Aidi injection, a traditional Chinese biomedical preparation for gynecologic tumors: a systematic review and PRISMA-compliant meta-analysis

Gynecologic tumors (GTs) pose a serious threat to the health and well-being of women, as they are the leading causes of cancer-related death worldwide. GTs mainly comprises cervical cancer (CC), endometrial cancer (EC), and ovarian cancer (OC), which are the 10th, 17th, and 20th most common cancers, respectively [1,2]. In 2018, approximately 1,247,330 newly diagnosed GT cases and 586,093 GT-related deaths occurred worldwide [1,2]. GT treatment includes different management strategies such as surgery, radiotherapy, and chemotherapy [3–6]. Although these therapeutic methods have greatly advanced in the past few decades, the prognosis of GT remains poor, as they are mostly diagnosed at stages III or IV [3–10]. In individuals with extensive invasion and distant metastasis, the management of these tumors is typically aimed at enhancing the quality of life (QoL) and survival rate, because current conventional treatments cannot be used to completely remove the tumor [3–6,8–11]. Moreover, the unpleasant side effects of GT treatment are one of the most important factors limiting the clinical application of radiochemotherapy.

Recently, traditional Chinese medicine has been widely used as an auxiliary treatment for malignancies, with promising therapeutic effects reported by several clinical studies [12–17]. Aidi injection (ADI) is an important injectable prepared from the extracts of various Chinese herbs: Mylabris phalerata, Radix astragali (Astragalus membranaceus [Fisch.] Bge. root), Radix ginseng (Panax ginseng C.A. Meyer root), and Acanthopanax senticosus (Acanthopanax senticosus [Rupr. & Maxim.] Harms) [18–20]. A study on the chemical constituents of ADI reported that 22 chemical components were detected and isolated from the preparation [19,21]. The main active ingredients included cantharidin, cantharidate, astragaloside, ginsenoside, elentheroside E, isofraxidin, syringin coniferin, among others [18,19]. ADI has been approved by the Chinese State Food and Drug Administration (SFDA) for the treatment of various malignant tumors when used alone or in combination with other drugs [19]. Previous studies have suggested that ADI mediates anti-tumoral effects by improving the body’s immunity, inducing tumor cell apoptosis, and inhibiting tumor cell proliferation [18–23]. It can also significantly improve the efficacy of radiochemotherapy and reduce any associated adverse events [18–20].

Several clinical studies have suggested that GT patients may benefit from ADI-mediated therapy [24–61]. However, despite extensive studies, the clinical efficacy and safety of conventional treatment combined with ADI have not been systematically evaluated. In the present study, we conducted a meta-analysis to determine the efficacy and safety of conventional GT treatment in combination with ADI compared with conventional GT treatment alone. This may provide insights that can be used for the development of new treatment strategies for GT patients (Figure 1).

This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [62].

Eligible prospective controlled clinical trials were searched from the following electronic databases: Web of Science, PubMed, Cochrane Library, EMBASE, Medline, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (CSJD), and the Wanfang database. Publications in English and Chinese dated from the inception of the database to December 2020 were shortlisted using the following search terms: ‘Aidi injection’ or ‘Ai-di injection’ or ‘Aidi zhusheye’ or ‘ADI’ combined with ‘gynecologic oncology’ or ‘gynecologic tumor’ or ‘gynecologic carcinoma’ or ‘gynecologic cancer’ or ‘ovarian oncology’ or ‘ovarian tumor’ or ‘ovarian carcinoma’ or ‘ovarian cancer’ or ‘cervical oncology’ or ‘cervical tumor’ or ‘cervical carcinoma’ or ‘cervical cancer’ or ‘endometrial oncology’ or ‘endometrial tumor’ or ‘endometrial carcinoma’ or ‘endometrial cancer’ or ‘EC’ or ‘OC‘ or ‘CC’. No other were restrictive search criteria applied.

• Studies wherein GT had been confirmed using cytological or pathological diagnostic methods (OC, CC, or EC).

• All available randomized controlled trials and high-quality prospective cohort studies involving GT patients.

• Studies involving more than 30 GT patients.

• Studies comparing the clinical outcomes of conventional treatment plus ADI adjuvant therapy (experimental group) with those of conventional treatment alone (control group); conventional treatment comprised surgery, radiation treatment, or chemotherapy.

Duplicated studies, publications without sufficient data, noncomparative clinical trials, case reports and series, meta-analyses, literature reviews, meeting abstracts, and other unrelated studies were excluded from the analysis.

Data were independently extracted by two investigators (Li, X. and Xiao, C.M.) using the aforementioned inclusion and exclusion criteria; disagreements were adjudicated by a third reviewer (Qu, K.).

The following data were extracted from eligible studies:

• Study characteristics such as name of the first author, year of publication, and sample size.

• Patient characteristics such as tumor stage and age.

• Details of the interventions such as intervention technique as well as dosage, administration route, and duration of ADI treatment.

• Outcomes measures and other parameters that included the overall response rate (ORR), disease control rate (DCR), overall survival (OS), QoL, immune indexes (CD3⁺, CD4⁺, and CD8⁺ percentages and CD4⁺/CD8⁺ cell ratios), tumor markers (HE4, CA125, CEA, and CA199), and adverse effects.

We attempted to contact the authors to request missing or incomplete data. If the relevant data could not be acquired, the studies were excluded from the analysis.

To ensure the quality of the meta-analysis, the quality of the included randomized and nonrandomized controlled trials was evaluated according to the Cochrane Handbook tool [63] and Methodological Index for Nonrandomized Studies (MINRRS, Table 2), respectively [64].

The primary outcomes for the present analysis included clinical efficacy and adverse effects, as defined by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST Criteria 1.1) [65].

• Short-term clinical efficacy was defined as the short-term tumor response measured by the ORR (sum of complete and partial response rates) and DCR (sum of complete response, partial response, and stable disease rates).

• Adverse events included gastrointestinal adverse effects, leukopenia, and thrombocytopenia, among others.

• Long-term clinical efficacy was determined using 1-, 2-, 3-, and 5-year OS.

• QoL was evaluated using the quality of life improved rate (QIR) and the Karnofsky score (KPS).

• Immune function of the GT patients was assessed using CD3⁺, CD4⁺, and CD8⁺ percentages, and CD4⁺/CD8⁺ ratios.

• Presence of tumor markers, namely HE4, CA125, CEA, and CA199, was evaluated.

Review Manager 5.3 (Nordic Cochran Centre, Copenhagen, Denmark) and Stata 14.0 (Stata Corp., College Station, TX, U.S.A.) statistical software were used for statistical analyses. Heterogeneity of treatment effects across trials was assessed using Cochrane’s Q test and I² statistics [66]. A P-value > 0.1 and I² < 50% suggested that there was no statistical heterogeneity, and the fixed-effects model was used for meta-analysis; otherwise, a random-effects model was used to calculate the outcomes. Continuous data were presented as standardized mean difference with corresponding 95% confidence intervals (CIs). Dichotomous data were reported as odds ratios (OR) with 95% CIs. A two-tailed P-value < 0.05 was considered statistically significant. Any publication bias was investigated using funnel plots and the Begg’s and Egger’s tests for parameters that were reported in more than 10 studies [67–69]. A trim-and-fill method was used to coordinate the estimates from unpublished studies if publication bias existed, and the adjusted results were compared with the original pooled OR [70]. Sensitivity analysis was performed to explore an individual study’s influence on the pooled results by deleting one study at a time from the pooled analysis.

The initial search retrieved a total of 465 articles, of which 348 were excluded due to duplication. After the title and abstract review, 44 articles were further excluded for the following reasons: not related to ADI (n=13), non-peer reviewed articles (n=18), non-comparative clinical trials (n=11), literature reviews or meta-analyses (n=5), and case reports and series (n=7). Thus, 63 studies were potentially eligible. After a detailed assessment of full texts, studies with less than 30 GT patients (n=4), trials with inappropriate inclusion and exclusion criteria (n=12), and papers with insufficient data (n=9) were excluded. Ultimately, 38 trials (OC, n=28; CC, n=6; EC, n=2; and mixed type, n=2) [24–61] involving 3309 patients with OC, CC, or EC were included in the final analysis (Figure 2).

All included studies were conducted at different medical centers in China. In total, 1729 GT patients were treated using conventional methods in combination with ADI, whereas 1580 patients were treated using conventional methods alone. The ADI used in all the included studies was manufactured by Guizhou Yibai Pharmaceutical Co., Ltd. with a manufacturing approval number issued by the Chinese SFDA (Z52020236). The study and patient characteristics are summarized in Table 1.

Quality assessment of the risk of bias has been given in Figure 3 and Table 2. The results revealed that the literature retrieved for the present study was of average quality.

Thirty-one clinical trials [25–27,29,30,32–47,50–52,54–61], involving 2360 patients, compared the ORR and/or DCR between the two groups. The pooled results revealed that patients who underwent combination therapy had improved ORR (Figure 4; OR = 2.40, 95% CI = 2.00–2.89, P<0.00001) and DCR (Figure 5; OR = 2.57, 95% CI = 1.97–3.34, P<0.00001), compared with those who received conventional treatments alone. Fixed-effect models were used to analyze OR rate because of low heterogeneity.

Only four clinical trials [28,31,49,53] with 348 GT patients reported the OS (Figure 6). Although the meta-analysis revealed that the 1-year (OR = 2.02, 95% CI = 0.76–5.34, P=0.16), 2-year (OR = 1.57, 95% CI = 0.83–2.99, P=0.17), 3-year (OR = 1.65, 95% CI = 0.96–2.84, P=0.07), and 5-year (OR = 1.04, 95% CI = 0.42–2.61, P=0.93), OS rates of patients in the combined treatment group were greater than those of the control group, there were no statistically significant differences. Fixed-effect models were used to analyze the ORR due to low heterogeneity.

Twenty-two trials [24–28,30–32,35,37,38,40–43,45,46,54,58–61] with 1461 participants evaluated the QIR, and five trials [34,48,50,56,57] including 826 patients reported the KPS data (Figure 7). The results demonstrated that the QoL of GT patients in the combined group was significantly better than that in the control group, indicated by significantly increased QIR (OR = 3.56, 95% CI = 2.84–4.45, P<0.00001) and KPS (OR = 11.70, 95% CI = 1.91–21.49, P=0.02). Since the QIR (P=0.94, I² = 0%) was not heterogeneous among the studies, a fixed-effect model was used to analyze the OR; otherwise, a random-effect model was used.

Differences in the immune status of patients between the two groups was examined in six controlled studies [29,34,45,46,50,56], which included a total of 448 patients (Figure 8). The percentages of CD3⁺ (OR = 10.33, 95% CI = 3.11–17.54, P=0.005) and CD4⁺ (OR = 7.99, 95% CI = 4.60–11.39, P<0.00001) and the CD4⁺/CD8⁺ ratios (OR = 0.33, 95% CI = 0.13–0.54, P=0.001) for the combined treatment group were significantly higher than those for the conventional treatment alone, whereas the CD8⁺ proportion (OR = 2.19, 95% CI = −4.56–8.94, P=0.52) did not significantly differ between the groups. A random effects model was used to pool this meta-analysis due to significant heterogeneity.

Two clinical trials [29,34] with 448 patients evaluated tumor markers in GT patients for the two groups. As shown in Figure 9, HE4 levels (OR = -28.26, CI = -64.02–7.50, P=0.12), CA125 (OR = -11.85, CI = -28.12–4.42, P=0.15), CEA (OR = -5.85, CI = -8.15–3.55, P<0.00001), and CA199 (OR = -3.31, CI = -26.80–19.82, P<0.00001) decreased after combination therapy. However, there were no significant differences in HE4 and CA125 between groups. A random effects model was used to pool this meta-analysis due to significant heterogeneity.

As shown in Supplementary Figure 1 and Table 3, patients treated with conventional methods combined with ADI exhibited lower incidences of gastrointestinal adverse effects (OR = 0.22, 95% CI = 0.16–0.31, P<0.00001), leukopenia (OR = 0.23, 95% CI = 0.16–0.32, P<0.00001), thrombocytopenia (OR = 0.31, 95% CI = 0.17–0.57, P=0.0001), hepatotoxicity (OR = 0.34, 95% CI = 0.23–0.50, P<0.00001), cardiotoxicity (OR = 0.23, 95% CI = 0.08–0.66, P=0.006), hematotoxicity (OR = 0.28, 95% CI = 0.16–0.51, P<0.0001), myelosuppression (OR = 0.47, 95% CI = 0.28–0.81, P=0.006), nausea and vomiting (OR = 0.50, 95% CI = 0.35–0.71, P=0.0001), and anemia (OR = 0.53, 95% CI = 0.30–0.94, P=0.03), whereas the incidence of nephrotoxicity (OR = 0.64, 95% CI = 0.27–1.47, P=0.29), diarrhea (OR = 0.59, 95% CI = 0.32–1.10, P=0.10), alopecia (OR = 0.68, 95% CI = 0.37–1.24, P=0.21), and neurotoxicity (OR = 0.52, 95% CI = 0.20–1.38, P=0.19) did not significantly differ between the groups. According to the heterogeneity test, statistical heterogeneity was observed for the incidence of thrombocytopenia (P=0.0008, I² = 65%) and neurotoxicity (P=0.09, I² = 58%), and a random effects model was used to pool this meta-analysis; otherwise, the fixed-effect model was used.

As shown in Supplementary Figure S2 and Table 4, funnel plots and the Begg’s and Egger’s regression tests showed that there was publication bias for the ORR (Begg = 0.032; Egger = 0.018) and thrombocytopenia incidence (Begg = 0.373; Egger = 0.031). To determine whether the bias affected the pooled risk of ORR and thrombocytopenia, a trim-and-fill analysis was performed. The adjusted OR indicated a trend similar to the results of the primary analysis (ORR, before: P<0.0001, after: P<0.0001; thrombocytopenia, before: P<0.0001, after: P<0.0001), indicating that the primary conclusions were reliable. Parameters reported in less than 10 papers were not used in the publication bias analysis.

As shown in Supplementary Figure S3, the results revealed that no individual studies significantly affected the primary outcomes, indicating statistically robust results. Parameters reported in less than 10 studies were not included in the sensitivity analysis.

We also conducted subgroup analyses for tumor type, the dosage of ADI, sample size, and study type. As shown in Table 5, our analysis revealed no significant differences in dosage of ADI, sample size, and study type. Further, combination therapy was more likely to improve the QoL of patients with OC and CC, as compared with EC patients. However, since only one study [35] reported the effect of combination therapy on the QoL of EC patients, these results cannot be generalized.

As a type of traditional Chinese biomedical preparation, ADI has been clinically applied as an effective adjuvant drug in cancer treatment for decades [18–20]. Although several studies have reported that addition of ADI could be beneficial to patients with GT [24–61], the exact therapeutic effects have yet to be systematically evaluated. Thus, in-depth knowledge of the efficacy and safety of ADI is needed. This systematic review provides evidence that clinicians can reference for the development of the most effective postoperative adjuvant treatment strategy for patients with OC, CC, or EC. These results may also provide the foundation for further research in this area.

Data from 38 trials [24–61] including a total of 3309 GT patients were used in our meta-analysis. The pooled results revealed that ADI in combination with conventional GT treatment was more beneficial than conventional treatment alone. Moreover, ADI significantly improved the ORR, DCR, and QoL in GT patients (P<0.05) compared with conventional treatment alone. Among the included studies, four also assessed whether ADI could increase the long-term survival rates in GT patients. Although the results showed that the 1- 2-, 3-, and 5-year OS rates of patients in the combined treatment group were greater than those of the control group, significant differences were not observed. Specific molecular markers including HE4, CA125, CEA, and CA199 are commonly used to predict the recurrence, metastasis, and prognosis of GT after treatment [71,72]. Our analysis showed that these tumor markers decreased after combination treatment, but HE4 and CA125 levels did not significantly differ between groups. Overall, these results indicated that ADI could improve the curative effects of conventional treatment methods to some extent.

T lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺ cell subsets) and CD4⁺/CD8⁺ ratio play an important role in antitumor immunity [22,23]. Several studies have reported that ADI can enhance the body’s immunity and resistance to tumors [22,23]. Our analysis demonstrated that the percentages of CD3⁺ and CD4⁺ and the CD4⁺/CD8⁺ ratios were all significantly increased in GT patients treated with ADI, indicating that immune function of GT patients improved after ADI adjuvant therapy.

Safety is the top priority in clinical treatment. Twenty-six clinical trials [25–28,31–37,39,41–48,52,55,56,59–61] with a total of 2415 GT patients reported adverse events, as defined by the World Health Organization standards. Meta-analysis revealed that patients who received ADI in combination with conventional treatment demonstrated a lower risk for gastrointestinal adverse effects, leukopenia, thrombocytopenia, hepatotoxicity, cardiotoxicity, hematotoxicity, myelosuppression, nausea and vomiting, and anemia, as compared with those who underwent conventional treatment alone. However, the incidence of other toxic side effects did not significantly differ between groups. Therefore, ADI appears to be a safe auxiliary anti-tumor drug for GT patients, and it can alleviate some of the adverse events associated with conventional treatment.

There were a few limitations to our analysis. First, there was publication bias for some indicators, as authors tend to report favorable results to editors. Second, different trials evaluated the treatment efficacy using different outcomes, resulting in a reduced sample size, which made it difficult to summarize results across studies using the same scale. Third, allocation concealment and blinding method were not clear in most of the included studies, which could have resulted in exaggerated estimates of the treatment effect. Finally, most of the included trials assessed efficacy immediately after the completion of treatment. Therefore, methodologically rigorous trials are needed to assess the long-term effects of ADI on OC, CC, and EC. Given these limitations, some of the findings of our study should be cautiously interpreted.

In summary, findings of this meta-analysis indicate that ADI in combination with conventional treatment is effective in treating patients with OC, CC, and EC. The clinical application of ADI in such patients not only clearly enhanced the therapeutic effects of conventional treatment, but also effectively improved the QoL and immune function. Thus, we anticipate that our study will provide valuable evidence for further evaluation of ADI. On the other hand, considering that only a few clinical trials evaluated the long-term efficacy and immune-regulatory effect of ADI, additional studies with high-quality evidence are needed to verify the effectiveness of ADI-mediated therapy for GT.

All supporting data are included within the main article and its supplementary files.

The authors declare that there are no competing interests associated with the manuscript.

This study was supported by grants from National Science Foundation of China [grant number 81201549].

X.C.M. and L.X. conceived and designed the methods. L.X., X.C.M., and Q.K. extracted the original data and drafted the manuscript. L.X., X.C.M., and Q.K. performed statistical analysis. X.C.M. and L.X. interpreted results. X.C.M. and L.X. revised the manuscript. All authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of data analysis.

ADI

Aidi injection

CA125

Cancer antigen 125

CA199

Cancer antigen 199

CBM

Chinese Biological Medicine Database

CC

cervical cancer

CEA

carcinoembryonic antigen

CI

confidence interval

CNKI

China National Knowledge Infrastructure

CSJD

Chinese Scientific Journal Database

DCR

disease control rate

EC

endometrial cancer

GT

gynecologic tumor

HE4

Human epididymal protein 4

KPS

Karnofsky Performance Score

MINRRS

Methodological Index for Non-randomized Studies

OC

ovarian cancer

OR

odds ratio

ORR

overall response rate

OS

overall survival

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

QIR

quality of life improved rate

QoL

quality of life

RECIST

Response Evaluation Criteria in Solid Tumors

SFDA

State Food and Drug Administration