Compound Taxus chinensis Capsule Combined with Chemotherapy for Non-Small-Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Compound Taxus chinensis capsule (CTCC), an antitumor Chinese patent medicine, has been commonly prescribed as an adjunctive agent to chemotherapy for the management of non-small-cell lung cancer (NSCLC); however, the effects of CTCC added to chemotherapy for NSCLC patients have never been comprehensively evaluated or summarized. Purpose To assess the synergistic effects of CTCC and chemotherapy on NSCLC. Study Design. Evidence-based study, systematic review, and quantitative meta-analysis. Methods This systematic review and meta-analysis was implemented in accordance with the PRISMA (Preferred Reported Items for Systematic Review and Meta-Analysis) guidelines. Eight databases including China National Knowledge Infrastructure, SINOMED, China Biomedical Literature Database, Wanfang Database, VIP, PubMed, Cochrane Library, and EMBASE were searched for relevant RCTs from their inception until May 24, 2021, and hand-searching was also carried out to identify additional studies. All randomized controlled trials (RCTs) that compared CTCC combined with chemotherapy versus chemotherapy alone were included in our study. The Cochrane Risk-of-Bias tool was used to determine the risk of bias and methodological quality of the included RCTs. Review Manager 5.3 software was used for comprehensive analysis. The primary outcome measure for this study was the disease control rate (DCR), and the secondary outcomes included the objective response rate (ORR), adverse reactions, and quality of life (QOL). Results Six RCTs with a total sample size of 410 were finally included. The pooled data showed that, compared with chemotherapy alone, CTCC combined with chemotherapy significantly improved DCR (RR = 1.15, 95% CI: 1.06–1.25, P = 0.006), ORR (RR = 1.38, 95% CI: 1.18–1.63, P < 0.00001), and QOL (MD = 8.69, 95% CI: 7.26–10.13, P < 0.006) and reduced the incidence of total adverse reactions (RR = 0.48, 95% CI: 0.38–0.60, P < 0.00001). The subgroup analyses indicated that CTCC plus chemotherapy significantly improved gastrointestinal reactions (P = 0.004), leukopenia (P = 0.0009), thrombocytopenia (P = 0.01), rash (P = 0.002), and fever (P = 0.007). Conclusion Based on the available evidence, compared with chemotherapy alone, CTCC used as an adjunctive agent to chemotherapy for NSCLC can improve the clinical efficacy and quality of life and decrease the likelihood of adverse reactions, suggesting that CTCC might be an effective and safe adjunctive medicine to chemotherapy for NSCLC. However, considering the relatively small sample size and the inherent imperfections of the included randomized controlled trials, more high-quality clinical trials with longer follow-up time are needed to further assess the efficacy and safety of this combined treatment regimen.


Introduction
According to the Global Cancer 2020 Statistics (GLOBOCAN 2020) [1], there were 19.3 million new cases of malignant tumors worldwide and approximately 10 million deaths from malignant tumors worldwide. By 2020, there were about 1.8 million lung carcinoma deaths which accounted for 18% of all carcinoma death [2]. Lung carcinoma is still the main cause of cancer-related deaths, and non-small-cell lung cancer (NSCLC) is the most common, accounting for about 80−90% of all cases of lung carcinomas [3]. Surgical operation is currently the first choice for the remedy of lung cancer, but it often brings heavy pain to patients, and most patients are not suitable for surgery once they are diagnosed with this disease. Although immunotherapy and targeted therapy have remarkably improved the clinical outcomes of patients with NSCLC, chemotherapy is still an irreplaceable treatment method for many patients who lack specific biomarkers or access to these therapies. Because chemotherapy is often associated with more adverse reactions, such as myelotoxicity and gastrointestinal symptoms, many patients cannot tolerate it. e quality of life (QOL) in lung cancer patients undergoing chemotherapy is usually poor. erefore, it is still a pressing need to look for optimal lung cancer treatment which not only effectively improves the clinical treatment efficacy but also reduces the physical, psychological, and economic burden of patients.
In recent decades, a lot of clinical studies have proved that traditional Chinese medicine plus chemotherapy has some advantages, as Chinese medicine might increase the response to chemotherapy and alleviate the adverse reactions of patients with NSCLC [4][5][6]. Compound Taxus chinensis capsule (CTCC) is an antitumor drug and has been increasingly prescribed as an adjunctive treatment to chemotherapy for the management of NSCLC. A few clinical trials have suggested that this combination treatment might bring benefits to the patients with NSCLC. However, due to the small sample sizes, most of the clinical studies provided insufficient evidence and had only borderline statistical power; therefore, a meta-analysis was needed to combine these clinical trial data, thus increasing the sample size and the power to obtain a more precise and stable estimate of the effect of CTCC plus chemotherapy on NSCLC patients, which has never been performed before. is evidence-based study was carried out to assess the effectiveness and safety of CTCC in combination with chemotherapy for NSCLC patients, aiming to obtain important evidence for the clinical application of this combined treatment regimen.

Materials and Methods
Following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines [7], we performed this systematic review and meta-analysis of RCTs that compared CTCC plus chemotherapy versus chemotherapy for NSCLC.

Types of Interventions.
e control group was treated with chemotherapy alone, and the experimental group was treated with CTCC plus chemotherapy.

Types of Outcome Measures.
In this study, the primary outcome measure was the disease control rate (DCR), and the secondary outcomes included the objective response rate (ORR), adverse reactions, and quality of life (Karnofsky score).
Following the WHO criteria [8,9], the common indicators for reporting the results of cancer treatment included progressive disease (PD), stable disease (SD) or no change (NC), partial response (PR), and complete response (CR). DCR and ORR are defined as DCR � (CR + PR + SD)/ total × 100%, ORR � (CR + PR)/total × 100%. Both outcomes are commonly used for evaluating the response to cancer treatment.
KPS is a common index to evaluate the quality of life. e higher the score, the better the quality of life. Adverse reactions refer to the chemotherapy-induced adverse drug reactions which include gastrointestinal reactions, leukopenia, thrombocytopenia, rash, and fever.  e Chinese databases were searched using the following terms: ("Fufanghongdonsan" (compound Taxus chinensis)' OR "Fufanghongdonsan jiaonang" (compound Taxus chinensis capsule) AND "feiai" (lung cancer) OR "feixiaoxibaofeiai" (non-small-cell-lung cancer OR carcinoma) AND "hualiao" (chemotherapy). e following terms were used to retrieve studies in the English databases: (("compound Hongdoushan capsule" OR "compound Taxus chinensis capsule") AND ("non-small-cell lung cancer" OR "non-smallcell lung carcinoma," "non-small-cell lung carcinomas" OR "non-small-cell lung" OR "lung cancer, non-small-cell" OR "lung carcinomas, non-small-cell" OR "lung carcinomas, non-small-cell" OR "cancer, non-small cell lung" OR "carcinoma, non-small cell lung") AND ("chemotherapy" OR "chemotherapeutics" OR "chemotherapeutic agents" OR "chemotherapeutic drugs")). A search strategy for PubMed with PICO model was presented as an example in the Appendix.

Screening and Evaluation of Literature Data.
e studies were screened and summarized, and the information was extracted and cross-checked by two independent researchers (KS Li and HB Cheng). If there was a disagreement, a third reviewer (QB Wu) would be invited to discuss and solve the disagreement. Data extraction included (a) the headline of the paper, the lead author, and issuing time; (b) the total RCT sample, the sample size, and the interventions in either group; (c) outcome measures including DCR, ORR, KPS, and adverse reactions. e Cochrane Risk-of-Bias tool was utilized to assess the methodological quality of all included RCTs and the risk of bias across the studies according to the following items: the random sequence generation, the allocation concealment, the blinding methods, the incomplete outcome data, the selective outcome reporting, and other bias sources. e bias risk was graded as high risk of bias (-), unclear risk of bias (?), and low risk of bias (+).

Statistical Analysis
Methods. RevMan 5.4.1 software was applied for this meta-analysis. e continuous data were represented by weighted mean difference (WMD) or standardized mean difference (SMD) with 95% CI. e dichotomous data were represented by risk ratio (RR), risk difference (RD), or odds ratio (OR) with 95% confidence intervals (CI). e chi-square and I 2 tests were used to evaluate the potential heterogeneity. When there was statistical homogeneity between studies (I 2 < 50%, P > 0.1), meta-analysis was carried out using the fixedeffects model. If there was substantial heterogeneity (I 2 ≥ 50%, P < 0.1), meta-analysis was performed using the random-effects model, and heterogeneity was further addressed by sensitivity analysis, subgroup analysis, etc. [10,11].

Main Features of the Included RCTs.
Six RCTs with a total sample size of 410 were finally included. e experimental and control groups have equal samples sizes. e experimental group was treated with CTCC combined plus chemotherapeutic drugs, and the patients in the control group received chemotherapy alone. e main features of the six RCTs included in our study are shown in Table 1.

Quality of the Included RCTs.
Among the 6 RCTs, two trials [15,18] clearly described the randomization method (the random number table method) in terms of random sequence generation. Randomization was used in the remaining four RCT [14,16,17,19], but they did not clearly describe the randomization method. In most studies, the allocation concealment, the blindness of the participants, the age of each person, the evaluation of the results, and the selective reporting were not clear. In all the included RCTs, the data were intact. Other risk of bias was unclear. e specific results are shown in Figures 2 and 3.

Meta-Analysis Results.
e meta-analysis results are shown in Table 2.

DCR and ORR.
All the six included RCTs reported the short-term clinical efficacy of CTCC in combination with chemotherapy for the management of NSCLC (DCR, ORR). Meta-analysis results indicated that, compared with chemotherapy alone, CTCC plus chemotherapy significantly improved the DCR (RR � 1.15, 95% CI: 1.06-1.25, P � 0.006) and ORR (RR � 1.38, 95% CI: 1.18-1.63, P < 0.00001). ere was statistical homogeneity for these two outcomes (both I 2 � 0%), a fixed-effects model was adopted to calculate pooled effect estimates (Figures 4 and 5).

Quality of Life (KPS Health Score).
ere were 3 RCTs [14,18,19] comparing the KPS scores of patients treated with CTCC plus chemotherapy vs. chemotherapy alone.  . e difference between the two groups was statistically significant (P < 0.05) ( Figure 6).

Publication Bias.
Because the total number of the included trials was less than 10, Egger's test and funnel plots were not implemented to assess the potential risk of bias across trials.

Discussion
As one of the widely used antitumor drugs in China, CTCC has been broadly utilized as an adjunctive drug treatment to chemotherapy for the management of NSCLC, but the effectiveness and safety of CTCC combined with chemotherapy for NSCLC have never been systematically assessed. e current meta-analysis demonstrates for the first time the synergic effects of CTCC and chemotherapy on the clinical outcomes of NSCLC patients. e findings of this evidence-     [20]. Taxus chinensis is the monarch herb of CTCC and possesses many components of taxanes, such as paclitaxel, 10-deacetylbaccatin III, baccatin III, and cephalomannine. Paclitaxel is the most important active component and has been widely used as an anticancer drug [20][21][22], which can suppress cancer cell mitosis and induce cell apoptosis [23]. e major active components of red ginseng are several ginsenosides, such as ginsenoside Rg1, Re, and Rb1, which can enhance immune function and suppress cancer cell proliferation. e major active ingredients of Gancao include glycyrrhizin, liquiritin, and      [7.26,10.13] Heterogeneity: Chi 2 = 0.80, df = 2 (P = 0.67); I 2 = 0% -10 -5 0 5 1 0 Test for overall effect: Z = 11.85 (P < 0.00001) Favours (Control) Favours (Experimental) Test for subgroup differences: Not applicable Evidence-Based Complementary and Alternative Medicine glycyrrhetinic acid [24]. Glycyrrhizin can release glucuronic acid and combine with the poison containing carboxyl, hydroxyl groups to reduce the absorption of poisons, thus alleviating the toxic and side effects of drugs. Gancao contains Glycyrrhiza glucan, which can enhance the immune function of the body [25].
Both DCR and ORR are the key outcome measures for reporting the short-term clinical efficacy of anticancer therapy [26][27][28]. A total of 410 sufferers with NSCLC were included in our study. e pooled data of the current metaanalysis clearly suggested that CTCC added to chemotherapy could significantly improve the DCR (RR � 1.15, 95% CI: 1.06-1.25, P � 0.006) and ORR (RR � 1.38, 95% CI: 1.18-1.63, P < 0.00001); CTCC in combination with chemotherapy was significantly better than chemotherapy alone, indicating that CTCC might have synergic interactions with chemotherapy drugs and increase the sensitivity of chemotherapy.
QOL is an important clinical outcome of cancer patients undergoing chemotherapy, to improve QOL representing a main treatment goal [29][30][31]; therefore, it is defined as one of the secondary endpoints in this study.
e meta-analysis result of QOL (MD � 8.69, 95% CI: 7.62-10.13, P < 0.006] revealed that the QOL of lung cancer patients treated with CTCC plus chemotherapy was significantly improved compared with chemotherapy alone (P < 0.00001). However, there were no trials that investigated the long-term effects of CTCC, such as  Figure 7: Forest plots representing the pooled risk ratio of the incidence of toxicities between the experimental and control groups. 8 Evidence-Based Complementary and Alternative Medicine survival rates of patients with lung cancer; therefore, it is necessary to perform more relevant clinical trials to evaluate more survival outcomes and further examine the long-term effectiveness of CTCC. is meta-analysis has a few limitations: (a) only six studies were eligible and included in our systematic review and the overall quality of them was not high. Only two clearly described the method of randomization procedures [15,18], and most did not distinctly depict the methods of randomization, concealment of allocation, or methods of blinding, which might have undermined the reliability of evidence to some extent. (b) e follow-up periods of the six included studies were relatively short, and no long-term outcomes were evaluated. (c) Due to the limited number of the included RCTs, it was infeasible to apply Egger's test or funnel plots to examine the possible publication bias. (d) Due to the insufficient individual data, sensitivity and subgroup analyses based on chemotherapy regimen, pathological type of lung cancer, or treatment duration, etc. were inadequate or infeasible.

Conclusion
Based on the available evidence, compared with chemotherapy alone, CTCC used as an adjunctive agent to chemotherapy for NSCLC can improve the clinical efficacy and quality of life and decrease the likelihood of adverse reactions, suggesting that CTCC might be an effective and safe adjunctive medicine to chemotherapy for NSCLC. However, considering the relatively small sample size and the inherent imperfections of the included randomized controlled trials, more high-quality clinical trials with longer follow-up time are needed to further assess the efficacy and safety of this combined treatment regimen.

Data Availability
All data are included within the article.

Conflicts of Interest
All the authors declare that they have no conflicts of interest.