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Efficacy of Aidi Injection Combined With Radiotherapy for the Treatment of Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis

Objective: Radiotherapy (RT) is the first choice in the treatment of nasopharyngeal carcinoma (NPC) but there are many adverse reactions. There is evidence that Aidi injection can improve the effect of RT and reduce the occurrence of adverse reactions after RT, but there is still a lack of evidence-based study. The objective of this study was to evaluate the efficacy and safety of Aidi injection combined with RT in the treatment of NPC. Methods: The PubMed, Cochrane Library, CNKI, EMBASE, Web of Science, CBM, Wanfang, and VIP data were thoroughly searched for randomized controlled trials (RCTs) on Aidi injection combined with RT against NPC until February 2021. The literature was screened, extracted, and evaluated by 2 investigators independently. Meta-analysis was performed by RevMan5.3 and Stata 14.0, and the quality of evidence was evaluated by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In this study, we included 9 RCT studies involving 422 patients. The results showed significant between-group differences in complete remission rate (CRR) [relative risk (RR) = 1.17, 95% CI (1.04, 1.31), P = .009], Karnofsky Performance Status Scale (KPS) score [RR = 1.30, 95% CI (1.19, 1.42), P < .00001], leukopenia [RR = 0.65, 95% CI (0.54, 0.78), P < .00001], hemoglobin reduction [RR = 0.60, 95% CI (0.43, 0.84), P = .003], nausea and vomiting [RR = 0.60, 95% CI (0.45, 0.80), P = .0004], oropharyngeal mucosa injury (OMI) [RR = 0.25, 95% CI (0.15, 0.44), P < .00001], but the differences were not statistically significant in total effective rate (TER) [RR = 1.03, 95% CI (0.98, 1.08), P = .20 > 0.05], thrombocytopenia [RR = 0.78, 95%CI (0.52,1.16), P = .22 > .05], and skin injury [RR = 0.81, 95% CI (0.64, 1.04), P = .1 > .05]. Conclusion: Aidi injection combined with RT can improve patients’ quality of life (KPS score) and reduce the adverse reactions caused by RT (such as leukopenia, hemoglobin reductio，OMI，nausea, and vomiting). However, limited by the quality and quantity of the included trials，more high-quality studies should be performed to verify our conclusions.


Introduction
Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelium of nasopharyngeal mucosa. 1 It is characterized by hidden onset, deep lesions, and atypical early symptoms. Therefore, once diagnosed, the condition has been in the middle or advanced stage, and among some patients, tumor metastasis has appeared. Radiotherapy (RT), chemotherapy, and surgery are commonly used for the treatment of NPC. Since this is mostly squamous cell carcinoma, RT is considered as the first choice. 2 However, the RT may damage important organs and tissues around the nasopharynx and neck. This treatment often leads to adverse reactions, such as salivary gland injury, dry mouth, radioactive oropharyngeal mucositis, radioactive dermatitis, and hemotoxic reactions, which reduce the life quality of the patients. 3 and even interrupts the treatment. In some patients whose lesions are under control, local recurrence or distant metastasis may appear later. 4 At present, traditional Chinese medicine (TCM) has been extensively applied against cancers at all stages. It may improve the curative effect of chemoradiotherapy and reduce the occurrence of toxic side effects which has been proved clinically. [5][6][7] Aidi injection (Z52020236, China Food and Drug Administration) is an important TCM injection, which is widely used in the adjuvant therapy of malignant tumors in China. 8 (Table 1). As an anticancer TCM drug, Aidi injection is often used with chemoradiotherapy as an adjuvant therapy for lung cancer, liver cancer, stomach cancer, and so on. [9][10][11] Aidi injection can reduce adverse reactions caused by tumor chemoradiotherapy, for example, gastrointestinal reactions and hepatorenal toxicity. 12,13 It is safe, and may significantly improve patients' life quality after chemoradiotherapy. 12,14 Aidi injection is also being broadly used in nasopharyngeal cancer.
A randomized controlled trial (RCT) 23 reported that Aidi injection combined with RT could improve the life quality score and reduce toxic and side effects. There are more and more similar reports but it is difficult to draw a reliable conclusion from them for lack of systematic evaluation on the efficacy. This paper conducted a meta-analysis on RCTs of Aidi injection combined with RT against NPC so that relevant clinical work and scientific research may have reliable treatment protocols and an evidence-based basis.

Study Registration
The paper was written under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 24 See statement (Supplementary Table S1). The study protocol was registered at https://osf.io/j4uyh/ (DOI 10.17605/OSF.IO/J4UYH).

Eligibility Criteria
Type of Studies. We included all the RCTs only and excluded the reviews and other studies such as cohort, case-control, case series, and qualitative studies. The published abstracts were also excluded when unable to get the details.
Types of Participants. The diagnostic criteria refer to the diagnosis of NPC in Radiotherapy of Oncology. The patient was clearly diagnosed with NPC, whose diagnostic criteria were referred to Radiotherapy of Oncology. 25 The international tumor-node-metastasis (TNM) system was used for tumor grading. 26 Interventions. Treatment group: Aidi injection combined with RT; control group: only the same RT as the treatment group.

Types of Outcome Measures
Primary Outcomes. Primary outcomes are as follows: (1) Karnofsky Performance Status Scale (KPS) and (2) total effective rate (TER). For evaluation criteria, refer to the WHO efficacy evaluation criteria 27 : (i) Complete response (CR): Disappearance of all targeted lesions in two observations no less than 4 weeks interval; (ii) Partial response (PR): a >50% decrease in sum of products of the greatest diameters (SPD) of all lesions; without new lesions nor progression of any lesions; (iii) Stable disease (NC): a 50% decrease or 25% increase in SPD of one or more lesions; and (iv) Progressive disease (PD): a >25% increase over the smallest measurement in the single lesion, or the appearance of new lesions. TER = (CR + PR)/total number *100%.
Secondary Outcome. Secondary outcome indicators are as follows: Toxic and side effects (refer to Radiation Therapy Oncology Group [RTOG]): Criteria for the classification of acute radiation injury) including leukopenia, hemoglobin reduction, thrombocytopenia, oropharyngeal mucosal injury (OMI), nausea, vomiting, and skin injury.

Exclusion Criteria
1. Repetitively published researches; 2. Studies of abstracts only or conference papers without available data; 3. Studies with noticeable errors or incomplete and unavailable data; 4. Studies with high bias risk 28 ;

Bias Risk Assessment
Bias risk assessment and results cross-check were performed by Renhong Wan and Anlan Zhao independently. Another investigator, Min Zhong, would resolve the discrepancies. The recommended tool for bias risk assessment in Cochrane Mnual 5.1.0 was adopted. 29

Statistical Analysis and Data Synthesis
The RevMan5.3 of Cochrane Collaboration was applied for metaanalysis. The weighted mean difference (WMD) was used for continuous variables if the measuring instruments and the units were consistent, otherwise standard mean difference (SMD) was used. Relative risk (RR) was used to analyze the dichotomous variables, and the 95% CI was provided for each effect size. Heterogeneity between the results was analyzed by the chi-square test, and quantitatively determined in combination with I 2 . P≥0.10 and I 2 <50% indicated no significant heterogeneity between studies, and a fixed effect model (FEM) was used for the meta-analysis. P < .10 and I 2 ≥50% indicated significance between studies. In this case, the sources of heterogeneity need be discussed by both subgroup analysis and sensitivity analysis. Only if significant clinical and methodological heterogeneity are excluded, a random effect model may be used for the meta-analysis. The sensitivity analysis was used for the influence of a single study on the combined effect size, as well as the stability of the meta-analysis results. Funnel plot would be used for publication bias for major outcome measures if >10 researches were included, and potential publication bias would be evaluated by Egger's and Begg's tests.

Description of the Included Studies
Preliminary screening obtained 83 relevant articles, and 38 remained after duplicate ones were removed. Through reading the titles and abstracts, 24 articles remained, and then, 15 of the 24 articles were excluded through full-text reading. At last, 9 articles were included. 23,[30][31][32][33][34][35][36][37] The screening procedure is shown in Figure 1. Table 2 shows the basic features of the included studies.

Bias Risk Assessment
The risk assessment tool by Cochrane Manual 5.1.0 was used to evaluate the quality of 9 included articles. 23,[30][31][32][33][34][35][36][37] One article 36 used the method of random sequence generation correctly. None of the studies mentioned blinding. Combined with the intervention method, all the studies were evaluated as high risk; all studies were evaluated as low risk in the distribution of hidden, incomplete outcome indicators, selective report, etc. The results of bias risk assessment are shown in Figure 2.

Sensitivity Analysis
The sensitivity analysis was carried out by a one-by-one elimination method, and effect size and P value changes were observed after one-by-one elimination of included studies. The effect size of outcome indicators did not change significantly after excluding any article, indicating the results were reliable and stable.       Natural Product Communications

Publication Bias
Considering that total 9 studies were included, we investigated the publication bias through Egger's test and Begg's test, and the results showed that there was no publication bias (P = .1920 > .05, P = .1078 > .05, respectively).

Evaluation of Quality of Evidence
Evidence quality was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). After being assessed by the GRADE evidence grading system, the KPS score, the degree of leukocyte, and hemoglobin reduction, the incidence of OMI, and the incidence of nausea and vomiting were all low, and the above outcome indicators all met the 2 downgrading criteria: (1) Risk of bias: Only one study accurately used the random method and none of the studies specifically described the allocation concealment and blinding. As it was an objective indicator, it was downgraded one level. (2) Imprecision: Downgrading was due to the small No. of included studies and wide confidence intervals (Table 3).

Discussion
The etiology of NPC is still unclear, but it is generally believed to be highly correlated with Epstein Barr (EB) virus, 38 environmental factors, dietary habits, and genetic susceptibility. 1,39 Traditional medicine assigned it to the categories of "sinusitis (Bi Yuan)", " upper stony flat abscess (Shang Shi Ju)", and "glanders (Bi Ju)". 40 According to the classification of TCM, the syndrome types of NPC can be divided into lung heat, blood stagnation, phlegm cagulation, and blood stagnationphlegm coagulation. 41 The TCM pathogenesis is deficiency in origin and excess in superficiality. Aidi injection is composed of cantharis (Mylabris phalerata Pallas), Radix Astragali (Astragalus membranaceus (Fisch.) Bge), ginseng (Panax ginseng C. A. Meyer), and acanthopanax root (Acanthopanax senticosus [Rupr. et Maxim.] Harms). 42 Ginseng (Ren Shen) can greatly invigorate primordial qi, promote production of fluid, and benefit lung; Radix Astragali (Huang Qi) invigorates qi for consolidating superficies and promotes pus discharge and tissue regeneration; Acanthopanax Root (Ci Wu Jia) can replenish qi and invigorate the spleen; Cantharis (Ban Mao) can remove blood stasis. All medicinal materials above are combined to treat both manifestation and root cause of the disease. 43 Modern pharmacological studies have shown that Aidi injection has antitumor and immunomodulatory effects. 44 The roles of active ingredients in it are as follows: ginsenoside can enhance the function of T and B cells, induce interferon and interleukin, and increase the activity of LAK and NK cells 45 ; astragalus polysaccharide can enhance reticuloendothelial phagocytosis, as well as the anticancer activity of T cells, NK cells, LAK cells, and IL-II. It can also enhance the ability to kill tumor cells 46 ; acanthopanax root (Ci Wu Jia) extract contains a variety of glycosides and acanthopanax polysaccharide, which can improve immunity, increase white blood cells, improve the adaptability of the body

⊕⊕OO LOW
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). a Only one study accurately used the random method, and none of the studies specifically described the allocation concealment and blind method. As it is an objective indicator, it is downgraded one level.
b Downgrading a notch was conducted because the number of included studies is small, and the confidence interval is wide. Abbreviations: CI, confidence interval; KPS, Karnofsky Performance Status Scale; RR, risk ratio.
to stress, intoxication, and other nonspecific damages 47 ; norcantharidin can increase active oxygen level, mediate SKOV3 cell apoptosis, as well as G2/M phase periodic arrest. 48 An animal test has confirmed that Aidi injection can inhibit tumor metastasis by reducing the expression of Vimentin and VEGF-A in tumor tissues and increasing the expression of cadherin-1. 44 For this paper, a meta-analysis was conducted on 9 RCTs of Aidi injection combined with RT for NPC (422 patients). The results showed that compared with RT alone, Aidi injection combined with RT was not different in efficacy for local lesions of NPC (based on the TER). Subgroup analysis on the dose of the TCM injection also showed no difference, indicating that Aidi injection may not reduce the tumor volume. In addition, we evaluated the CRR of patients separately, and it was demonstrated that the experimental group was superior to the control group in the CRR, which indicated that Aidi injection had certain advantages in patients with obvious effects. Considering that the No. of studies is limited, the results are to be further verified by more relevant studies.
KPS score is an indicator reflecting patients' physical functioning status. In this meta-analysis, the significant difference in KPS score between the 2 groups indicates that Aidi injection did improve the life quality and daily behavior ability of patients.
In terms of adverse reactions, the Aidi injection combined with RT group has more advantages than the RT group. Aidi injection can reduce the toxic and side effects caused by RT. It can improve leukopenia and hemoglobin reduction, and reduce the incidence of OMI, nausea and vomiting. However, it cannot improve the adverse reactions of thrombocytopenia and skin damage.
All the results showed good homogeneity, and the sensitivity analysis showed good stability. The study showed that compared with the RT alone group, the Aidi injection combined with RT group had more advantages in improving the symptoms of patients with NPC and alleviating adverse reactions.
This study has some limitations. First, limited by the quality and quantity of the included trials, more high-quality studies are needed to confirm the above conclusions. Second, the operation of allocation concealment and blinding was not specifically described, and there might be selection bias, measurement bias, or implementation bias. Third, the included studies were all from China, with regional limitations and poor universality.

Conclusion
Current evidence suggests that Aidi injection combined with RT for NPC treatment can improve patients' KPS score and reduce some toxic and side effects. However, the difference of TER between 2 groups is still yet to be evaluated, and Egger's test and Begg's Test did not indicate publication bias.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

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