Abstract
Objective:
The purpose of this overview is to assess systematic reviews (SRs)/ meta-analyses (MAs) of Huachansu (HCS) combination chemotherapy for treating non-small cell lung cancer (NSCLC) and provide summarized evidence for clinical decision making.
Methods:
From the creation of the database to JUNE 2023, 8 databases in English and Chinese were searched. SRs/MAs that met the inclusion and exclusion criteria were included. Two reviewers independently screened research, extracted data and assessed methodological quality, risk of bias, report quality and evidence quality by using relevant criteria from AMSTAR-2, ROBIS scale, PRISMA, and GRADE system.
Results:
The short-term effect, long-term effect, quality of life improvement, safety and pain relief effect in 8 included SRs/MAs were assessed in this overview according to quantitative synthesis. Results assessed by AMSTAR-2, PRISMA, and ROBIS were generally unsatisfactory, with the results of the AMSTAR-2 assessment showing that all of them were of low or critically low quality; the number of items in the included research that were fully reported (compliance was 100%) by the PRISMA checklist was only 50%, while there were 38.10% of the research reporting less than 60% completeness; the ROBIS assessment showed a small number of systems to be low risk of bias. In addition, 26 items were rated as moderate quality, while 50.94% of items were rated as low or critically low quality by GRADE.
Conclusion:
HCS may be a promising adjuvant therapy for NSCLC. However, high-quality SRs/MAs and randomized control trials (RCTs) should be conducted to provide sufficient evidence so as to draw a definitive conclusion.
Keywords: Huachansu, non-small cell lung cancer, overview, TCM, adjuvant therapy
Introduction
According to 2018 global cancer statistics, lung cancer accounts for 11.6% of all diagnosed cancers, 1 and in the 2022 U.S.-China Cancer Statistics, lung cancer is the most common malignant tumor disease and the leading cause of death in China. 2 Small-cell lung cancer (SCLC) and NSCLC are both classified under lung cancer. NSCLC is more common than SCLC, accounting for approximately 85% of all lung cancers. A majority of patients are already in advanced stages, resulting in the loss of surgical opportunities when they are first diagnosed. 3 So far, chemotherapy, targeted therapy and immunotherapy are available for advanced NSCLC, among which 2-drug combination chemotherapy based on platinum-based drugs is still the standard first-line treatment option. Although its therapeutic effect has been affirmed, most of the patients will ultimately experience recurrence or progression of the disease after the initial treatment, and the systemic toxicity and side-effects brought about by the process of application will also limit the application and therapeutic efficacy.
Since the advent of cancer chemotherapy, more and more evidence has demonstrated that extracts from plants and animals could play an important role in exploring new treatment in cancers. A prime model is paclitaxel, an extract from the natural Taxus brevifolia plant, which has gained recognition as a primary therapeutic agent to treat breast cancer, ovarian cancer, some head and neck cancer, and lung cancer. Although there is no concept of “cancer” from a pathological perspective in Chinese medicine, it is easy to find the descriptions of cancer-like symptoms in the ancient Chinese medical documents described as lumps, bumps, and toxins, termed “Chuang, Yong, Zhong and Du (疮痈肿毒).” These symptoms can be alleviated with herbs that have the ability of dissipating internal heat and detoxify the body. One of the typical herbs is bufo, which has become a key herb in the treatment of “Chuang, Yong, Zhong and Du” due to its excellent efficacy after the long period of clinical observation and practice. Huachuansu (HCS, Cinobufacini) is a Chinese medicinal preparation for which the main active component is extracted only from the dried skin of the Chinese toad, Bufo gargarizans or Bufo nigricollis. 4 There are 3 main categories of active substances in HCS. The first is steroidal cardiac glycosides, including bufalin, resibufo-genin, cinobufagin, marinobufagin, bufotalin, and others. The second category is indole alkaloids, including bufotenine, bufotenidine, dehydrobu-fote-nine, and others. The last one is other alkaloids and pteridine, such as cyclic (proline-glycine) dipeptide, cyclic (alanine-alanine) dipeptide, and others. 5 Figure 1 provides a graphic representation of the 3 relationships. Basic research has shown that HCS has an anticancer effect on a variety of cancer cell lines, and steroidal cardiac glycosides are more likely to be the source of this action. 6 Its anticancer molecular mechanisms are mainly involved in anti-proliferation, induction of apoptosis, anti-metastasis, anti-angiogenesis, inhibition of epithelial-mesenchymal transition, anti-tumor invasion, targeting of Na+/K+-ATPase activity, inhibition of steroid receptor coactivator family, etc.7 -10 Clinical studies have also shown that the combination of these treatments works synergistically to improve treatment efficacy, reduce side effects and improve quality of life in liver cancer, 11 lung cancer, pancreatic cancer, 12 colorectal cancer. 13 As a result, it is currently approved by the Chinese State Food and Drug Administration (SFDA) for the treatment of inflammatory diseases and liver, lung, pancreatic and colorectal cancer in China.
Figure 1.
The link between bufo, HCS, and the active component of HCS.
Up to now, there have been a number of SRs/MAs on the efficacy and safety of HCS combined with traditional chemotherapy regimens in the treatment of lung cancer; however, evidence-based results of efficacy and safety for HCS are still debatable due to the inconsistent quality of SRs/MAs, which limits its clinical application. The purpose of this overview is to reveal the shortcomings and improvements of the current SRs/MAs on this topic through objective evaluations (PRISMA, AMSTAR2, GRADE, ROBIS), providing more reasonable potential adjuvant therapeutic options for cancer patients.
Methods
Registration and Instructions
This protocol for this overview was registered with PROSPERO (ID: CRD42023413595). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement 14 and the Cochrane Handbook for Systematic Reviews. 15 The third reviewer could intervene if 2 reviewers appeared to disagree about the search and selection of SRs/MAs for inclusion, data analysis and assessment.
Literature Search
From the creation of each database until January 2024, we conducted a comprehensive search of Chinese and English databases, including CNKI, Wanfang, EMBASE, Web of Science, PubMed, SinoMed, VIP, and Cochrane Library.
The search strategy was as follows:
#1 (Carcinoma, Non-Small-Cell Lung) [MeSH Terms].
#2 (non small cell lung cancer, non small lung cancer, non-small cell cancer, non-small cell lung, non-small cell lung cancer, non-small cell lung cancers, non-small-cell lung cancer, NSCLC) [Title/ Abstract].
#3 #1 OR #2.
#4 (Huachansu) [MeSH Terms].
#5(cinobufacini) [Title/ Abstract]
#6 #4 OR #5
#7 (meta-analysis [Publication Type].
#8 (meta-analysis) OR (systematic review) OR (review) [Title/ Abstract].
#9 #7 OR #8.
#10 #3 AND #6 AND #9.
Furthermore, it is essential to conduct a thorough search for references of studies and other gray literature that have been included.
Study Selection
After eliminating duplicated literature, we examined the titles and abstracts of all studies, and sought full texts of papers that might qualify for further selection.
The following criteria were used for inclusion:
(a) study design: SRs/MAs Patients including patients diagnosed with NSCLC through controlled clinical or randomized controlled trials.
(b) intervention methods: HCS plus traditional chemotherapy treatment versus traditional chemotherapy treatment alone;
(c) quantitative analysis SRs/ MAs;
(d) The language was limited to Chinese and English;
The exclusion criteria were as follows:
(a) studies with unavailable full text;
(b) studies whose data couldn’t be extracted
(c) repeated publications, protocol studies.
(d) treatment group involving other anti-tumor proprietary Chinese medicines
Quality Assessment
First, the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), which comprises 16 items, was used to evaluate the methodological quality of each included study. 16 The critical domains include 7 items (Q2, Q4, Q7, Q9, Q11, Q13, and Q15). Based on the degree of satisfaction with the evaluation items, the researcher made a yes, part yes, and no assessment. The evaluation’s findings allow for the classification of SRs/MAs into 4 quality categories: critically low, low, moderate, and high quality. The following is a summary of the comprehensive evaluation standard: None or only 1 non-critical item that did not comply with standard was rated as high-quality; more than 1 non-critical items that did not comply with standard were as medium-quality; study that did not comply with 1 critical item was rated as low-quality, and study that did not comply with more than 1 critical item were rated as critically low quality. Secondly, we evaluated the reporting quality of each included study with the help of the PRISMA 2020 version checklist, which includes 27 items. 14 Thirdly, according to the Risk of Bias in Systematic Reviews (ROBIS) assessment, 17 the risk of bias in each included SRs/MAs was categorized as “low risk,” “high risk,” or “unclear.” Finally, the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) 18 were utilized to evaluate outcomes of the included SRs/MAs.
Data Extraction and Analysis
The included SRs/MAs were analyzed using a standardized format, and the findings are as follows: author and year of publication (country), risk of bias assessments, intervention method, sample size, primary outcomes. Short-term effects (ORR or DCR), long-term effects (OS or DFS), quality of life improvement, and safety (incidence of adverse reactions) were our key focus areas. A narrative synthesis was performed on the included studies.
Results
Literature Search and Selection
Based on the established search strategy, a total of 48 papers were initially identified. After removing 25 duplicates papers, 11 papers were excluded after assessing the title and abstract, 2 were eliminated after reading the full text, and finally, 10 articles were included. Finally, 10 SRs/MAs13,19 -25 were included for further comprehensive analysis. More details and screening flowchart is shown in Figure 2.
Figure 2.
Literature selection process.
Characteristics of Included SRs/MAs
A total of 10 studies, comprising of 6 articles in Chinese and 4 articles in English, were published between 2011 and 2023. Those sample sizes were ranging from 267 to 2967 cases, and the number of RCTs included in these studies was 183, with standard chemotherapy treatment in the control group, and HCS combined with standard chemotherapy treatment in the treatment group. All included SRs/MAs, except for Lin’s 23 studies, provided a description of a tool to evaluate the methodological quality of the outcome. Among these, 3 studies13,24,25 utilized the Jadad score, 2 studies20,22 opted for the risk of bias tool recommended by the Cochrane Handbook, and 4 studies19,21,26,27 selected the GRADE tool. Regrettably, Gao’s study omitted the presentation of this assessment.
All of the included SRs/MAs used bias risk assessment instruments: 5 studies19 -23,26,27used the Cochrane risk of bias assessment tool, while 3 studies13,24,25 used the Jadad. The trial results of these SRs/MAs, which evaluate the effectiveness in the short and long term, improvement in quality of life, enhancement of immune response, and safety, have not yet achieved a consistent agreement. Further basic characteristics can be found in Table 1.
Table 1.
The Characteristics of the Included SRs/Mas.
| Author [year] | Risk of bias assessments | Intervention | Sample size | Outcome | Main results | |
|---|---|---|---|---|---|---|
| TG | CG | |||||
| Gao Xin et al. [2013] | Jadad | Chemo + HCS injection | Chemo | 267 | ①② | Short-term effect: ORR (RR = 0.39 95%CI:0.17-2.34, P = .02). Long-term effect: KPS (RR = 0.40 95%CI:0.23-0.68, P = .0007). |
| Huang Ruo Chen et al. [2018] | Cochrane Review’s Handbook | Chemo + HCS capsule | Chemo | 601 | ①④⑤ | Short-term effect: ORR (RR = 1.39 95%CI: 1.20-1.62, P < .01) Long-term effect: 1-y OS (RR = 1.41 95%CI: 1.24-1.61, P < .01; 2-y OS (RR = 1.73 95%CI: 1.31-2.80, P < .01). |
| Xu Yong et al. [2019] | Cochrane Review’s Handbook | Chemo + HCS injection | Chemo | 2125 | ①②④⑤⑦ | Short-term effect: ORR (RR = 1.47, 95%CI: 1.33-1.63 , P < 0.01) Long-term effect: 1-y OS (RR = 1.34, 95%CI: 1.17-1. 55, P < .01); 2-y OS (RR = 1.84, 95%CI: 1.31-2.59, P < .01). KPS (RR = 1.54, 95%CI: 1.37-1.72, P < .01); AE: leukopenia (RR = 0.63, 95% CI: 1.37-1.72, P < .01); thrombocytopenia (RR = 0.54, 95% CI: 0.35-0.84, P < .01); nausea and vomiting (RR = 0.60, 95% CI: 0.45-0.80, P < .05); Pain (RR = 1.68, 95% CI: 1.38-2.03, P < .01); alopecia (RR = 0.76, 95% CI: 0.59-0.98, P < .05) |
| Tu Chao et al. [2012] | Cochrane Review’s Handbook | Chemo + HCS injection | Chemo | 498 | ①②⑦⑩ | Short-term effect: ORR (RR = 1.29, 95% CI: 1.07-1.56, P = .009); Long-term effect: KPS (RR = 1.86, 95% CI 1.14-3.05, P0.01). AE: nausea and vomiting (RR = 0.72, 95% CI: 0.53-0.99, P = .04); leukopenia (RR = 0.70, 95% CI: 0.54-0.91, P = .008); thrombocytopenia (RR = 0.53, 95% CI: 0.38-0.75, P = .0003); liver injury (RR = 0.59, 95% CI: 0.26-1.34, P = .20); renal injury (RR = 0.37, 95% CI: 0.17-0.79, P < .01). Others: weight gain (RR = 1.56, 95%CI: 1.20-2.03, P = .0009) |
| Lin Meiying et al. [2022] | Cochrane Review’s Handbook | Chemo + HCS injection | Chemo | 1766 | ①②④⑤⑦ | Short-term effect: ORR (RR = 1.46, 95% CI: 1.29-1.64, P < .00001); Long-term effect: 1-y OS (RR = 1.13, 95%CI: 0.93-1.38, P = .21); 2-y OS (RR = 1.09, 95% CI:0.54-2.22, P = .81). KPS (RR = 1.48, 95% CI: 1.30-1.68, P < .00001). AE: nausea and vomiting (RR = 0.69, 95% CI: 0.55-0.85, P = .0006); leukopenia (RR = 0.75, 95% CI: 0.63-0.90, P < .001); lower risk of neutropenia (RR = 0.57, 95% CI: 0.35-0.95, P = .03); thrombocytopenia (RR = 0.59, 95% CI: 0.49-0.70, P < .00001). |
| Zhan Qi et al. [2011] | Jadad | Chemo + HCS injection | Chemo | 827 | ①③ | Short-term effect: ORR (RR = 1.68, 95% CI: 1.25-2.25, P = .0008). DCR (RR = 2.11, 95%CI: 1.41-3.15, P = .0003). |
| Xinmei Tan et al. [2021] | Cochrane Review’s Handbook | Chemo + HCS injection | Chemo | 2753 | ①③④⑤⑦⑨ | Short-term effect: ORR (RR = 1.43, 95% CI: 1.31-1.56, P < .00001); DCR (RR = 1.18, 95% CI: 1.13-1.23, P < .00001). Long-term effect: 1-y OS (RR = 1.12, 95%CI: 1.05-1.20, P = .0007); 2-y OS (RR = 1.72, 95% CI:1.26-2.36, P = .00007). QQL (RR = 1.62, 95% CI 1.43-1.85, P < .00001). AE: lower risk of neutropenia (RR = 0.71, 95% CI: 0.65-0.78, P < .00001); thrombocytopenia (RR = 0.62, 95% CI: 0.54-0.70, P < .00001); nausea and vomiting (RR = 0.65, 95% CI: 0.59-0.71, P < .0001); anemia (RR = 0.74, 95% CI: 0.64-0.87, P = .0002); liver injury (RR = 0.68, 95% CI: 0.58-0.81, P < .0001); renal injury (RR = 0.63, 95% CI: 0.50-0.78, P < .0001); alopecia (RR = 0.84, 95% CI: 0.77-0.92, P = .0002) |
| Bingduo Zhou et al. [2015] |
Jadad | Chemo + HCS injection | Chemo | 1142 | ①②④⑦⑧ | Short-term effect: ORR (RR = 1.379, 95% CI: 1.190-1.599, P < .0001). Long-term effect: 1-y OS (RR = 1.316, 95%CI: 1.077-1.607, P = .007); KPS (RR = 1.397, 95% CI: 1.185-1.648, P < .0001). Pain relief effect: (RR = 1.64, 95% CI: 1.293-2.080, P < .0001). AE: nausea and vomiting (RR = 0.523, 95% CI: 0.333-0.822, P = .005); leukocytopenia (RR = 0.644, 95% CI, 0.473-0.876, P = .005); thrombocytopenia (RR = 0.593, 95% CI: 0.334-1.054, P = .075). |
| Wenpan Peng et al. [2021] |
Cochrane Review’s Handbook | Chemo + HCS capsule | Chemo | 1564 | ①④⑤⑦⑪ | Short-term effect: ORR (RR = 1.49, 95% CI: 1.33-1.66, P < .0001) Long-term effect: 1-y OS (RR = 1.44, 95%CI: 1.28-1.63, P > .05); 2-y OS (RR = 1.78, 95%CI: 1.42-2.22, P > .05). AE: leukocytopenia (RR = 0.61, 95% CI, 0.5-0.72, P > .005); thrombocytopenia (RR = 0.52, 95% CI, 0.41-0.67, P > .005); nausea and vomiting–Others + HCS (RR = 0.59, 95% CI: 0.50-0.69, P > .005); nausea and vomiting-GP + HCS (RR = 1.12, 95% CI: 0.96-1.32, P > .005). Immune response: CD3+ T Cells (RR = 1.25, 95% CI: 1.05-1.45, P>0.005); CD4+ T Cells-84 days (RR = 1.88, 95% CI: 1.58-2.18, P>0.005); CD4+ T Cells-42 days(RR = 1.27, 95% CI: 1.02-1.51, P > .005); CD4+/CD8+ T Cells-0.5g-tid-po (RR = 1.01, 95% CI: 0.76-1.26, P > .005); CD4+/CD8+ T Cells-0.5g-bid-po (RR = 1.78, 95% CI: 1.50-2.06, P > .005). |
| Yisheng Zhao et al. [2023] |
Cochrane Review’s Handbook | Chemo + HCS injection and capsule | Chemo | 2967 | ①④⑤⑦⑪ | Short-term effect: DCR (RR = 2.63, 95% CI: 2.15-3.21, P < .00001). Long-term effect: 1-y OS (RR = 2.41, 95%CI: 1.75-3.33, P < .00001); 2-y OS (RR = 2.28, 95%CI: 1.56-3.33, P < .00001). AE: leukocytopenia (RR = 0.4, 95% CI, 0.33-0.49, P < .00001). Immune response: CD3+ T Cells (RR = 1.15, 95% CI: 0.89-1.42, P < .00001); CD4+ T Cells (RR = 1.60, 95% CI: 1.26-1.94, P < .00001); CD4+/CD8+ T Cells (RR = 2.15, 95% CI: 1.45-2.86, P < .00001). |
Abbreviations: ① overall response rate (ORR); ② KPS improvement; ③ DCR; ④ 1-year overall survival; ⑤ 2-year overall survival; ⑥ 3-y overall survival; ⑦ AE; ⑧ pain relief effect; ⑨ QOL; ⑩ weight gain; ⑪ immune response.
Quality Assessment of Included SRs/MAs
Methodological quality
After AMSTAR-2 evaluation, 5 studies20,21,23 -25 were deemed of critically low quality and 5 studies13,19,22,26,27 were rated as low quality, The disadvantages of these studies were as follows:
In the area of focused evaluations, (1) All studies did not provide a list of excluded studies and detailed description of the reasons for exclusion; (2) Partial studies did not indicate that detailed search strategies was developed prior to the study; (3) None of the studies stated that they had searched the gray literature, so all study entries 4 were rated partially yes; (4) Seven studies failed to report their protocols in advance, nor did they provide any explanations for discrepancies in the pre-report protocols. In non-focused area, (1) Sources of funding and all potential conflicts of interest for the inclusion of individual studies were not reported in all studies; (2) Four studies did not indicate in the article that they used 2-person replication for literature selection and extraction; (3) only 3 studies declared that there were no conflicting interests among the authors. Unsatisfactory data in the above areas undermined our confidence in the results of included. Further details are presented in Figure 3.
Figure 3.
The assessment of AMSTAR-2.
Reporting quality
Based on the PRISMA review, nearly all studies, with the exception of 1, were comprehensively described in the TITLE, INTRODUCTION, and DISCUSSION sections, and the remaining abstracts were also completely reported. Additionally, the descriptions of Q6 (Information sources), Q20d (Results of syntheses) were flawed in 50.00% of the reports. The cause is the absence of comprehensive searches of clinical databases and the omission of sensitivity assessments of the findings. In the results section, Q20a (Results of syntheses) was not properly addressed in all studies (0%); while Q20c was 70% and Q20d was 50%. Furthermore, inadequate assessment of Q25 (Support) and Q26 (Competing interests) was observed in other areas, with only 30% of studies properly reporting these aspects. Generally speaking, there was a higher percentage of low-quality reports, which diminishes the certainty of the evidence, and future study may alter its evaluation. More details can be found in Figure 4.
Figure 4.
The assessment of PRISMA.
Risk of bias
According to ROBIS assessment, the items of all SRs/MAs in Phase 1 and Domain 1 in Phase 2 were assessed as low risk, However, in Domain 2 and 4 of Phase 2, 4 SRs/MAs projects were identified as high-risk. Three studies in Domain 3 were assessed as having a high risk. Further information is available in Figure 5.
Figure 5.
The assessment of ROBIS.
Efficacy and safety evaluation with evidence quality
In performing a GRADE assessment, we evaluated all 10 SRs/MAs and found that they collectively included a total of 69 outcome metrics. Out of these, 32 (46.38%) were graded as having middle quality evidence, 28 (40.58%) were graded as low quality, and 9 (13.04%) were graded as having critically low quality evidence. The key reason for downgrading the evidence was the risk of bias and significant inconsistency. More information was shown in Table 2.
Table 2.
Evidence Evaluation Results of GRADE Criteria of Total Effective Rate.
| Author/Year | Outcome | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Quality |
|---|---|---|---|---|---|---|---|
| Gao Xin et al. [2013] | ORR | D | ND | ND | D③ | D⑤ | Critically low |
| KPS | D | ND | ND | D③ | D⑤ | Critically low | |
| Huang Ruo chen et al. [2018] | ORR | D | ND | ND | ND | ND | Middle |
| 1-y OS | D | D② | ND | ND | ND | low | |
| 2-y OS | D | ND | ND | ND | ND | Middle | |
| Xu Yong et al. [2019] | ORR | D | D② | ND | ND | ND | low |
| 1-y OS | D | ND | ND | ND | ND | Middle | |
| 2-y OS | D | ND | ND | ND | ND | Middle | |
| KPS | D | ND | ND | ND | ND | Middle | |
| Incidence of leukopenia | D | ND | ND | ND | ND | Middle | |
| Incidence of thrombocytopenia | D | ND | ND | ND | ND | Middle | |
| Incidence of nausea and vomiting | D | ND | ND | ND | ND | Middle | |
| Incidence of alopecia | D | ND | ND | ND | ND | Middle | |
| pain relief effect | D | ND | ND | ND | ND | Middle | |
| Tu Chao et al. [2012] | ORR | D | ND | ND | ND | D⑥ | low |
| KPS | D | D② | ND | D③ | D⑥ | Critically low | |
| Incidence of leukopenia | D | D② | ND | ND | D⑥ | Critically low | |
| Incidence weight gain | D | ND | ND | ND | D⑥ | low | |
| Incidence of nausea and vomiting | D | D② | ND | ND | D⑥ | Critically low | |
| Incidence of thrombocytopenia | D | ND | ND | ND | D⑥ | low | |
| Incidence of liver injury | D | ND | ND | ND | D⑥ | low | |
| Incidence of neurotoxicity | D | ND | ND | D③ | D⑥ | Critically low | |
| Incidence of renal injury | D | ND | ND | ND | D⑥ | low | |
| Lin Meiying et al. [2022] | ORR | D | ND | ND | ND | D⑥ | low |
| KPS | D | ND | ND | ND | D⑥ | low | |
| 1-y OS | D | ND | ND | ND | D⑥ | low | |
| 2-y OS | D | ND | ND | ND | D⑥ | low | |
| pain relief effect | D | ND | ND | ND | D⑥ | low | |
| Incidence of nausea and vomiting | D | D② | ND | ND | D⑥ | Critically low | |
| Incidence of leukopenia | D | D② | ND | ND | D⑥ | Critically low | |
| Incidence of neutropenia | D | D② | ND | ND | D⑥ | Critically low | |
| Incidence of thrombocytopenia | D | ND | ND | ND | D⑥ | low | |
| Zhan Qi et al. [2011] | ORR | D | ND | ND | ND | D④ | low |
| DCR | D | ND | ND | ND | ND | Middle | |
| Xinmei Tan et al. [2021] | ORR | D | ND | ND | ND | ND | Middle |
| DCR | D | ND | ND | ND | ND | Middle | |
| 1-y OS | D | ND | ND | ND | ND | Middle | |
| 2-y OS | D | ND | ND | D③ | ND | low | |
| QOL improvement | D | ND | ND | ND | ND | Middle | |
| Incidence of leukopenia | D | ND | ND | ND | ND | Middle | |
| Incidence of renal injury | D | ND | ND | ND | ND | Middle | |
| Incidence of liver injury | D | ND | ND | ND | ND | Middle | |
| Incidence of nausea and vomiting | D | ND | ND | ND | ND | Middle | |
| Incidence of thrombocytopenia | D | ND | ND | ND | ND | Middle | |
| Incidence of anemia | D | ND | ND | D③ | ND | low | |
| Incidence of alopecia | D | ND | ND | D③ | ND | low | |
| Bingduo Zhou et al. [2015] | ORR | D | ND | ND | ND | ND | Middle |
| 1-y OS | D | ND | ND | ND | ND | Middle | |
| KPS | D | ND | ND | ND | ND | Middle | |
| pain relief effect | D | ND | ND | ND | ND | Middle | |
| Incidence of nausea and vomiting | D | ND | ND | ND | ND | Middle | |
| Incidence of leukopenia | D | ND | ND | ND | ND | Middle | |
| Incidence of thrombocytopenia | D | ND | ND | ND | D④ | low | |
| Wenpan Peng et al. [2021] | ORR | D | ND | ND | ND | ND | Middle |
| 1-y OS | D | ND | ND | ND | ND | Middle | |
| 2-y OS | D | ND | ND | ND | ND | Middle | |
| Incidence of leukopenia | D | ND | ND | D② | ND | low | |
| Incidence of thrombocytopenia | D | ND | ND | D② | ND | low | |
| Incidence of nausea and vomiting | ND | ND | ND | ND | D③ | Middle | |
| CD3+T Cells level improvement | ND | ND | ND | D② | D③ | low | |
| CD4+T Cells level improvement | ND | ND | ND | D② | D③ | low | |
| CD4+/CD8+ T Cells level improvement | ND | ND | ND | D② | D③ | low | |
| Yisheng Zhao et al. [2023] | DCR | D | ND | ND | ND | ND | Middle |
| 1-y OS | D | ND | ND | ND | ND | Middle | |
| 2-y OS | D | ND | ND | D② | ND | low | |
| Incidence of leukopenia | D | ND | ND | ND | ND | Middle | |
| CD3+T Cells level improvement | D | D② | ND | ND | ND | low | |
| CD4+T Cells level improvement | D | D② | ND | ND | ND | low | |
| CD4+/CD8+ T Cells level improvement | D | D② | ND | ND | ND | low |
Abbreviations: D: downgrade 1 level; ND: no downgrade. ① The experimental design had a bias in randomization, distribution, findings or blinding method. ② The overlap of confidence intervals in the included studies was narrow, or the level of heterogeneity was substantial. ③ Inclusion of studies with small sample sizes or wide confidence intervals across the null line. ④ Funnel chart asymmetry. ⑤ The studies included had a small sample size, which could lead to potential publication bias. ⑥ All results were positive and no publication bias was assessed. ⑦ There are conflicts of interest.
Short-term effect
The main short-term efficacy metrics in involved studies were ORR and DCR, and the results show a significant increase in efficacy in the treatment group compared to the control group. For ORR, four13,19,20,26 SRs/MAs presented a medium level of evidence, four21 -24 studies were of low quality and one 25 was critically low quality. Regarding DCR, 3 studies19,24,27 reported the metric, and the results demonstrated a significant improvement in DCR for the treatment group, supported by evidence of moderate quality.
Long-term effect
Seven studies reported the 1-year survival, and 6 reported the 2-year survival. In all cases, patients’ long-term survival was significantly improved in treatment groups compared with the control group. Regarding 1-year survival, 5 studies13,19,21,26,27 were of middle quality, 2 studies20,23 were of low quality. In terms of 2-year survival, 3 studies20,21,26 were moderate quality, 3 studies19,23,27 were low quality. According to the GRADE statement, while the results show that this combination treatment prolongs patient survival, a notable percentage of indications are still ranked as low, which could potentially diminish our trust in this outcome.
Quality of life
Six papers reported evaluations on the quality of life. The findings indicate that the treatment group significantly improved the quality of life in comparison to the control group. Five of them used the Karnofsky Performance Status (KPS) assessment instrument: 2 of these13,21 were rated as moderate quality, 1 study 23 was rated as low quality, and the remaining22,25 were rated as critically low quality. One paper 19 did not provide a comprehensive description of the assessment tools, only referring to them in a generic manner as quality of life (QOL) assessments, and its quality of evidence presented was moderate.
Pain relief effect and immune response
Three trials have shown the pain relief impact, with data indicating that the treatment group significantly decreased patients’ pain responses and exhibited higher rates of pain relief compared to the control group. Two of these trials13,21 were of moderate quality, while 1 study 23 was of low quality.
Regarding the immunological response, 2 studies26,27 indicated that the combination of HCS and chemotherapy significantly enhances the effectiveness of CD3+, CD4+, and CD4+/CD8+ ratio compared with chemotherapy alone. Nevertheless, their quality level was evaluated as low and one study 26 did not reach statistical significance.
Safety evaluation
Seven reported the incidence of leukopenia, results showed a significant reduction in the incidence of leukopenia in the treatment group, among those, 4 SRs/MAs13,19,21,27 were of moderate quality evidence, 2 SRs/MA22,23 were of critically low level of evidence. Specifically, a single study 26 was evaluated as having low quality and did not achieve statistical significance. One study reported the incidence of neutropenia and showed that the treatment group mitigated this adverse effect, albeit with a critical low level of evidence. 23 Six studies reported the incidence of thrombocytopenia, of which 4 showed an improvement in the treatment group, the quality of the studies ranged from moderate19,21 to low.22,23 Two studies13,26 presented findings with low-quality evidence and did not demonstrate statistical significance.
Six SRs/MAs reported the presence of nausea and vomiting. The findings indicated that the treatment group exhibited a reduction in the occurrence of adverse reactions, with moderate13,19,21,26 to critically low quality.22,23 Two studies documented the occurrence of renal dysfunction in patients and showed a reduction in renal dysfunction in the treatment group compared to the control group. The level of evidence was classified as moderate in one study 19 and low in the other. 22
Two articles documented the frequency of liver injury. The first study 19 reported that the treatment group showed an improvement in liver injury in patients with moderate quality of evidence, whereas the second study 22 showed that the result was negative with low quality of evidence. Two studies reported alopecia incidence and showed a reduction in the treatment group with 1 study being of moderate quality 21 and the other of low quality. 19 Another study 22 reported neurotoxicity incidence, however, the results did not achieve statistical significance and the level of evidence was deemed low. In conclusion, HCS effectively decreases the occurrence of chemotherapy adverse event, especially in myelosuppression, but the poor quality evidence reduces credibility.
Discussion
Increasing evidence indicates that HCS serves as a useful adjunct in improving cancer survival, quality of life, and mitigating the adverse effects of chemotherapy. Notwithstanding, the current clinical trials on the adjuvant treatment of HCS in NSCLC are hindered by various limitations, including small sample numbers, research conducted exclusively in China, insufficient experimental design, and possible bias. Therefore, the results of these RCTs lack convincing force and impede their broad implementation in clinical practice. SRs/MAs are rigorous and quantitative analyses of data derived from clinical trials. Although the quantity of SRs/MAs published on this subject is increasing, SRs/MAs face difficulties in drawing consistent outcomes and dependable conclusions due to the inadequate quality of the primary data from RCTs. In addition, it also should be noted that not all SRs/MAs conform to the PRISMA criteria or the GRADE criteria, which are used to evaluate the quality of evidence. This lack of adherence reduces our confidence in the conclusions from these studies. All mentioned shortcomings erode our confidence in their conclusions. Overview is a systematic research approach that involves re-analyzing relevant SRs/MAs to synthesize their data and evaluate their quality. Its objective is to furnish clinicians with superior quality evidence for the practice of evidence-based medicine. Furthermore, on a methodological level, it can provide guidance for the development of more rigorous RCTs and SRs/MAs through the implementation of standardized evaluation procedures.
Our overview encompassed 10 SRs and MAs that examined the effectiveness of HCS adjuvant therapy in the treatment of NSCLC, and systematically assessed their methodological quality, reporting quality, and risk of bias. The effectiveness and safety data relating to the subject were subsequently integrated and summarized. In a word, HCS has notable efficacy in improving short-term efficacy, prolong survival rate, enhancing quality of life as well as improving immune response. When it comes to adverse event incidence, it also showed a significantly mitigate effectiveness in reducing myelosuppression and the occurrence of nausea and vomiting. However, in the aspects of liver function and neurological impairment that are less reported, the results of the statistics show greater variability, which may be related to the small sample size and differences in data synthesis methods.
Research Gaps to be Addressed
According to our review, we have also identified the common shortcomings of the current stage of these SRs/MAs. In the methodological quality section, those results exhibited a common deficiency concerning the registration of advance protocols, the search of gray literature, the provision of lists of excluded literature, and the declaration of financial support availability.
The PRISMA, AMSTAR, and ROBIS evaluations suggest that the quality of SRs/MAs has been affected by several common deficiencies, including the absence of program registration, non-standardized literature retrieval, extraction and screening, as well as biased data processing. According to the GRADE score, none of the outcome indicator results met the criteria for high-quality evidence, with 50.95% being of low or very low quality. The primary reason was that the original studies that were included in the systematic evaluation did not provide a clear description of random allocation method, allocation concealment, blinding and outcomes which resulted in a lower level of evidence. The GRADE score indicated that the outcome indicators had poor reporting quality. More than half of the outcomes were rated as low or very low quality, primarily due to the risk of bias and inconsistency, which could be attributed to the inclusion of the original low-quality RCTs. Besides, during an evaluation the scales mentioned above, many items undergoing assessment were evaluated subjectively by researchers. The evaluative decisions were based on the evaluation criteria and background knowledge. The scales also could not provide accurate and definitive information regarding crucial aspects such as the “whether there was a plan prior to the systematic evaluation,” potentially resulting in discrepancies in the evaluations.
To summarize, there is significant potential for enhancing the quality of rigorously designed and executed RCTs. Additionally, it is crucial to continually update and refine the evaluation scales used in these trials.
Implications for Research and Practice
As is known to us, methodological deficiencies can restrict the dependability of SRs/MAs. Inadequate reporting of SRs/MAs can overstate the effectiveness of interventions or conceal adverse events, and the presence of risk of bias will undermine their evidence precision.
Based on the results above, researchers are strongly advised to register their research protocols prior to conducting SRs/MAs in order to ensure a transparent process. To ensure accuracy and mitigate the potential risk of bias, it is necessary to conduct information extraction when extracting and evaluating data. Additionally, in order to guarantee the transparency and replicability of the SRs/MAs, the researcher ought to enumerate and elucidate the list of literature that was excluded, as well as provide a comprehensive and complete search strategy including all databases. Besides, making sensitivity analysis is essential to ensure the stability of the aggregated data. If any heterogeneity were obvious, subgroup analyses should be chosen, or the study with significant influence should be excluded, or in some instances, the pooled analyses can be ignored. Moreover, it is imperative for authors of RCTs to adhere to the fundamental standards for reporting clinical trials, which include implementing the double-blind technique and allocation concealment, as well as promptly analyzing cases that are lost to follow-up or withdrawn from the study, implementing such measures would ultimately enhance the quality of research in evidence-based medicine by facilitating the decrease of methodological discrepancies and reporting bias.
Strengths and Limitations
As we know, this overview is the first article of SRs/MAs on HCS as an adjuvant treatment in cancer care. It offers a lucid and comprehensive portrayal of the level of evidence and limitations related to the effectiveness and safety of SRs/MAs regarding this topical, which can be a valuable reference for the development and clinical application of corresponding SRs/MAs in the future.
However, there are also some limitations in the overview. Firstly, a manual search was not conducted, and the literature searched was predominantly in Chinese and English, which may cause selection bias. Secondly, the evaluation criteria were subjectively assessed by the researchers, leading to potential bias due to differences in levels and interpretations between evaluators. Finally, there is no clear standard currently available for systematic evaluation methods, resulting in possibly inaccurate and incomplete evaluation results.
Conclusion
HCS can be used as an adjuvant therapy for NSCLC, with a role in improving immune response, prolonging survival, improving quality of life and mitigating adverse effects. Nevertheless, the existence of methodological deficiencies and discrepancies in the outcomes renders inadequate quality and trustworthiness in current evidence, which makes it harder to come to a clear conclusion. Therefore, with the goal of improving the quality of evidence utilized in clinical decision-making, we propose a more rigorous adherence to the relevant standards and protocols for systematic reviews and meta-analyses in the future. Furthermore, it is equally crucial to have meticulously planned, thoroughly published, and rigorously implemented RCTs.
Acknowledgments
None.
Footnotes
Abbreviations: AMSTAR2: The Assessment of Multiple Systematic Reviews 2; AE: Adverse event; Chemo: chemotherapy; CT: conventional treatment; CG: control group; CNKI: China national knowledge infrastructure database; DCR: disease control rate; GRADE: Grading of Recommendations Assessment, Development and Evaluation; GP: gemcitabine + cisplatin; HCS: Huachansu; KPS: Karnofsky Performance Scale; MAs: meta-analyses; NSCLC: non-small cell lung cancer; ORR: overall response rate; OS: overall survival; PRISMA: guidelines Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines; QOL: quality of life; ROBIS: Risk of Bias in Systematic Reviews; RCT: randomized clinical trial; SRs: systematic reviews; SinoMed: Chinese BioMedical Literature Database; TG: treatment group; VIP: Chinese Scientific Journals Database;
Credit Authorship Contribution Statement: All authors have no objection to the distribution of contributions. Tiantian Yang: Conceptualization, Methodology, Investigation, Resources, Data curation, Writing-original draft, Writing-review & editing, Visualization. Caixian Wu: Formal analysis, Investigation, Writing-original draft, Visualization. Peicong Li: Formal analysis, Investigation, Writing-original draft, Visualization. Yuetong Zhong: Investigation, Writing-review & editing. Sumei Wang: Writing Software, Resources, Data curation, Supervision. Wanyin WU: Writing-review & editing, Project administration, Funding acquisition. Xiaobing Yang: Conceptualization, Writing-review & editing, Project administration, Funding acquisition.
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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by grants from the Key Project of State Key Laboratory of dampness syndrome of Chinese medicine jointly built by the province and Ministry (SZ2021ZZ38). The funders had no role in the study design, data analysis, or decision to publish.
ORCID iDs: Tiantian Yang 
https://orcid.org/0009-0003-0497-8110
Yuetong Zhong
https://orcid.org/0009-0003-6804-1685
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