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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 549-555

Effects of Shenfu injection on chemotherapy-induced adverse effects and quality of life in patients with advanced nonsmall cell lung cancer: A systematic review and meta-analysis


Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China

Date of Web Publication24-Sep-2018

Correspondence Address:
Gang Chen
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, No 169 East Lake Road, Wuhan 430071
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187299

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 > Abstract 


Objective: To investigate the efficacy of Shenfu injection (SFI) in reducing chemotherapy-induced adverse effects in nonsmall cell lung cancer (NSCLC) patients by conducting a meta-analysis.
Methods: A systematic review of Cochrane Library, PubMed, Embase, CNKI, Chinese Biomedical Literature Database, VIP, and Wanfang Database was performed from their inception to December 2015. Eligible studies were randomized controlled trials (RCTs) comparing chemotherapy with or without SFI for patients with NSCLC. The main outcomes were improvement in chemotherapy-induced grade 3/4 marrow suppression (leukopenia, neutropenia, anemia, and thrombocytopenia) or gastrointestinal toxicities (nausea and vomiting, diarrhea, and constipation), quality of life, and T-lymphocytes subsets.
Results: Sixteen RCTs involving 948 patients were identified. Compared with chemotherapy alone, SFI plus chemotherapy had lower 3/4 grade toxicity for leukopenia (risk ratio [RR] 0.34; 95% confidence intervals [95% CIs] 0.21–0.55), thrombocytopenia (RR 0.36; 95% CI 0.19–0.71), anemia (RR 0.39; 95% CI 0.16–0.99), nausea and vomiting (RR 0.29; 95% CI 0.14–0.58), and diarrhea (RR 0.21; 95% CI 0.07–0.63), Moreover, SFI plus chemotherapy significantly increased Karnofsky Performance Status (weighted mean difference 11.34; 95% CI 7.26–15.42).
Conclusions: Adjuvant treatment with SFI improves the quality of life, attenuates the chemotherapy-induced gastrointestinal toxicities and bone marrow suppression, thus improving compliance to chemotherapy in patients with NSCLC. As for limited English literature about SFI and NSCLC, only trials publishing in the Chinese were included in the meta-analysis. More well-designed multicenter RCTs are needed before a definitive conclusion can be drawn.

Keywords: Adverse effects, meta-analysis, nonsmall cell lung cancer, quality of life, Shenfu injection


How to cite this article:
Chen G. Effects of Shenfu injection on chemotherapy-induced adverse effects and quality of life in patients with advanced nonsmall cell lung cancer: A systematic review and meta-analysis. J Can Res Ther 2018;14:549-55

How to cite this URL:
Chen G. Effects of Shenfu injection on chemotherapy-induced adverse effects and quality of life in patients with advanced nonsmall cell lung cancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2018 [cited 2018 Oct 24];14:549-55. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/549/187299




 > Introduction Top


Lung cancer is the leading cause of cancer-related mortality worldwide.[1] According to the broad histological types, lung cancer can be classified as nonsmall cell lung cancer (NSCLC) or SCLC. NSCLC comprises approximately 85% of all incidences of lung cancer.[2] Surgical resection is the preferred treatment for early stage NSCLC. However, approximately 70% of the cases have been diagnosed with local advanced or metastatic stage, typically unresectable cancer.[3] Chemotherapy is the dominant standard therapy for treatment of unresectable NSCLC.[4] Unfortunately, many patients have difficulty in completing the recommended number of dose cycles because of the chemotherapy-induced adverse effects.[5]

Chinese herbal medicine is frequently combined with chemotherapy in the treatment of lung cancer. Shenfu injection (SFI), derived from Shenfu decoction, is a preparation of an extract from Red Ginseng and black aconiti, with the active ingredients of ginseng saponin and aconitum alkaloids. SFI has been used as adjuvant treatment for alleviating the chemotherapy-induced adverse effects in patients with NSCLC[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17] and improving quality of life.[18],[19],[20],[21] This study aimed to investigate the efficacy of SFI in reducing chemotherapy-induced adverse effects in patients with NSCLC by conducting a meta-analysis on available studies.


 > Methods Top


Search strategy

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.[22] A systematic literature search was conducted in Cochrane Library, PubMed, Embase, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP, and Wanfang Database from their inception to December 2015. The search key words were Shenfu injection OR Shenfu OR Ginseng OR aconiti praeparata AND nonsmall cell lung cancer OR NSCLC. The literature search was limited to randomized clinical trials (RCTs). No restrictions were implicated on the publication language. References lists of the included trials and relevant reviews were manually searched to identify additional articles.

Trials selection

The trials satisfying the following criteria were included: (1) Study design: RCTs; (2) participants: age ≥18 years with diagnosis of NSCLC by pathology or cytology; (3) type of intervention: SFI in combination with standard chemotherapy versus chemotherapy alone; (4) outcome measures: reporting at least one of the following outcome measures: grade 3/4 marrow suppression (leukopenia, neutropenia, anemia, or thrombocytopenia) or gastrointestinal toxicities (nausea and vomiting, diarrhea, and constipation) assessing by the World Health Organization Hematological Toxicity Scale,[23] and quality of life using the Karnofsky Performance Status (KPS).[24] Improvement in quality of life was calculated as the proportion of >10-point KPS increment divided by the total.[25] Studies were excluded based on the following criteria: (1) The design of the study was not RCTs; (2) duplicated publications or overlapping study population; and (3) use of other type of Shenfu formula as in the experimental group.

Data extraction and quality assessment

The following data were extracted from the original trials: (1) baseline demographics ( first authors' surname and publication year); (2) participants (sample size and age); (3) SFI intervention (dose and treatment duration); (4) chemotherapy regimen; (5) number of chemotherapy cycles; and (6) outcome measures. We contact the corresponding author through E-mail or telephone for additional information. The methodological quality of each study was evaluated in accordance with the guidelines in the Cochrane reviewers' handbook.[26] The quality of each study was reported as low risk of bias, high risk of bias, and unclear risk of bias.

Statistical analysis

All the meta-analyses were performed using the STATA statistical software (version 12.0, StataCorp LP, College Station, TX, USA). The dichotomous data were calculated as risk ratio (RR) and 95% confidence intervals (95% CIs), and continuous data were calculated as weighted mean difference (WMD) and 95% CI, respectively. Homogeneity across trials was assessed using the Cochrane Q statistic and I2 statistic. P < 0.10 from the Cochrane Q statistic and I2 >50% was considered as an indicator of significant heterogeneity.[27] We selected a random effects model when the heterogeneity was observed; otherwise, a fixed-effect model was applied. Potential publication bias was tested by the Begg's rank correlation test and Egger's linear regression test. P < 0.05 was defined as statistically significant for all analyses.


 > Results Top


Study characteristics

After application of search strategy, a total of 329 potentially relevant articles were identified. After the full-text articles assessed for eligibility, only 16 RCTs[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] involving 948 patients (SFI plus chemotherapy, n = 480; chemotherapy alone, n = 468). Met our predefined inclusion criteria [Figure 1]. All the included trials were conducted in China and published in Chinese. Of the included trials, the most common chemotherapy regimens were vinorelbine plus cisplatin (NP),[6],[8],[10],[11],[12],[13],[14],[21] docetaxel plus cisplatin (DP),[16],[17],[18],[20] and gemcitabine plus cisplatin (GP).[7],[9],[15] The cycle of chemotherapy regimen varied from 2 to 4. SFI was used at the start of chemotherapy by intravenous injection and accompanied by the chemotherapy. The dosage of SFI ranged from 50 to 100 ml/day. The detailed characteristics of the included trials are listed in [Table 1]. According to the Cochrane risk bias tool, all the trials were generally classified as low quality of unclear risk of bias [Figure 2].
Figure 1: Flow chart showing the trials selection process

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Table 1: Summary of trials included in the meta-analysis

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Figure 2: Risk of bias graph (a) and risk of bias summary (b)

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Improvement in bone marrow suppression

Of the included trials, 11 trials[6],[7],[8],[9],[10],[11],[12],[13],[15],[16],[17] reported the number of patients with grade 3/4 leukopenia, five trials[6],[7],[10],[15],[17] reported the number of patients with grade 3/4 neutropenia, six trials[7],[9],[10],[11],[15],[16] reported the number of patients with grade 3/4 anemia, and six trials reported the number of patients with grade 3/4 thrombocytopenia. As shown in [Figure 3], SFI plus chemotherapy was associated with significantly lower risk of leukopenia (RR 0.34; 95% CI 0.21–0.55), anemia (RR 0.39; 95% CI 0.16–0.99), and thrombocytopenia (RR 0.36; 95% CI 0.19–0.71), but not for neutropenia (RR 0.78; 95% CI 0.41–1.48) compared with chemotherapy alone.
Figure 3: Forest plots showing comparison of improvement in grade 3/4 bone marrow suppression comparing Shenfu injection plus chemotherapy to chemotherapy alone

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Reduction in gastrointestinal toxicities

Eight trials[7],[9],[10],[12],[13],[15],[16],[17] reported the number of patients with grade 3/4 nausea and vomiting, five trials[7],[10],[12],[16],[17] reported the number of patients with grade 3/4 diarrhea, and four trials[7],[10],[16],[17] reported the number of patients with grade 3/4 constipation. As shown in [Figure 4], SFI plus chemotherapy was associated with significantly lower risk of nausea and vomiting (RR 0.29; 95% CI 0.14–0.58) and diarrhea (RR 0.21; 95% CI 0.07–0.63), but not for constipation (RR 0.49; 95% CI 0.13–1.93) compared with chemotherapy alone.
Figure 4: Forest plots showing comparison of reduction in grade 3/4 gastrointestinal toxicities comparing Shenfu injection plus chemotherapy to chemotherapy alone

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Improvement in quality of life based on Karnofsky Performance Status

The KPS were expressed as either dichotomous data in five trials[9],[14],[15],[16],[21] or continuous data in six trials.[6],[8],[12],[18],[19],[20] As shown in [Figure 5]a and [Figure 5]b, compared with the chemotherapy alone, SFI in combination with chemotherapy significantly increased KPS (WMD 11.34; 95% CI 7.26–15.42) in a random effects model, as well as improved the KPS (RR 1.90; 95% CI 1.45–2.50) in a fixed-effect model.
Figure 5: Forest plots showing comparison of improvement in Karnofsky Performance Status as continuous (a) or dichotomous data (b) comparing Shenfu injection plus chemotherapy to chemotherapy alone

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Changes of T-lymphocyte subsets

Two trials[9],[13] reported the changes of T-lymphocyte subsets. As shown in supplemental [Figure 6], SFI plus chemotherapy significantly increased the proportion of T-lymphocytes CD4+ (WMD 12.33; 95% CI 2.71–21.94) as well as the proportion of CD4+ T-lymphocytes (WMD 12.33; 95% CI 2.71–21.94) compared with chemotherapy alone. However, there was no statically significance in CD3+ T-lymphocytes (WMD 10.89; 95% CI −0.20–21.99) and CD8+ T-lymphocytes (WMD 1.72; 95% CI −8.20–11.65) between with and without SFI treatment.
Figure 6: Forest plots showing comparison of T-lymphocyte subsets comparing Shenfu injection plus chemotherapy to chemotherapy alone

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Subgroup analysis and publication bias

As for grade 3/4 leukopenia and nausea and vomiting were reported in the majority of the included trials, we conducted the subgroup analysis and publication bias on these two outcomes. We conducted subgroup analysis based on the dose of SFI (>50 ml vs. ≤50 ml), chemotherapy regimen (NP vs. GP vs. DP), and publication year (>2010 vs. ≤2010). Results of subgroup analysis are summarized in [Table 2]. Results of Begg's and Egger's test for publication bias were summarized in [Table 3].
Table 2: Subgroup analyses on leukopenia and nausea and vomiting

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Table 3: Results of Begg's and Egger's test for publication bias

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 > Discussion Top


Our meta-analysis focused on the use of SFI as an adjuvant treatment for patients receiving chemotherapy for NSCLC. The major findings of this study provide evidence that adjuvant treatment with SFI can attenuate the chemotherapy-reduced gastrointestinal toxicities, prevent leukopenia, anemia, and thrombocytopenia as well as improve the quality of life. Moreover, SFI showed a beneficial effect in modulating T-lymphocytes subsets.

Toxicity is a severe concern that chemotherapy is facing. Chemotherapy-reduced adverse events are considered an important cause for treatment adjustment and/or discontinuation in clinical settings. Gastrointestinal toxicity is common adverse reaction during chemotherapy including nausea, vomiting, diarrhea, and constipation. Chemotherapy-induced nausea and vomiting can be either acute (commencing shortly after administration and most severe during the next 6–8 h) or delayed (occurring after 24 ours). In this study, SFI in combination with chemotherapy reduced 71% nausea and vomiting rate and 79% diarrhea rate than chemotherapy alone. However, reduction in nausea and vomiting was not significant in SFI plus NP regimen (RR 0.49; 95% CI 0.21–1.12) and SFI dose ≤50 ml (RR 0.40; 95% CI 0.12–1.21) in the subgroups analysis. Therefore, clinicians should be aware of the regimen of chemotherapy and dose of SFI before application of SFI. In addition, the constipation rate was similar in patients who received SFI in combination with chemotherapy and chemotherapy alone.

In addition to reducing gastrointestinal toxicity, adjuvant treatment with also showed benefits in improvement in bone marrow suppression. Our study showed that patients receiving chemotherapy plus SFI had a lower rate of leukopenia, anemia, and thrombocytopenia. Different chemotherapy regimen resulted in different toxicities in patients. Subgroups analysis indicated that the improvement in leukopenia was not significant in SFI plus GP regimen (RR 0.45; 95% CI 0.17–1.22). This finding suggested that SFI achieved greater improvement in NP- and DP-induced leukopenia.

The majority of the included trials used the KPS scale to assess the quality of life. The KPS was expressed as either dichotomous or continuous data in the original studies. The pooled results showed significant increases in KPS scale in patients treated with SFI plus chemotherapy compared to those treated with chemotherapy alone in the current study. The improvement in quality of life for patients would help to improve the compliance to chemotherapy. In addition, SFI appeared to increase the proportion of T-lymphocytes CD4+. Moreover, SFI plus conventional treatment significantly increased serum levels of IgA, IgM, and IgG in the literature.[28] The beneficial effects of SFI might be correlated with its immunomodulating action.

SFI is a product of traditional Chinese medicine (TCM). It contains ginsenoside 0.8 mg and aconite 0.1 mg in each milliliter of injection, which is the equivalent crude drug of Ginseng 0.1 g and black aconiti 0.2 g.[15] A particular safe problem was the potential adverse effects of toxic aconite use. However, no significant hepatic or renal dysfunction was reported in either SFI in combination with chemotherapy or chemotherapy alone group in the included trials. The most frequent reported adverse events of SFI in the literature included stretching head, dry mouth, irritability, insomnia, and facial flushing.[29] Therefore, medical practitioners should be aware of the potential adverse effects associated with SFI.

This meta-analysis had several limitations. First, methodological weaknesses of the included trials were the main concerns. The trials reported randomization, but most of them did not give sufficient information on the detail of randomization method. In addition, lack of sufficient descriptions of study design, allocation concealment, withdrawal/dropout, and adverse events. Second, we only investigated the efficacy of SFI for attenuating the adverse effects during chemotherapy but not assess the potential clinical efficacy of SFI in NSCLC. Third, potential publication bias cannot be excluded due to all the included trials were conducted in China, and most of them were not listed in the PubMed. Finally, patient selection was only based on Western approach; a number of patients might be not suitable for the TCM pattern. Pattern differentiation should be considered in the patients' diagnostic process.[25] The inclusion of pattern differentiation into the diagnostic process will improve the efficacy of SFI.


 > Conclusions Top


This meta-analysis suggests that adjuvant treatment with SFI can improve the quality of life, attenuate the chemotherapy-induced gastrointestinal toxicities and bone marrow suppression thus improving compliance to chemotherapy in patients with NSCLC. However, these tentative conclusions need to be confirmed by more high-quality trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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