preparata, has been commonlyused as an adjutant chemotherapy drug in China. A numberof trials revealed that SFI had attenuation and synergisticefficacy to platinum-based chemotherapy [12, 13]. Our pre-vious meta-analysis demonstrated that SFI combined withplatinum-based chemotherapy might improve the qualityof life, enhance the immune functions, and reduce adverseevents compared with chemotherapy alone [14]. Neverthe-less, the meta-analysis failed to manifest the benefit of SFIon the tumor response because of inconsistent or conflictingoutcomes of the included studies, possibly caused by thelimited quantity and quality of enrolled trials. Recently,there have emerged some new studies evaluating the efficacyof SFI combined with platinum-based chemotherapy forNSCLC. To shed light on these contradictory results andmore precisely reveal its real synergistic efficacy and toxicityattenuation to platinum-based chemotherapy, we conductedthis updated systematic review and meta-analysis to evaluateall related studies.

2. Methods

2.1. Literature Search Strategy. The following major Chi-nese or English language electronic databases includingthe PubMed, EMBASE, China National Knowledge Infras-tructure Database (CNKI), the Cochrane Library, WanFangDatabase, and China Biological Medicine Database (CBM)were searched up to February 2017. Two reviewers (AilingCaoandHailangHe) independently searched articles in electronicdatabases using the search strategy (Neoplasm [Mesh] ORLung Neoplasm [Mesh] OR Pulmonary Neoplasms OR Pul-monary Neoplasm OR Lung Cancer ORThoracic NeoplasmOR Pulmonary Cancer OR Lung Carcinoma OR PulmonaryCarcinoma OR NSCLC OR Non-small Cell Lung Cancer)AND (Shenfu OR Shenfu injection). All retrievals wereimplemented by the Mesh and free word.

2.2. Inclusion Criteria. Included studies must meet the fol-lowing criteria: the disease was diagnosed and confirmedwith NSCLC by histopathological or cytological diagnosticcriteria. 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. Theintervention of one arm was platinum-based chemother-apy alone, whereas the intervention in the other armwas platinum-based chemotherapy plus SFI. Moreover, thereported 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) grade3 or 4 white blood cell, platelet, hemoglobin, and vomitingtoxicity; (5) relevant indicators of cellular immune function:percentages of total T lymphocytes (CD3+), helper T lympho-cytes (CD4+), and helper T lymphocytes (CD4+)/cytotoxic Tlymphocytes (CD8+). The reported data also needed to havesufficient details to permit the calculation of the risk ratiosand its 95% CIs for each outcome.

2.3. Exclusion Criteria. Relevant clinical trials were manuallyremoved if any of the following factors was identified: (1) thestudies that included patients with other malignancy; (2) theinterventions that were combined with other Chinese herbsor other TCM therapies; (3) duplicated articles; (4) the designscheme of the research was not clear, or the data was notcomplete.

2.4. Outcome Measures. Outcome measures included pri-mary and secondary indices. ORR and DCR were primaryoutcomes. KPS, adverse effects of white blood cell, platelet,hemoglobin, and vomiting toxicity and the percentagesof CD3+, CD4+, and CD4+/CD8+ were regarded as thesecondary indices of evaluation. ORR, formulated by theWHO scale [15], equals complete response (CR) + partialresponse (PR) and DCR equals complete response (CR) +partial response (PR) + no change (NC). The KPS [16] wasemployed to investigate the performance status of patientsin many of the included studies which applied a 10-pointchange as the cutoff for improved or worse performancestatus. Therefore, we calculated the improved performancestatus as the number of patients with improved performancestatus (>10-point increase) divided by the total. The 5-pointWHO scale [15] was used to evaluate chemotherapy toxicityand the rate of severe chemotherapy toxicity was definedas the number of patients with any severe toxicity (WHOgrade 3 or 4) divided by the total number of patients in eachtreatment group (WHO grades 0, 1, 2, 3, and 4). Relevantindicators of cellular immune function includingCD3,CD4+,and CD4+/CD8+ were also used to assess the efficacy of SFI.

2.5. Data Extraction and Quality Assessment. Two investi-gators (Ailing Cao and Hailang He) reviewed the eligiblestudies and extracted the data independently. This coursehad to be cross-checked in order to ensure accuracy andreliability. Any discrepancy was resolved by consultation ofthe 3rd reviewer (Xianmei Zhou). The required informationwas collected from each article: (1) basic information such aslanguage, year of publication, and name of the first author;(2) number of participants, sex, age, physical status, andTNM stage information in each group; (3) details of interven-tions and outcomes from each studies. The methodologicalquality of the included RCTs was assessed independentlyby two reviewers (Ailing Cao and Hailang He) based onthe criteria in the Cochrane evaluation handbook of RCTs5.1.0 [17]. Briefly, the main questions about quality were (1)sequence generation; (2) allocation concealment; (3) blindingof participants and study personnel, blinding of outcomeassessments; (4) incomplete outcome data: including baselinemeasurements before the intervention and effect parametersafter intervention, dropout/exit (whether the dropout rate isless than 10%); (5) selective outcome reporting. Each termwas identified as having low, unclear, or high risk of biasaccording to information provided by the protocol.

2.6. Statistical Analysis. The RevMan 5.3 software (CochraneCollaboration) was used to perform the meta-analysis. Theweighted mean differences (WMD) and relative risk (RR)with 95% confidence were calculated to compare continuous

Evidence-Based Complementary and Alternative Medicine 3

Records identi�ed through database searching(n = 266)

Additional records identi�ed through other sources(n = 4)

Records a�er duplicates removed(n = 94)

Records screened(n = 62)

39 records were excluded for thefollowing reasons:Inappropriate interventionsNonrandomized controlled trialsNo relative outcomesIncomplete dataRetrospective analysisReviewsAnimal experimentNot being advanced NSCLC

Studies included inquantitative synthesis (meta-analysis)(n = 23)

Figure 1: Flow diagram of the literature search process.

and dichotomous variables, respectively. If the heterogeneityexisted in pooled studies (𝐼2 > 50%), the random model wasapplied. Otherwise, the fixed model was used. Statistical sig-nificant difference was considered as 𝑃 < 0.05. Funnel plotswere employed to evaluate the potential publication bias forprimary outcomes if more than 10 studies were included fora meta-analysis [17]. Publication bias was further evaluatedby Egger’s test with Stata 12.1 software.

2.7. Sensitivity Analysis. In this study, sensitivity analysis wasemployed to verify the robust and reliable results from ourstudy.We conducted the analysis by deleting the poor studieswith relatively high overall risk of bias.

3. Results

3.1. Retrieval Result. The initial database search identified270 potentially relevant possible studies by using our searchstrategies from electronic database searching. A total of 62records were identified after removing duplicates and screen-ing the titles and abstracts. 39 trials were excluded with thefollowing reasons: animal experiment (𝑛 = 3), reviews (𝑛 =9), inappropriate interventions (𝑛 = 10), retrospective study(𝑛 = 1), non-RCTs (𝑛 = 8), no relative outcomes (𝑛 = 3),incomplete data (𝑛 = 2), and not being advancedNSCLC (𝑛 =3). 23 clinical trials were finally involved in thismeta-analysis.A flow diagram describing literature search and study selec-tion was shown in Figure 1.

3.2. Characteristics of Included Trials. Table 1 presents asummary of the baseline characteristics of the enrolledstudies, including authors, published years, number of cases,the performance status, TNM stage information, details ofinterventions, and outcomes. As shown, all of the studieswereconducted in China and published in Chinese journals. Thedosage of SFI was 30–100ml per day and the duration of ther-apy was 1–3 weeks and 2–4 cycles by intravenous injection.NP regimen was the most common chemotherapy regimen[23, 27–29, 31, 32, 36, 38, 40], and the remainder included GP,TP, DP, GC, and TC regimens that were applied in 6 [19, 20,24–26, 34], 4 [21, 30, 37, 39], 2 [18, 22], 1 [33], and 1 [35] studies,respectively. The stages of NSCLC TNM of the patientsenrolled in the present studies were all advanced stage.

3.3. Methodological Bias of the Included Studies. All of theincluded trials mentioned randomization, but only 16 [18, 19,21–23, 25, 28–30, 33, 35–40] described the specific method ofrandomization. After attempts verification by contacting theauthors of the original papers through phone or e-mail, 16[18, 19, 21–23, 25, 28–30, 33, 35–40] trials were randomizedby using random number tables to generate a sequence. Two[20, 24] of the remaining trials alsowere randomized by usingthe same methods. Although much effort had been made tocontact the original authors, we still failed to get in touchwith5 [26, 27, 31, 32, 34] of them. None of the trials mentionedallocation concealmentmethods.Theblinding procedurewasnot mentioned in all studies. These indicated that there were


Table 1: Baseline characteristics of included studies.

Study N (T/C) Physical Stage Interventions OutcomesT C

Liang et al., 2016 [18] 39/39 KPS ≥ 60 III-IV DP + SFI (80ml/d, d1–d10) DP GWang et al., 2016 [19] 96/96 PS ≤ 2 IIIb-IV GP + SFI (100ml/d, d1–d15) GP ABCDEZhang, 2015 [20] 64/64 NR III-IV GP + SFI (60ml/d, d1–d21) GP AGXie et al., 2015 [21] 40/40 PS ≤ 2 III-IV TP + SFI (80ml/d, d1–d7) TP BDEBai et al., 2014 [22] 39/39 KPS ≥ 60 III-IV DP + SFI (80ml/d, d1–d10) DP ABCDEFLi, 2014 [23] 30/30 PS ≤ 2 III-IV NP + SFI (50ml/d, d1–d10) NP AFChen and Zhao, 2013 [24] 40/36 KPS ≥ 60 IIIb-IV GP + SFI (30ml/d, d1–d14) GP BDEGao et al., 2008 [25] 43/43 KPS ≥ 60 III-IV GP + SFI (60ml/d, d1–d10) GP ABCDEFHu, 2011 [26] 19/19 PS ≤ 2 III-IV GP + SFI (60ml/d, d1–d9) GP BCDJiang et al., 2011 [27] 38/38 KPS ≥ 60 III-IV NP + SFI (60ml/d, d1–d10) NP GLiu and Huang, 2011 [28] 30/30 KPS ≥ 70 III-IV NP + SFI (60ml/d, d1–d14) NP FLu et al., 2011 [29] 30/30 KPS ≥ 60 III-IV NP + SFI (60ml/d, d1–d10) NP ABDEGLiu and Zhang, 2010 [30] 18/19 PS ≤ 2 IIIb-IV TP + SFI (60ml/d, d1–d14) TP ABCDEChen, 2010 [31] 24/23 NR III-IV NP + SFI (50ml/d, d1–d10) NP ABCDEXie et al., 2010 [32] 25/25 KPS ≥ 60 III-IV NP + SFI (50ml/d, 1–d10) NP BCDEZhang et al., 2009 [33] 31/28 KPS ≥ 60 IIIb-IV GC + SFI (60ml/d, d1–d10) GC ABCDEGLiu, 2008 [34] 21/20 KPS ≥ 60 III-IV GP + SFI (50ml/d, d1–d10) GP BCDELi et al., 2008 [35] 26/28 KPS ≥ 70 IIIb-IV TC + SFI (100ml/d, d1–d7) TC ATang et al., 2008 [36] 18/19 KPS ≥ 60 IIIb-IV NP + SFI (60ml/d, d1–d7) NP AEFLiu et al., 2008 [37] 35/35 PS ≤ 2 IIIb-IV TP + SFI (40–60ml/d, d1–d10) TP GGong and Luo, 2008 [38] 30/30 KPS ≥ 50 IIIb-IV NP + SFI (50ml/d, d1–d14) NP ABCDLu et al., 2005 [39] 36/29 KPS ≥ 60 IIIb-IV TP + SFI (50ml/d, d1–d14) TP BCDLiu et al., 2004 [40] 21/21 KPS ≥ 60 IIIb-IV NP + SFI (50ml/d, d1–d14) NP ABDN, number of participants; T, treatment; C, control; KPS, Karnofsky performance score; PS, performance status; SFI, Shenfu injection; NR, not reported; DP,docetaxel + platinum; GP, gemcitabine + platinum; TP, taxol + platinum; NP, navelbine + platinum; GC, gemcitabine + cisplatin; TC, taxol + cisplatin; Aobjective tumor response;B white blood cell toxicity;C hemoglobin toxicity;D platelet toxicity;E vomiting toxicity;F KPS;G immune function.

the selective bias and high implementation bias. Three trials[18, 22, 29] showed the results of data integrity. Selectivereporting did not appear in all of the studies. Other bias wasnot clear.The detailed information of methodological qualityof the included studies is listed in Figure 2.

3.4. Meta-Analysis for Objective Tumor Response. 13 trials[19, 20, 22, 23, 25, 29–31, 33, 35, 36, 38, 40] including 954 casesreported ORR (Figure 3). There was no significant hetero-geneity among the trials (𝐼2 = 0%, 𝑃 = 0.87). Therefore, thefixed-effects model was applied for the analysis.The results ofmeta-analysis showed that the combination treatment of SFIand platinum-based chemotherapy significantly improvedthe objective tumor response of patients with NSCLC whencompared with the chemotherapy alone [RR = 1.33, 95% CI(1.12, 1.59), 𝑃 = 0.001].

3.5. Meta-Analysis for Disease Control Rate. DCR could bedefinitively extracted from twelve reports [19, 20, 22, 23, 25,29–31, 33, 35, 38, 40]. There was heterogeneity between stud-ies (𝐼2 = 48%, 𝑃 = 0.03). The pooled RR for DCR revealedthat there was a remarkable improvement for the combina-tion treatment of SFI and chemotherapy treatment yieldinga RR of 1.13 [95% CI (1.02, 1.25), 𝑃 = 0.02] by random-effectsmodel (Figure 4).

3.6. Meta-Analysis for Improved KPS. In 23 trials, 5 trials [22,23, 25, 29, 35], including 336 cases, reported improvementrates of KPS (Figure 5). The heterogeneity test found thatthe data was homogeneous (𝐼2 = 0%), employing the fixed-effects model in this meta-analysis. In meta-analysis, a statis-tically significant difference [RR = 1.88, 95% CI (1.43, 2.47),𝑃 < 0.00001] existed between SFI combination group andcontrol group, which meant that a combination of SFI andchemotherapy could result in better quality of life.

3.7. Meta-Analysis for Chemotherapy Toxicity

3.7.1. White Blood Cell. The incidence of white blood cell tox-icity was reported in 15 trials [19, 21, 22, 24–26, 29–34, 38–40],which included 1010 patients (Figure 6). As the heterogeneitytest showed 𝐼2 = 0%, a fixed-effects model was applied tocalculate the combined RR and 95% CI. The results indi-cated that SFI group exhibited significant reduction in whiteblood cell toxicity compared with chemotherapy group alone[RR = 0.29, 95% CI (0.20, 0.41), 𝑃 < 0.00001].

3.7.2. Hemoglobin. 11 studies [19, 22, 24, 26, 30–34, 38, 39]provided data on the hemoglobin toxicity with 753 cases aftertreatment (Figure 6). There was no significant heterogeneityin the included trials (𝐼2 = 0%). As shown in Figure 7,


Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

Low risk of biasUnclear risk of biasHigh risk of bias

25 50 75 1000(%)

(a)

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Random sequence generation (selection bias)Allocation concealment (selection bias)Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other bias

Zhang et al., 2009Zhang, 2015

Xie et al., 2010Xie et al., 2015

Wang et al., 2016

Tang et al., 2008Lu et al., 2011Lu et al., 2005

Liu et al., 2004Liu, 2008

Liu et al., 2008Liu and H

uang, 2011Liu and Zhang, 2010

Li et al., 2008Li, 2014

Liang et al., 2016Jiang et al., 2011

Hu, 2011

Gong and Luo, 2008

Gao et al., 2008

Chen and Zhao, 2013Chen, 2010

Bai et al., 2014+

++++++

+++++

++++++++++

+++++++

+ + + + + + + + + + + + +

(b)

Figure 2: Risk of methodological bias of the included studies. (a) Risk of bias graph: review authors’ judgments about each risk of bias itempresented as percentages across all included trials. (b) Risk of bias summary: review authors’ judgments about each risk of bias item presentedas percentages across all included trials.

there was statistically significant lower severe toxicity forhemoglobin [RR = 0.28, 95% CI (0.14, 0.54), 𝑃 = 0.0002]between the 2 groups by fixed-effects model, which suggestedthat SFI combined with chemotherapy could greatly decreasethe rate of hemoglobin toxicity in the treatment of NSCLCwhen compared with chemotherapy alone.

3.7.3. Platelet. Trials [19, 21, 22, 24–26, 29–34, 38–40] con-taining 1010 patients evaluated the platelet toxicity (Figure 6).It proved to be homogeneous according to the heterogeneitytest (𝐼2 = 0%), so the fixed-effects model effect modelwas used in this meta-analysis. As illustrated in Figure 6,combination treatment with chemotherapy plus SFI had anadvantage in mitigating the toxicity of platelet compared to

chemotherapy alone [RR = 0.31, 95% CI (0.20, 0.47), 𝑃 <0.00001].

3.7.4. Vomiting. There were 12 trials [19, 21, 22, 24, 25, 29–34, 36] included in the meta-analysis with 858 patientsof vomiting toxicity (Figure 6). The heterogeneity test washomogeneous (𝐼2 = 0%), and fixed-effects model wasapplied in this pooled analysis. Meta-analysis revealed thatSFI treatment could significantly reduce the incidence ofvomiting toxicity than control group [RR = 0.27, 95%CI (0.17,0.43), 𝑃 < 0.00001].

3.8. Meta-Analysis for Immune Function. In all includedstudies, 6 trials [18, 20, 27, 29, 30, 37] containing 471 patients


ControlEvents Total Events Total

Weight Risk ratio

20 39 39Bai et al., 2014 15 10.9% 1.33 [0.81, 2.20]13Chen, 2010 24 5 23 3.7% 2.49 [1.06, 5.88]16Gao et al., 2008 43 14 43 10.1% 1.14 [0.64, 2.04]12Gong and Luo, 2008 30 13 30 9.4% 0.92 [0.51, 1.68]17Li, 2014 30 14 30 10.1% 1.21 [0.74, 1.99]14Li et al., 2008 26 13 28 9.1% 1.16 [0.68, 1.98]7Liu and Zhang, 2010 18 6 19 4.2% 1.23 [0.51, 2.97]8Liu et al., 2004 21 7 20 5.2% 1.09 [0.48, 2.44]12Lu et al., 2011 30 9 30 6.5% 1.33 [0.66, 2.69]11Tang et al., 2008 26 10 26 7.2% 1.10 [0.57, 2.13]18 96Wang et al., 2016 10 96 7.2% 1.80 [0.88, 3.70]20 64Zhang, 2015 10 64 7.2% 2.00 [1.02, 3.93]17Zhang et al., 2009 31 12 28 9.1% 1.28 [0.75, 2.18]

476 100.0% 1.33 [1.12, 1.59]

Chemotherapy

Total (95% Cl) 478

Total events 185 138

Test for overall e�ect: Z = 3.23 (P = 0.001) 2 50.50.2 1SFl + chemotherapy

Study or subgroup ExperimentalM-H, �xed, 95% Cl

Risk ratioM-H, �xed, 95% Cl

Heterogeneity: 2 = 6.83, ＞＠ = 12 (P = 0.87) ; I2 = 0%

Figure 3: Forest plot of improved objective tumor response. Objective tumor response evaluated from meta-analysis of pairwise comparisonsin patients with chemotherapy combined SFI versus chemotherapy alone.

1.23 [0.94, 1.61]21Chen, 2010 24 14 23 5.6% 1.44 [1.00, 2.06]29Gao et al., 2008 43 24 43 6.1% 1.21 [0.86, 1.69]

Gong and Luo, 2008 24 30 27 30 10.3% 0.89 [0.72, 1.10]Li, 2014 28 30 28 30 14.3% 1.00 [0.87, 1.14]

25Li et al., 2008 28 24 26 12.4% 0.97 [0.82, 1.15]14Liu and Zhang, 2010 18 14 19 5.5%15 21

1.06 [0.73, 1.52]Liu et al., 2004 14 20 4.9% 1.02 [0.69, 1.51]Lu et al., 2011 26 30 19 30 7.0% 1.37 [1.01, 1.86]

51Wang et al., 2016 96 37 95 6.7% 1.36 [1.00, 1.87]55Zhang, 2015 47 12.0% 1.17 [0.98, 1.40]

Zhang et al., 2009 27 3164 64

18 28 6.9% 1.35 [1.00, 1.84]

447 Total (95% Cl) 454 100.0% 1.13 [1.02, 1.25]

2 50.2 0.5 1Chemotherapy Chemotherapy

+ SFI

Total events 347 292

Test for overall e�ect: Z = 2.31 (P = 0.02)

ControlEvents Total Events Total Weight Risk ratio

32 39 39Bai et al., 2014 26 8.2%

Study or subgroup ExperimentalM-H, random, 95% Cl

Risk ratioM-H, random, 95% Cl

Heterogeneity: 2 = 0.01, 2 = 21.17, ＞＠ = 11 (P = 0.03) ; I2 = 48%

Figure 4: Forest plot of improved disease control rate. Disease control rate evaluated from meta-analysis of pairwise comparisons in patientswith chemotherapy combined SFI versus chemotherapy alone.

reported the percentages of CD3+, CD4+, and CD4+/CD8+(Figure 7). According to the heterogeneity test, the random-effects model was used to calculate the combined WMD and95% CI. Meta-analysis indicated that there was a statisticallysignificant difference between two groups for CD3+ [WMD= 15.09, 95% CI (11.13, 19.05), 𝑃 < 0.00001], CD4+ [WMD =10.25, 95% CI (7.31, 13.20), 𝑃 < 0.00001], and CD4+/CD8+[WMD = 0.44, 95% CI (0.25, 0.63), 𝑃 < 0.00001], whichexplained that SFI combined with chemotherapy could obvi-ously enhance the immune function of NSCLC patients.

3.9. Analysis of Publication Bias. Funnel plots and Egger’s testwere performed to identify potential publication bias amongthe included studies. The funnel plots were asymmetricin the studies about objective tumor response and diseasecontrol rate (Figures 8(a) and 8(b)), which showed thatthere was potential risk of publication bias. Not only wouldpublication bias cause asymmetry in funnel plots, but clinicalheterogeneity or methodology heterogeneity between studiesmight affect the shape of funnel plots. So Egger’s test wasfurther applied to evaluate publication bias. Egger’s test for


22 39 3911 22.9%24 43 13 43 27.1%20 30 11 30 22.9%10 30 5 30 10.4%14 26 8 26 16.7%

168 100.0%

Bai et al., 2014Gao et al., 2008Li, 2014Liu and Huang, 2011 Tang et al., 2008

2.00 [1.13, 3.54]1.85 [1.09, 3.12]1.82 [1.07, 3.10]2.00 [0.78, 5.15]1.75 [0.89, 3.45]

1.88 [1.43, 2.47]

0.05 0.2 1 5 20Chemotherapy SFl + chemotherapy

Total (95% Cl) 168Total events 90 48

Test for overall e�ect: Z = 4.50 (P < 0.00001)

ControlEvents Total Events Total Weight Risk ratioStudy or subgroup Experimental

M-H, �xed, 95% ClRisk ratio

M-H, �xed, 95% Cl


Figure 5: Forest plot of improved KPS. KPS evaluated from meta-analysis of pairwise comparisons in patients with chemotherapy combinedSFI versus chemotherapy alone.

objective tumor response (𝑃 = 0.386) and disease controlrate (𝑃 = 0.697) revealed that no proof of publication biaswas obtained.

4. Sensitivity Analysis

The results of the fixed-effects and random-effects model hadgood consistency. After deleting the low quality studies withrelatively high overall risk of bias, the results were still similarto the results before they were excluded (Table 2), whichrevealed that the results of ourmeta-analysiswere reliable andverifiable.

5. Discussion

TCMs, used in Asia for centuries, are beginning to play arole in western health care as complementary and alternativemedicines. For cancer patients, they can enhance efficacyand decrease toxicity when combined with radiotherapy andchemotherapy. As a traditional Chinese medicine injection,SFI, which consists of extract of Radix Ginseng and RadixAconiti Lateralis Preparata (prepared aconite root), hasbeen widely used in the treatment of NSCLC. The activeingredients of SFI are mainly ginsenoside, aconitine, andginseng polysaccharide. Modern pharmacological researcheshave proved that the ginsenoside Rg3 plays an importantrole in suppressing tumor cell proliferation, inhibiting tumorcell invasion and metastasis, and promoting the apoptosisof tumor cells [41]. Aconitine has effects on inhibiting cellproliferation invasion and metastasis of human adenocarci-noma A549 cell lines through decreasing the expression ofMMP-2 andMMP-9 activity [42]. Furthermore, it can reducehigh KBV200 cell protein expression, partially reverse the cellresistance, and increase the sensitivity of chemotherapy drugs[43]. Ginseng polysaccharide has multiple immunomodula-tory effects and inhibitive action on A549 cell growth andapoptosis promoting effect as well [44]. Consequently, SFImay significantly increase the clinical efficacy through induc-ing the cancer cell apoptosis, inhibiting cell proliferationmetastasis, and upregulating tumor immunity.

In this study, 23 RCTs containing 1574 NSCLC patientswere included, which ensured adequacy specimen for meta-analysis.Most of outcomes have goodobjectivity and stability.Prior to our meta-analysis [14], a meta-analysis included19 studies was published in Chinese, but it did not revealsignificant results of SFI on the ORR and there was no eval-uation associated with DCR. Different inclusion criteria andthe limited quantity may be responsible for the inconsistentfindings between these two meta-analyses. Notably, as anupdated systematic reviewwithmore data, the present resultsfor ORR and DCR exhibited the same consistently superioreffect of SFI combinedwith platinum-based chemotherapy interms of efficacy enhancing for advancedNSCLC. Egger’s testindicated that there was lower publication bias about ORRand DCR. After excluding the poor studies with relativelyhigh overall risk of bias, meta-analysis showed that the resultsbefore and after exclusion had a good consistency. The abovedata suggested that SFI likely potentiated antitumor action ofchemotherapy.

Adverse effects often occur in patients with advancedNSCLCwhen chemotherapy is used.The leukopenia, anemia,thrombocytopenia, and vomiting at toxicity grade of III-IV were clearly decreased in patients with SFI-containingtreatments.The results were also in accordance with previousfindings [14]. After deleting the low quality studies, the resultswere still similar to the results before they were excluded,which showed that the results had a good consistencyand stability. Furthermore, the animal experimental studyindicated that SFI couldmarkedly enhance the level ofWBCs,platelets, RBCs, and hemoglobin of myelosuppressed ratsthrough promoting hematopoiesis [45]. Sowe believe that SFIplus chemotherapy can play a constructive role in reducingchemotherapy toxicity.

The toxicity of chemotherapy can impair immune func-tion and lower the quality of life for NSCLC patients. Themeta-analysis suggested that SFI could improve the qualityof life. However, the results were limited by smaller samplesin the meta-analysis of KPS. This might lead to insufficientassessment to them. Many experiments had reported thatSFI could stimulate immune cells to enhance their anticanceractivity [46, 47]. In this meta-analysis, we collected data


3 39 13 39 11.5% 0.23 [0.07, 0.75]0 24 6 23 5.9% 0.07 [0.00, 1.24]0 40 10 36 9.8%

1.2.1 WBC Bai et al., 2014Chen, 2010 Chen and Zhao, 2013 0.04 [0.00, 0.71]

3 43 6 43 5.3% 0.50 [0.13, 1.87]30 3 30 2.7% 0.33 [0.04, 3.03]

0 19 2 19 2.2%

Gao et al., 2008Gong and Luo, 2008Hu, 2011 0.20 [0.01, 3.91]

4 18 6 19 5.2%0 21 20 1.4%1

1

1

121 4 20 3.6%

0 36 4 29 4.4%3 30 5 30 4.4%7 96 31 96 27.4%2 40 8 40 7.1%2 25 3 25 2.7%4 31 7 28 6.5%

513Subtotal (95% Cl) 497 100.0%

Liu and Zhang, 2010 Liu, 2008Liu et al., 2004Lu et al., 2005Lu et al., 2011Wang et al., 2016Xie et al., 2015Xie et al., 2010Zhang et al., 2009

0.70 [0.24, 2.09]0.32 [0.01, 7.38]0.24 [0.03, 1.95]0.09 [0.01, 1.61]0.60 [0.16, 2.29]0.23 [0.10, 0.49]0.25 [0.06, 1.11]0.67 [0.12, 3.65]0.52 [0.17, 1.58]0.29 [0.20, 0.41]

3 39 39 16.0% Bai et al., 2014 6 0.50 [0.13, 1.86]Chen, 2010 0 24 23 4.1% 0.32 [0.01, 7.48]

43 Gao et al., 2008 4 43 10.7%

Total events 30 109

Test for overall e�ect: Z = 6.68 (P < 0.00001) 1.2.2 HGB

0.25 [0.03, 2.15]2 Gong and Luo, 2008 30 3 30 8.0% 0.67 [0.12, 3.71]

Hu, 2011 0 19 1

1

19 4.0% 0.33 [0.01, 7.70]0 Liu and Zhang, 2010 18 3 19 9.1% 0.15 [0.01, 2.72]0 Liu, 2008 21 1 20 4.1% 0.32 [0.01, 7.38]0 Lu et al., 2005 36 0 29 Not estimable 2 Wang et al., 2016 96 14 96 37.4% 0.14 [0.03, 0.61]

Xie et al., 2010 0 25 2 25 6.7% 0.20 [0.01, 3.97]0 Zhang et al., 2009 31 0 28 Not estimable

382 Subtotal (95% Cl) 371 100.0% 0.28 [0.14, 0.54]

39 0 39 Not estimable 24 1

1

1

1

23 1.3% Bai et al., 2014 0 Chen, 2010 0.96 [0.06, 14.43]

0 40 Chen and Zhao, 2013 3 36 4.8%

Total events 8 35

Test for overall e�ect: Z = 3.75 (P = 0.0002) 1.2.3 PLT

0.13 [0.01, 2.41]1 Gao et al., 2008 43 5 43 6.5% 0.20 [0.02, 1.64]0 Gong and Luo, 2008 30 0 30 Not estimable

Hu, 2011 0 19 19 2.0% 0.33 [0.01, 7.70]0 18 19 Liu and Zhang, 2010 0 Not estimable 0 Liu, 2008 21 20 2.0% 0.32 [0.01, 7.38]1

1

Liu et al., 2004 21 2 20 2.7% 0.48 [0.05, 4.85]0 Lu et al., 2005 36 2 29 3.6% 0.16 [0.01, 3.25]

Lu et al., 2011 3 30 5 30 6.5% 0.60 [0.16, 2.29]12 Wang et al., 2016 96 43 96 56.0% 0.28 [0.16, 0.50]0 Xie et al., 2015 40 40 2.0%

Xie et al., 20100.33 [0.01, 7.95]

0 25 3 25 4.6% 0.14 [0.01, 2.63]3 Zhang et al., 2009 31 6 28 8.2% 0.45 [0.12, 1.64]

513 Subtotal (95% Cl) 497 100.0% 0.31 [0.20, 0.47]

0 Bai et al., 2014 39 4 39 6.1% 0.11 [0.01, 2.00]Chen, 2010 0 24 5 23 7.6% 0.09 [0.01, 1.49]

0 Chen and Zhao, 2013 40 6 36 9.3%

Total events 21 73

Test for overall e�ect: Z = 5.41 (P < 0.00001) 1.2.4 Vomiting

0.07 [0.00, 1.19]1

1

1

1

1

Gao et al., 2008 43 5 43 6.8% 0.20 [0.02, 1.64]0 Liu and Zhang, 2010 18 19 2.0% 0.35 [0.02, 8.09]

21 Liu, 2008 3 20 4.2% Lu et al,. 2011

0.32 [0.04, 2.80]3 30 7 30 9.5% 0.43 [0.12, 1.50]0 Tang et al., 2008 26 2 26 3.4% 0.20 [0.01, 3.97]9 Wang et al., 2016 96 26 96 35.3% 0.35 [0.17, 0.70]

40 Xie et al., 2015 6 40 8.2% Xie et al., 2010

0.17 [0.02, 1.32]2 25 4 25 5.4% 0.50 [0.10, 2.49]0 Zhang et al., 2009 31 28 2.1% 0.30 [0.01, 7.13]

433 Subtotal (95% Cl) 425 100.0% 0.27 [0.17, 0.43]

2000.005 0.1 10SFl +

chemotherapy Chemotherapy

Total events 17 70


ControlEvents Total Events Total Weight Risk ratioStudy or subgroup Experimental

M-H, �xed, 95% ClRisk ratio

M-H, �xed, 95% Cl





1

Figure 6: Forest plot of chemotherapy toxicity. White blood cell, hemoglobin, platelet, and vomiting toxicity evaluated from meta-analysis ofpairwise comparisons in patients with chemotherapy combined SFI versus chemotherapy alone.


62.2 5.43 38 50.24 3.87 38 18.3% 11.96 [9.84, 14.08]84.04 14.91 39 59.25 15.73 39 12.3% 24.79 [17.99, 31.59]54.33 5.09 35 40.18 4.74 35 18.2% 14.15 [11.85, 16.45]64.19 9.86 30 59.13 9.72 30 14.8% 5.06 [0.11, 10.01]63.56 2.52 64 44.21 3.14 64 19.1% 19.35 [18.36, 20.34]62.76 6.98 31 46.37 5.24 28 17.3% 16.39 [13.26, 19.52]

237 234 100.0% 15.09 [11.13, 19.05]

Jiang et al., 2011Liang et al., 2016Liu et al., 2008Lu et al., 2011Zhang, 2015Zhang et al., 2009Subtotal (95% Cl)

40.54 4.1 38 33.28 3.18 38 20.1% 7.26 [5.61, 8.91]57.98 15.83 39 40.36 15.17 39 9.9% 17.62 [10.74, 24.50]35.78 6.31


35 29.87 3.4 35 18.9%36.81 6.33 30 29.32 8.32 30 16.0%42.83 3.75

5.91 [3.54, 8.28]7.49 [3.75, 11.23]

64 31.43 3.99 64 20.6% 11.40 [10.06, 12.74]45.69 8.63 31 29.29 8.5 28 14.6% 16.40 [12.02, 20.78]

237 234 100.0% 10.25 [7.31, 13.20]


1.48 0.18 38 0.92 0.15 38 22.8%2.68 1.29 39 2.01 1.83 39 5.5%1.42 0.63 35


0.99 0.43 35 16.6%1.53 0.39 30 1.53 0.21 30 20.3%1.85 0.23 64 1.31 0.24 64 22.7%1.54 0.81 31 0.89 0.67 28 12.1%

237 234 100.0% 0.44 [0.25, 0.63]

0.56 [0.49, 0.63]0.67 [−0.03, 1.37]0.43 [0.18, 0.68]

0.00 [−0.16, 0.16]0.54 [0.46, 0.62]0.65 [0.27, 1.03]


−20 −10 0 10 20Chemotherapy SFl +

chemotherapy


Heterogeneity: 2 = 21.09; 2 = 76.54, ＞＠ = 5 (P < 0.00001) ; I2 = 93%


1.6.1 CD3+

1.6.2 CD4+

1.6.3 CD4+/CD8+


ControlMean SD SDTotal Mean Total

Weight Mean di�erenceStudy or subgroup ExperimentalIV, random, 95% Cl

Mean di�erenceIV, random, 95% Cl

Figure 7: Forest plot of immune function. CD3+, CD4+, and CD4+/CD8+ evaluated from meta-analysis of pairwise comparisons in patientswith chemotherapy combined SFI versus chemotherapy alone.

0.5

0.4

0.3

0.2

0.1

0

0.5 1 2 50.2RR

SE(ＦＩＡ[２

２])

(a)

0.5

0.4

0.3

0.2

0.1

0

0.5 1 2 50.2RR

SE(ＦＩＡ[２

２])

(b)

Figure 8:The funnel plots for assessing publication bias. (a) Objective tumor response. (b) Disease control rate.


Table 2: Sensitivity analysis of this study.

Outcomes 𝑁 RR or WMD (95% CI) 𝐼2 Excluded the studies 𝑁 RR or WMD (95% CI) 𝐼2

ORR 13 1.33 (1.12, 1.59) 0% [20, 31] 11 1.23 (1.02, 1.48) 0%DCR 12 1.17 (1.08, 1.27) 48% [20, 31] 10 1.15 (1.05, 1.26) 51%WBC 15 0.29 (0.20, 0.41) 0% [24, 26, 31, 32, 34] 10 0.32 (0.22, 0.48) 0%HBG 11 0.28 (0.14, 0.54) 0% [26, 31, 32, 34] 7 0.28 (0.13, 0.59) 0%PLT 15 0.31 (0.20, 0.47) 0% [24, 26, 31, 32, 34] 10 0.32 (0.20, 0.50) 0%Vomiting 12 0.27 (0.17, 0.43) 0% [24, 31, 32, 34] 8 0.30 (0.17, 0.50) 0%CD3+ 6 15.09 (11.13, 19.05) 93% [20, 27] 4 14.75 (9.33, 20.17) 88%CD4+ 6 10.25 (7.31, 13.20) 87% [20, 27] 4 11.36 (5.76, 16.97) 83%CD4+/CD8+ 6 0.44 (0.25, 0.63) 88% [20, 27] 4 0.38 (0.22, 0.74) 82%Note. WBC, white blood cell; HBG, hemoglobin; PLT, platelet;𝑁, the number of trials.

relevant to immune function and pooled them together tofind out whether SFI did have an effect on the cellularimmunity of advanced NSCLC patients. The meta-analysisshowed the percentages of CD3+, CD4+, and CD4+/CD8+were significantly improved with a good consistency. Theresults seemed to indicate that SFI may exert its antitumoreffect via enhancing the immune function of cancer patients.This conclusion needs to be confirmed by further largesample, high-quality RCTs and further investigation aboutunderlying mechanisms of antitumor effect.

Although our meta-analysis demonstrates favorable out-comes in a combination of SFI and chemotherapy, severallimitations in the present meta-analysis must be taken intoaccount. Firstly, all the included trials manifested at leastsome methodological deficiencies leading to potential highrisks of bias. The reporting of trial methods, procedures,and execution was frequently unclear, vague, and insufficient.After attempts verification by contacting the authors of theoriginal papers through phone or e-mail, 18 trials wererandomized by using random number tables to generatea sequence. We failed to get in touch with the remain-ing authors. None of included trials provided the detailedinformation on the concealment of treatment allocation andblinding. Therefore, there were potential risk of selectionbias, performance bias, and detection bias in the presentsystematic review, which would lead to the overestimation ofthe clinical efficacy and attenuation of the treatment group.Secondly, all of the included studies were published in Chi-nese which might lead to ethical bias.Thirdly, the diversity oftherapeutic dose, the small samples, and the lack of long-termfollow-ups degraded the validity of the evidence of the clinicaltrials. Fourthly, all of the included studies applied an “A + Bversus B” design where patients were randomized to acceptSFI plus chemotherapy versus chemotherapy alone, withouta rigorous placebo control. Such a design probably resultedin false positive results [48]. Altogether, the methodologicalquality of the included trials is insufficient and the potentialbenefits of SFI for NSCLC patients need to be furtherappraised through RCTs that employ rigorous methodologyand include adequate assessment of the safety profiles of theinterventions.

6. Conclusion

In summary, we find evidence that SFI combined withchemotherapy may amend tumor response, improve KPS,reduce chemotherapy toxicity, and enhance immune func-tion when combined with chemotherapy alone in NSCLCpatients. However, due to the poor quality of trials, theconclusion should be interpreted with caution. High-quality,precisely evaluated, and large sample size researches, particu-larly in the descriptions of methodology and study processes,are urgently needed to support the conclusion.

Conflicts of Interest

All authors declare that they have no conflicts of interest.

Authors’ Contributions

Xianmei Zhou and Hailang He conceived and designed theproject. Ailing Cao performed the review. Ailing Cao andHailang He analyzed the data and wrote the paper. XianmeiZhou was responsible for quality control of the study. Dr.Ailing Cao and Dr. Hailang He contributed equally to thiswork.

Acknowledgments

This work was supported by the Project of Key Discipline forTCM Construction of Jiangsu Province, China (no. JS1302).

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