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REVIEW ARTICLE
Year : 2023 | Volume
: 9
| Issue : 3 | Page : 270-277
Efficacy and safety of huachansu capsules for the treatment of esophageal cancer: A systematic review and meta-analysis
Meng-Meng Wang1, Xing-Hui Zhang1, Jun-Yan Wang1, Jing Xua1, Ming-Zhu Chen1, Shu-Yue Wang1, Min Jia1, Zhi-Wen Shen1, Ling-Jian Zhang1, Yang Gong2, Jian Gong1
1 Research Group of Jian Gong on Pharmacoepidemiology and Clinical Drug Evaluation, Scool of Life Science and Biopharmaceutics, Shenyang PharmaceuticalUniversity, Shenyang, China
2 School of Biomedical Informatics, University of Texas Health Science Center, Houston, Texas, USA
Correspondence Address:
Dr. Jian Gong
Research Group of Jian Gong on Pharmacoepidemiology and Clinical Drug Evaluation, Shenyang Pharmaceutical University, Shenyang 110016
China
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2311-8571.355009
The objective of this study was to systematically evaluate the efficacy and safety of Huachansu capsules in the treatment of esophageal cancer. We searched all relevant Chinese and English documents in the Cochrane Library Clinical Controlled Trials, PubMed, EMBASE, CNKI, and VIP databases, from the time the databases were established to December 2020. The studies were selected according to the inclusion and exclusion criteria, and their quality was evaluated. We used RevMan 5.4 to conduct the meta-analysis of measurement indicators and intervention measures. Six randomized controlled trials comprising 526 patients with esophageal cancer were included in the study. Compared with radiotherapy and chemotherapy alone, oral Huachansu capsules combined with radiotherapy and chemotherapy improved the clinical efficacy (risk ratio [RR] = 1.35, 95% confidence interval [CI], 1.17–1.55, P < 0.0001), quality of life (weighted mean difference [MD] = 10.01, 95% CI [3.39–16.64], P = 0.003), and immune level (CD3+: MD = 4.99, 95% CI [3.70–6.29], P < 0.0001; CD4+: MD = 6.49, 95% CI [5.55–7.42], P < 0.0001; CD5+: MD = 0.20, 95% CI [0.11–0.28], P < 0.0001), and reduced toxic and side effects (reductions in white blood cell count: RR = 0.63, 95% CI [0.44–0.90], P = 0.01; Reductions in blood platelet: RR = 0.70, 95% CI [0.52–0.94], P = 0.02; Gastrointestinal reaction: RR = 0.73, 95% CI [0.59–0.89], P = 0.002). However, the number of included studies was small, and conclusions still need to be further verified using larger samples and high-quality randomized, double-blind controlled trials.
Keywords: Cinobufagin, efficacy, esophageal cancer, meta-analysis, safety
Esophageal cancer is a common gastrointestinal tumor with the seventh highest incidence rate of malignant tumors and the sixth highest mortality rate globally.[1] The global proportion of esophageal cancer cases in China is as high as 62.90%, and of related deaths, as high as 52.70%.[2] Esophageal cancer has become a major threat to the health of the Chinese population. The occurrence and development of esophageal cancer are mainly related to genetic factors and regional characteristics. Factors such as gene mutation, abnormal DNA damage repair, and the tumor microenvironment can all be involved in the occurrence and development of esophageal cancer. The early symptoms of esophageal cancer are not obvious; however, in the advanced stage, it mainly manifests as progressive dysphagia. The patient gradually became emaciated, dehydrated, and weakened. Persistent chest or back pain indicates advanced symptoms and that cancer has invaded tissues outside the esophagus. Horner syndrome can occur when cancer compresses the cervical sympathetic ganglia; it invades the trachea and bronchi, which can form esophageal, tracheal, or bronchial fistulas and cause respiratory infection. Metastasis to the liver, brain, and other organs can be life-threatening. The diagnosis of esophageal cancer is not easy. Most patients are diagnosed when the disease is at an advanced stage, missing the opportunity to receive surgical treatment. Radiation and chemotherapy are more effective means of treating esophageal cancer, thus becoming the doctor and patient's first choice.[3] However, radiotherapy and chemotherapy may reduce immune function and cause serious adverse reactions such as nausea and vomiting. Studies have shown that certain Chinese medicines, such as Huachansu, affect cancer conditions and alleviate the side effects of radiotherapy and chemotherapy. Therefore, they can be used as adjuvant drugs for radiotherapy and chemotherapy, helping to improve patient's quality of life and prolong survival.[4]
As a valuable asset of the Chinese civilization, Chinese medicine has unique advantages in tumor treatment. Therefore, Chinese medicine is widely used in clinical practice as an adjuvant for radiotherapy and chemotherapy. This study found that combining Huachansu injection with radiotherapy or chemotherapy can significantly improve the curative effect in patients with esophageal cancer and effectively reduce the adverse reactions caused by radiotherapy or chemotherapy.[5] A few clinical studies on the treatment of esophageal cancer with Huachansu (isolated from ChanSu, a traditional Chinese medicine) injection and some clinical studies on the application of cinobufacin capsules by oral administration have been conducted. However, a systematic evaluation is currently lacking. Therefore, this study aimed to objectively evaluate the safety and effectiveness of oral Huachansu capsules in the treatment of esophageal cancer by collecting existing clinical research data and using statistical methods to provide a basis for clinical workers' medication decisions.
MethodsSearch strategy
We searched the electronic databases of CNKI, VIP Database, Wanfang Data, PubMed, Cochrane Library, and EMBASE from database construction to December 2020. The keywords used were “cinobufotalin,” “huachansu,” “esophageal cancer,” and “esophageal neoplasms.”
Inclusion criteria
(1) Patients diagnosed with esophageal cancer by pathology, histology, or imaging; (2) research type: randomized controlled trial (RCT); (3) intervention measures: oral Huachansu capsule combined with radiotherapy and chemotherapy; (4) observation indicators: at least one of the clinical efficacy, quality of life (Karnofsky Performance Score), adverse reactions, and immune indicators.
Exclusion criteria
(1) Nonclinical research; (2) clinical studies that were not related to the purpose of this study; (3) combined use of other drugs or methods and other treatment plans that do not match the literature; (4) nonrandomized study; (5) intravenous injection and other nonoral administration routes; and (6) repeated publication or similar literature.
Data extraction and analysis
Two researchers independently read the title and abstract of each publication to exclude items not meeting the requirements. Then, they further screened the full text according to the inclusion and exclusion criteria. Finally, disagreements were resolved by a discussion and settlement involving a third participating researcher.
A researcher extracted data from the final included literature, including the title of the paper, the first author, the journal published, the status of the research object (number of cases, age, sex, disease status, etc.), intervention measures (drug dosage, usage, course of treatment, etc.), observation indicators (disease control rate, quality of life, adverse reactions, etc.); these data were finally checked by another researcher.
Methodology quality assessment
We assessed the methodological quality of each RCT using the Cochrane risk-of-bias tool. Three quality judgments were made of all included trials: low, unclear, or high risk of bias. Trials that met all criteria were classified as having low risk of bias. Trials that did not meet any criteria were classified as having high risk of bias. Trials without enough information to make a judgment were classified as having an unclear risk of bias.
Statistical analyses
We used the RevMan 5.4 (Cochrane, London, UK) provided by the Cochrane Collaboration Network for data processing to design the study. The enumeration data used the Mantel–Haenszel method to calculate each study's Risk Ratio (RR) and their combinations. Continuous variables were analyzed using mean difference (MD) analysis statistic standardized mean; both were expressed with a 95% confidence interval (CI). Heterogeneity between the studies was assessed using the Cochrane Q test. If the test results indicated that there was no significant heterogeneity (P ≥ 0.1, I2 ≤ 50%), the fixed-effects model was used for analysis. Results with significant heterogeneity (P < 0.1, I2 > 50%) were combined and analyzed using the random-effect model. If necessary, subgroup analysis and sensitivity analysis were performed. Statistical significance was set at P < 0.05.
ResultsSearch results
We initially retrieved 96 articles; six RCTs were included after screening [Figure 1].
Study description
Six RCTs included 526 patients with esophageal cancer. Most of the patients included were in the advanced stages or were unsuitable for surgery and had not received radiotherapy or chemotherapy. Among them, 323 were male, and 203 were female. All publications provided baseline comparability between groups and statistical evidence.
All six RCTs used oral Huachansu capsules combined with radiotherapy and chemotherapy as interventions in the treatment group compared with radiotherapy and chemotherapy alone, including three using combined radiotherapy and chemotherapy,[6],[7],[8] one using radiotherapy alone,[9] and two using chemotherapy alone.[10],[11] The published studies used 0.25 g/capsule, 2 capsules/time, 3 times/day, and treatment durations of more than 4 weeks [Table 1].
Table 1: The general conditions of included randomized controlled trial studiesQuality assessment
Among the six RCTs, only three mentioned the use of the random number table method for grouping. The other three documents did not indicate the specific random method. No blinding was used in any included studies. Allocation concealment was not mentioned, and no baseline and other balance biases were indicated. [Figure 2] and [Figure 3] show the risks associated with the biased data.
Efficacy evaluation
Clinical efficacy
This outcome was reported in all the studies. According to the WHO regulations, the efficacy evaluation was categorized as complete response (CR), partial response (PR), stable disease, and progressive disease. The effective dose was CR + PR.
The heterogeneity test showed no significant statistical heterogeneity among the studies (P = 0.66, I2 = 0%), and the fixed-effects model was used for meta-analysis. The results showed that, compared with the control group, the oral Huachansu capsule significantly increased the effective rate of radiotherapy and chemotherapy for esophageal cancer (RR = 1.35, 95% CI [1.17–1.55], P < 0.0001). A subgroup analysis showed that oral Huachansu capsules improved the efficacy of radiotherapy, chemotherapy, and radiotherapy (RR = 1.27, 95% CI [1.06–1.52], P = 0.01; RR = 1.31, 95% CI [1.03–1.67], P = 0.03; RR = 1.56, 95% CI [1.13–2.15], P = 0.006), respectively, with the differences being was statistically significant [Figure 4].
Quality of life - Karnofsky Performance Score
Two studies reported this indicator; both used the intervention measure “Huachansu + chemotherapy VS chemotherapy,” and the data types were all measurement data.
The measurement data showed significant statistical heterogeneity among the studies (P = 0.0006, I2 = 91%), and the random-effects model was used for meta-analysis. The results showed that oral Huachansu capsules significantly improved the quality of life of patients with esophageal cancer (MD = 10.01, 95% CI [3.39–16.64], P = 0.003), and the results were statistically significant [Figure 5].
Figure 5: Karnofsky Performance Score scoring. CI: Confidence interval, SD: Standard deviation, MD: Mean differenceImmune function
Two articles reported indicators, including CD3+, CD4+, and CD4+/CD8+; the intervention measures were “Huachansu + radiotherapy and chemotherapy versus radiotherapy and chemotherapy,” and the data types were all measurement data.
The heterogeneity test showed no significant statistical heterogeneity among the studies (P = 0.89, I2 = 0%; P = 0.74, I2 = 0%; P = 0.85, I2 = 0%) using a fixed-effect model for meta-analysis. The results showed that, compared with the control group, oral administration of Huachansu capsule significantly increased the immune level after radiotherapy and chemotherapy for esophageal cancer (MD = 4.99, 95% CI [3.70–6.29], P < 0.0001; MD = 6.49, 95% CI [5.55–7.42], P < 0.0001; MD = 0.20, 95% CI [0.11–0.28], P < 0.0001), respectively. The results were considered to be statistically significant [Figure 6].
Figure 6: CD3+, CD4+, and CD4+/CD8+. CI: Confidence interval, SD: Standard deviation, MD: Mean differenceAdverse reactions
Reductions in white blood cell
The following indicators were observed in six studies, with a total of 12 types of adverse reactions. The most frequent were leukopenia, thrombocytopenia, and gastrointestinal reactions. In addition, statistics on liver damage, anemia, myalgia, and fatigue have been reported in some studies based on quantitative data.
The heterogeneity test showed significant statistical heterogeneity among the studies (P = 0.02, I2 = 65%), and the random-effects model was used for the meta-analysis. Compared with the control group, the results showed that oral Huachansu capsules reduced leukopenia after radiotherapy and chemotherapy for esophageal cancer (RR = 0.63, 95% CI, [0.44–0.90], P = 0.01). The results were considered to be statistically significant [Figure 7].
Figure 7: Reductions in WBC counts. CI: Confidence interval, WBC: White blood cellReductions in platelet
The heterogeneity test showed no significant statistical heterogeneity among the studies (P = 0.68, I2 = 0%), and the fixed-effects model was used for meta-analysis. Compared with the control group, the results showed that oral Huachansu capsules reduced thrombocytopenia after radiotherapy and chemotherapy for esophageal cancer (RR = 0.70, 95% CI, [0.52–0.94], P = 0.02). The results were considered to be statistically significant [Figure 8].
Gastrointestinal reaction
The heterogeneity test showed no significant statistical heterogeneity among the studies (P = 0.61, I2 = 0%), and the fixed-effects model was used for meta-analysis. The results showed that, compared with the control group, oral Huachansu capsules reduced the incidence of gastrointestinal reactions after radiotherapy and chemotherapy for esophageal cancer (RR = 0.73, 95% CI [0.59–0.89], P = 0.002). The results were considered to be statistically significant [Figure 9].
Publication bias review
The funnel diagram of the effect of Huachansu combined with radiotherapy and chemotherapy on the curative effect was relatively symmetric. Further analysis by the Egger test results at P = 0.265 proved that there was no obvious publication bias in this study [Figure 10].
Sensitivity analysis
Sensitivity analysis showed that the combined RR values of the six included studies were eliminated in sequence. Their combined RR values did not change significantly, indicating that the meta-analysis results were stable [Figure 11].
DiscussionBecause of the strong side effects caused by radiotherapy and chemotherapy cancer treatment, researchers have recently explored the potential of traditional Chinese medicine's anti-cancer active ingredients. Clinical studies have shown that Huachansu capsules improve the sensitivity of radiotherapy and chemotherapy, improve treatment outcomes, reduce the adverse reactions caused by radiotherapy and chemotherapy, and relieve pain caused by malignant tumors or chemotherapy drugs.[12] Combining Chinese and Western medicine to treat cancer can effectively improve the survival cycle of patients, improve the quality of life, eliminate residual cancer cells, with improvements over conventional treatment.[13]
Huachansu capsule is a Chinese medicinal anti-tumor preparation developed by extraction and processing. Dry toad skin treatment was first recorded in Shen Nong's Herbal Classic with detoxification, swelling, pain relief, and other effects. Its active ingredients, including steroids, alkaloids, and amino acids, exert anti-tumor effects.[14] The same bioactive compounds are present in warfarin, and the anti-tumor activity of valufon may also be due to such ingredients.[15] The research shows that Huachansu and its active compounds have significant anti-tumor activity by affecting the cell growth cycle, inducing tumor apoptosis, inhibiting tumor cell metastasis, etc.[16] In one study, Huachansu effectively inhibited the proliferation of KYSE-70 cells in esophageal cancer cells, induced apoptosis, reduced Bcl-2 protein expression, improved Bax expression, lowered NF-Bp65 and extracellular signal-regulated kinase phosphorylation levels, and increased p-38 and JNK phosphorylation levels. Cellular reactive oxygen species accumulation, glutathione content, mitochondrial membrane potential, and adenosine triphosphate production decreased, promoting the apoptosis and inhibiting the proliferation of esophageal cancer cells.[17] In addition, Huachansu has a sensitizing effect on adjuvant chemoradiotherapy and reverses multidrug resistance. In clinical treatment, cross-resistance of tumor cells to various anti-tumor drugs is a common phenomenon and is also the main cause of chemotherapy failure. The main drug resistance mechanism of anti-tumor drugs is the overexpression of the membrane transporters P-glycoprotein and multidrug-resistant proteins 1–6 in cancer cells, which transport cytotoxic drugs out of cancer cells, resulting in lower drug utilization and inhibiting the therapeutic effect. Cinobufacin reverses the expression of P-glycoprotein and multidrug-resistant proteins by downregulating the reverse transcription pathway, thereby reversing drug resistance and increasing patient sensitivity to chemotherapeutic drugs. Traditional Chinese medicine for the treatment of esophageal cancer has the advantages of precise curative effects, flexibility and variety, and less toxicity and side effects. Cinobufacin can be used as adjuvant therapy for radiotherapy and chemotherapy or as the main drug therapy for the treatment of esophageal cancer.
Currently, Huachansu capsules have been recognized by the medical community for their advantages of good curative effect, low toxicity, and low price, and they have been widely used in clinical practice. Meta-analyses by Jin et al.,[18] Ge et al.[19] and Huang and Su[20] pointed out that the combined application of Huachansu capsule and chemotherapy drugs can improve the curative effect on gastric and other cancers, increase the effects of radiotherapy and chemotherapy, and reduce the occurrence of side effects. Clinical studies by Dong et al.,[21] Zhu et al.,[22] and Cheng et al.[23] have shown that Huachansu capsules combined with radiotherapy and chemotherapy have a significant therapeutic effect in patients with advanced pancreatic cancer and gallbladder cancer.
This study collected clinical data from six RCTs involving 526 patients on Huachansu capsules combined with radiotherapy and chemotherapy used to treat esophageal cancer. The efficacy and safety were systematically evaluated from four aspects. The experimental group was treated with Huachansu capsules combined with radiotherapy and chemotherapy, and the control group was treated with radiotherapy and chemotherapy alone. All study participants received treatment for 4–12 weeks. The results showed that compared with radiotherapy and chemotherapy alone, oral Huachansu capsules combined with radiotherapy and chemotherapy improve the clinical efficacy, quality of life, and immune level, and reduce toxic side effects, including leukopenia, thrombocytopenia, and gastrointestinal reactions.
From the perspective of methodological quality, there are the following problems and limitations. (1) The quality of the published literature was relatively low. Only three of the six papers included in our study mentioned detailed random allocation methods. None of the papers described the blinding method and distribution hidden. (2) Only three papers reported follow-up, the statistical standards were inconsistent, and there was insufficient information to judge the long-term effectiveness. (3) The number of studies included in this study was small. Larger, high-quality randomized, double-blind controlled trials are required to obtain more evidence. Therefore, there may be some bias in this meta-analysis. Although our results can, to some extent, provide a basis for clinical decision-making, the conclusions need more high-quality clinical research validation.
However, our findings support the clinical treatment with Huachansu capsules combined with chemoradiotherapy for esophageal cancer patients. A series of remarkable achievements in the theory and practice of modern Chinese medicine has attracted increasing attention from researchers. Therefore, efforts should be made to conduct higher-quality clinical trials and improve long-term follow-up results to obtain more accurate conclusions and provide a stronger basis for the clinical application of Traditional Chinese Medicine.
ConclusionThis meta-analysis suggests that in esophageal cancer patients, cinobufagin can be considered an effective and safe adjuvant chemotherapy treatment compared to chemotherapy alone. This study offers significant guidance for the clinical treatment of esophageal cancer.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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