Xiao-ai-ping injection adjunct with platinum-based chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis

Background Xiao-ai-ping injection (XAPI), as patented Chinese medicine, has shown promising outcomes in non-small-cell lung cancer (NSCLC) patients. This meta-analysis investigated the efficacy and safety of XAPI in combination with platinum-based chemotherapy. Methods A comprehensive literature search was conducted to identify relevant studies in Pubmed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Wangfang Database, VIP Database, and Chinese Biology Medical Database from the date of their inception to September 2018. The RevMan 5.3 software was applied to calculate the risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). Results We included and analyzed 24 randomized controlled trials. The meta-analysis showed that XAPI adjunctive to platinum-based chemotherapy had better outcomes in objective tumor response rate (ORR) (RR: 1.27, 95% CI, 1.14–1.40); improved Karnofsky performance scores (KPS) (RR: 1.70, 95% CI, 1.48–1.95); reduction in occurrence of grade 3/4 leukopenia (RR: 0.49, 95% CI, 0.38–0.64), anemia (RR: 0.63, 95% CI, 0.46–0.87) and thrombocytopenia (RR: 0.53, 95% CI, 0.38–0.73), nausea and vomiting (RR: 0.57, 95% CI, 0.36–0.90); and enhanced immune function (CD8+ [MD: 4.96, 95% CI, 1.16–8.76] and CD4+/CD8+ [MD: 2.58, 95% CI, 1.69–3.47]). However, it did not increase dysregulated liver and kidney function, diarrhea, constipation, and fatigue. Subgroup analysis of ORR and KPS revealed that dosage, treatment duration, and methodological quality did not affect the outcome significantly. Conclusions Our meta-analyses demonstrated that XAPI in combination with platinum-based chemotherapy had a better tumor response, improved the quality of life, attenuated adverse side effects, and enhanced immune function, which suggests that it might be used for advanced NSCLC. Moreover, low dosage (< 60 ml/d) and long-term treatment of XAPI might be a choice for advanced NSCLC patients.


Background
Lung cancer is becoming a health burden in recent years, despite some advances in treatment in the past few decades [1]. It remains one of the leading causes of cancer-related death worldwide, with approximately 1.8 million new lung cancer cases and 1.6 million deaths per year [2]. Non-small-cell lung cancer (NSCLC) is the common subgroup, which accounts for approximately 85% of lung cancer cases [3] and most NSCLC patients present with advanced-stage, unresectable disease. Platinum-based chemotherapy is still the cornerstone for the treatment of advanced NSCLC [4], with response rates of 25 to 35% and 1-year survival rate of about 30 to 40% [5]. However, platinum-based dual chemotherapy might result in frequent adverse effects and prevent completion of the recommended period of treatment, which finally may affect the therapeutic efficacy [6]. Therefore, there is a need to develop new strategies to maximize tumor control and minimize adverse effects in patients with advanced NSCLC.
Recently, many trials have reported that XAPI in combination with platinum-based chemotherapy is superior in improving objective tumor response, decreasing the severe adverse side effects, improving the quality of life and ameliorating symptoms in patients with advanced NSCLC. However, in some Chinese clinical trials, it is uncertain whether there is robust evidence on the efficacy and safety of XAPI as an adjuvant therapy to platinum-based chemotherapy. Thus, we conducted a comprehensive systematic review on the efficacy and safety of XAPI as an adjunctive therapy for advanced NSCLC.

Data resources and searching strategies
To explore the efficacy and safety of XAPI on patients with advanced NSCLC, relevant electronic data sources, including PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database and Chinese Biology Medical  This research was conducted by two independent reviewers (FCF and ZCW), and any discrepancies were resolved either by discussion or by a third author (HLH).

Inclusion and exclusion criteria
Studies satisfying the following criteria were included: All studies that did not meet the abovementioned inclusion criteria were excluded. In addition, studies were also excluded, if they were review articles, animal experiments, duplicated publications, inappropriate interventions, or they if did not present sufficient data.

Outcome measures
The primary outcomes included ORR and improvement of KPS. ORR was considered as an indicator of antitumor  [19]. ORR was calculated by adding the complete response (CR) and partial response (PR). KPS was considered as an indicator of the quality of life in NSCLC patients after treatment [20]. An increase or decrease of 10-points in the KPS was regarded as an improvement or deterioration of quality of life, respectively. Hence, the improved performance status of patients was investigated and set as another primary outcome. In addition, secondary outcomes included reduction in grade 3/4 myelosuppression, nausea and vomiting, other adverse side effects (e.g. dysregulated liver and kidney function, diarrhea, constipation and fatigue), and immune function effects (the percentage of CD4 + , CD8 + , CD4 + /CD8 + ).

Data extraction and quality assessment
Data were extracted by two independent reviewers (FCF and JRZ) and the divergences were resolved by discussion with the third expert adjudicator (HLH). From the eligible articles, the following data were collected, (1) basic information such as the name of the first author, publication year, and language; (2) patient demographics, including the number of patients, performance status, and TNM stage in each group; and (3) detailed interventions, duration of treatment, and outcomes. The quality of the included studies was assessed according to the criteria in the Cochrane Handbook for the Systematic Reviews of Interventions (version 5.1.0) [21]. The seven aspects evaluated in the report were random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selecting reporting and other bias. Each aspect was categorized as a high, low, or uncertain risk. Furthermore, the quality of each trial was also assessed quantitatively with a scoring system from 0 to 14, which evaluated the following aspects including randomization, blinding, analysis, patient selection, comparability of groups at baseline, extent of follow-up, treatment protocol, cointerventions, and outcomes, as shown in Additional file 7: Table S1 [22]. This assessment strategy has been widely used in previous meta-analysis publications [23,24]. Therefore, we adopted it in our study. The two independent reviewers (FCF and QW) performed the assessment and the disagreement was resolved by discussion or consulting the expert adjudicator (XMZ).

Subgroup analysis
Pre-specified subgroup analyses were performed to determine the potential causes of heterogeneity in the effects of XAPI on the primary outcomes. It was hypothesized that the treatment efficacy of XAPI was higher in trials using: i) a higher XAPI dose (≥ 60 ml per day) rather than lower dose usage; ii) a longer duration (> 14 days) rather than shorter duration, and iii) those with a low methodological quality (as studies with a higher methodological quality tend to exhibit more modest treatment effect).

Statistical analysis
Data were analyzed using RevMan 5.3. Pooled risk ratio (RR) and 95% confidence interval (95% CI) were used for statistical analysis of dichotomous variables, while statistical analysis for continuous variables was performed using mean difference (MD) and 95% CI. If the heterogeneity present in pooled studies (I 2 ) was > 50% and/or P < 0.1, a random-effect model was used. Otherwise, a fix-effect model was applied. Outcomes were calculated using P values and P < 0.05 was considered statistically significant. Funnel plots were applied to evaluate the potential publication bias for primary outcomes if more than ten studies were included for a meta-analysis. Publication bias was further evaluated by Begg's test using Stata 14.0 software.

Data collection
Overall, 271 potentially relevant articles were identified from the seven databases in the initial search. After removing duplicated articles, the titles and abstracts of the remaining 100 studies were screened, and 57 records were removed owing to inappropriate intervention (n = 19), animal or in vitro experiments (n = 25), review articles (n = 8), combination with herbs extracts other than XAPI (n = 3), and treatment for malignant pleural effusions (n = 2). Subsequently, the full-text of 43 articles were screened, and eight were excluded because of repeated data, retrospective nature of the study, incomplete raw data, and inappropriate control group. Finally, 24 were included in the meta-analysis after removing studies that did not provide detailed TNM stage. A flow diagram of the selection process is presented in Fig. 1.

Characteristics of the included studies
Twenty-four studies    author name, year of publication, case number, performance status, pathological TNM stage, interventions, and outcomes, are presented in Table 1.

Methodological bias of the included studies
The risk of bias for each study was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. All 24 studies declared the randomization, but only eleven [26-28, 30, 34-36, 39, 40, 44, 46] provided the details of the randomization process. Allocation concealment or blinding procedure was not mentioned. Only one study reported the drop-out data. No selective reporting bias was observed among all the trials. The presence of other bias was unclear. The detailed delineation of methodological quality of the included studies is summarized in Fig. 2. According to the score system we used in this meta-analysis, the mean methodologic score of the individual trials was 7.7 and median was 7.5 (range 7-9). The individual methodologic scores of each trial are available in Table 1.

Primary outcomes
Objective tumor response rate ORR was reported in all 24 studies, for a total of 1725 patients . As shown in Fig. 3, there was no significant heterogeneity (I 2 = 0%, p = 1.00) among the   Fig. 5c) than those who received platinum-based chemotherapy alone.
The XAPI dose had no significant influence on the ORR, as shown in Fig. 9 and Additional file 1: Figure S1.

Publication bias
To identify the publication bias among the eligible studies, funnel plots and Begg's test were utilized. As shown in Fig. 11, the funnel plots were asymmetric for ORR and improved KPS, suggesting potential publication bias. Begg's test further confirmed that publication bias did not exist, as the P value for objective tumor response and improvement of KPS were 0.843 and 0.087, respectively.

Discussion
In China, many patented Chinese medicines have been clinically integrated with standard chemotherapy in cancer patients for many years [49,50]. However, their effectiveness is still a controversy worldwide due to the lack of systematic reviews summarizing the present evidence. Marsdenia tenacissima is known as "Tong-guan-Teng" or "Tong-guang-san" in Traditional Chinese Medicine (TCM) and its use was first recorded in 'Dian Nan Ben Cao' compiled by M-Lan dating back to Ming Dynasty. Its dried stems have been used for treating several kinds of diseases such as cancer, pneumonia, and tonsillitis. The extract of Marsdenia tenacissima has been available in China as a patented Chinese medicine named Xiao-ai-ping and is widely used for several cancers including NSCLC [51]. According to TCM, it is capable of relieving cough and asthma, eliminating phlegm, purging heat and has detoxifying effects. Modern pharmacology has identified polyoxypregnanes as the main effective ingredient, which can modulate Pglycoprotein and reverse multiple drug resistance in cancer [52]. XAPI could target apoptosis and autophagy leading to the death of NSCLC cells death [53]. Therefore, XAPI might enhance the efficacy of platinum-based chemotherapy. In addition, polysaccharide, another active ingredient of XAPI, can regulate the immune function and suppress tumor growth in mice [54]. Furthermore, XAPI can inhibit the migration of A549 cells [55], and serve as a potential anti-angiogenesis agent [56]. Taken together, XAPI might enhance the clinical efficacy of chemotherapeutic regimens by overcoming drug resistance, immunomodulation, and prevention of metastasis and tumor angiogenesis.
In the present meta-analysis, 1797 patients involved in 24 RCTs, were evaluated for the efficacy of XAPI in combination with platinum-based chemotherapy. The results of this meta-analysis showed that XAPI plus platinum-based chemotherapy was associated with better outcomes than platinum-based chemotherapy alone, as evidenced by higher ORR and improvement in KPS. In our subgroup analysis of different regimens, XAPI showed a relatively high ORR in the TP and GP regimens, which suggested that XAPI might play a synergistic effect in these subgroups. In addition, XAPI could improve the quality of life for NSCLC patients in all the subgroups, by increasing KPS. These results were encouraging and demonstrated that XAPI not only locally inhibit tumor growth but also improve the overall quality of life in NSCLC patients.
Adverse side effects are inevitable in most patients with advanced NSCLC receiving platinum-based chemotherapy, the severity of which can lead to treatment cessation in some cases. Myelosuppression and gastrointestinal reactions are the common platinum-based side effects. Study of the data showed, leukopenia, thrombocytopenia, anemia, nausea, and vomiting were the common grade 3/ 4 adverse side effects and our meta-analysis results revealed a significant reduction in their occurrence when XAPI was added to the platinum-based chemotherapy. Moreover, other side effects including dysregulated liver and kidney function, diarrhea, constipation, and fatigue, were also considered in this meta-analysis. The results showed that XAPI combined with chemotherapy did not increase the toxicity in the liver and kidney, which suggests that XAPI did not bring any metabolic burden to these organs. XAPI also did not cause more events in diarrhea, constipation, and fatigue, when combined with chemotherapy. Therefore, our results demonstrated that XAPI add-on platinum-based chemotherapy could decrease the platinum-based drugs induced severe myelosuppression and, nausea and vomiting but did not increase other side effects, supporting the efficacy and safety of XAPI.
In addition, immune function plays a vital role in lung cancer. Evidence showed that XAPI could improve the immune function to exert antitumor effects in mice [54]. Hence, the data associated with immune function were pooled into this meta-analysis to determine whether XAPI could potentiate the cellular immunity of advanced NSCLC patients. Though a small number of trials reported on these, the results revealed the percentages of CD8 + and CD4 + /CD8 + cells were increased after treatment with XAPI, but not of CD4 + T cells. Collectively, these results illustrated that XAPI might exert anti-tumor effects by regulating immune function. Furthermore, to address the potential heterogeneity in the primary outcomes, a hypothesis-based subgroup analysis of ORR was performed. The result showed that patients administrated with a low dose of XAPI exhibited better outcomes. It also suggested that doses under 60 ml/d might be the appropriate dose for NSCLC patients. The present meta-analysis also indicated that patients who received long duration treatment might have a higher ORR, though without significant subgroup difference (p = 0.86). Due to limitations in the methodological quality, subgroup analysis revealed better outcomes in studies with low methodological quality than those with high methodological quality. In the subgroup analysis of the KPS, the results were similar to ORR. We found that treatment dose and methodological quality did not influence the KPS. However, the results also demonstrated that advanced NSCLC patients who received long term treatment had a better outcome than those who received short term treatment. Collectively, this present metaanalysis demonstrated the efficacy of XAPI as an adjunctive therapy for advanced NSCLC.
Of note, there were some shortcomings in this metaanalysis. First, all the included studies were susceptible to some bias due to following reasons: flaws in the methodology, since specific method and procedure of the trials were unclear and obscure; dropouts and withdrawals that could not be extracted from the trials; lack of description of the details of randomization and concealment of allocation and blinding, although all the trials referred to randomization; no information on whether the syndrome differentiation based on TCM theory was taken into consideration in diagnostic procedures. Hence, the selection bias, performance bias, and detection bias were likely to be present in this meta-analysis. Second, our results only exhibited the overall efficacy and adverse side effects of XAPI plus platinum-based chemotherapy when compared with platinum-based chemotherapy alone. However, XAPI related efficacy and adverse side effects could not be uncovered in NSCLC patients. Further, there was a lack of information on long-term follow-up to evaluate the efficacy and safety of XAPI. Third, all trials were conducted in China and published in Chinese. Therefore, whether it could be beneficial to a wide population is uncertain. Fourth, the results of our meta-analysis might be affected by various therapeutic dosages and durations of treatment. Finally, we did not contact the authors for detailed information and failed to search for unpublished trials. Altogether, due to the insufficient methodological quality of the included trials, the potential benefits of XAPI for NSCLC patients need to be further verified through high-quality RCTs with rigorous methodology and adequate assessment of the safety profiles of the interventions.

Conclusions
In summary, this meta-analysis suggested that XAPI in combination with platinum-based chemotherapy had a better tumor response, improved the quality of life, attenuated adverse side effects, and enhanced immune function in NSCLC patients. In addition, low dosage and long-term treatment of XAPI might be a choice for advanced NSCLC patients However, the results should be interpreted with caution, due to possible methodological flaws. More well-designed trials with bigger sample sizes and multicenter studies are urgently warranted to confirm this conclusion.