Astragalus injection as an adjuvant treatment for colorectal cancer: a meta-analysis

Jia Wang, Zhu Yang, Fengxi Long, Li Luo, Jinlin Wu, Ting Yu, Dongxin Tang

Astragalus injection as an adjuvant treatment for colorectal cancer: a meta-analysis

Jia Wang1, 3, Zhu Yang1, 3, Fengxi Long1, 3, Li Luo3, 4, Jinlin Wu1, 3, Ting Yu1, 3, Dongxin Tang2, 3*

1Guizhou University of Traditional Chinese Medicine, Guiyang, 550002, China.;2First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China;3Guizhou TCM Inheritance and Innovation Team on Oncology, Guiyang, 550001;4Guihang Guiyang Hospital, Guiyang, 550025, China.

The combination of Chinese patent medicine Astragalus injection and Western medicine has achieved a certain clinical effect in colorectal cancer patients. However, due to the uneven basic conditions and research indicators of these clinical trials, it is difficult to comprehensively evaluate the effect of Astragalus injection in the adjuvant treatment of colorectal cancer. This study aimed to systematically evaluate the efficacy and safety of Astragalus injection as an adjuvant treatment for colorectal cancer.The Cochrane Library, VIP database, Wanfang database, and Chinese Academic Journal Full Text database were searched for potentially eligible articles from inception to December 15, 2018. Randomized controlled trials in which patients were diagnosed with colorectal cancer were included. Patients in the control group received chemotherapy alone or combined with other drugs, or chemotherapy combined with radiotherapy. Patients in the experimental group were treated with Astragalus injection combined with interventions in the control group.A total of 8 articles were included. Compared with Western medicine alone, the Astragalus injection could improve the therapeutic effect (RR = 1.18, 95% CI (1.01, 1.38),= 0.03), improved the quality of life of colorectal cancer patients (SMD = 1.18, 95% CI (0.86, 1.50),<0.001), inhibited leukopenia (RR = 0.55, 95% CI (0.42, 0.71),< 0.001), reduced neurotoxicity (RR = 0.43, 95% CI (0.34, 0.56),< 0.001), and reduced the incidence of nausea and vomiting (RR = 0.67, 95% CI (0.55, 0.80),< 0.001).Astragalus injection can reduce the toxicity and improve the efficiency of the conventional Western medicine in the treatment of colorectal cancer.

Astragalus injection, Colorectal cancer, Adjuvant therapy, Meta-analysis, Randomized controlled trial

As an adjuvant treatment of colorectal cancer, a Chinese patent medicine Astragalus injection can reduce the toxicity and improve the efficiency of the conventional Western medicine.

The herb Huang Qi ((Fisch.) Bge.) was first recorded in the the classical ancient Chinese medicine book entitled(Shennong’s Classic of Materia Medica) (Three Kingdoms period of China, 25 C.E.–220 C.E.). Huang Qi ((Fisch.) Bge.) was considered as one of the representative herb with the function of tonifying the Qi (one of the vital energies in the traditional Chinese medicine theory that circulates around the body at all times). Pharmarcology studies have found that Huang Qi ((Fisch.) Bge.) plays an anti-cancer role by regulating immunity, inducing apoptosis of tumor cells, and inhibiting the growth and metastasis of tumor cells. Astragalus injection, a Chinese patent medicine approved by the State Food and Drug Administration of China with the serial number of 2001ZFB0171, contains Huang Qi ((Fisch.) Bge.) and other ingredients that are widely used in clinical practice of cancer treatment.

Background

Colorectal cancer is the third most common cancer in the world and the fourth leading cause of death from malignant tumors[1]. A report in 2015 showed an increase in the incidence and mortality rates of colorectal cancer in China [2]. Surgery is the main treatment for colorectal cancer, while radiotherapy and chemotherapy can reduce the incidence of recurrence and metastasis. Moreover, studies have shown that the 5-year overall survival rate of colorectal cancer is 90%. Local recurrence occurs in 5% to 10% of patients after operation. The overall survival rate of patients with metastatic or recurrent colorectal cancer is reduced to 5% [3, 4]. Therefore, it is necessary for patients with colorectal cancer to undergo radiotherapy and chemotherapy after operation. However, the side effects caused by radiotherapy and chemotherapy often deter patients. Traditional Chinese medicine can reduce their adverse reactions and increase the therapeutic effect, thus prolonging the survival rate of colorectal cancer patients [5]. Studies have shown that most patients receiving chemotherapy develop gastrointestinal toxicity and myelosuppression, including diarrhea, mucositis, nausea, vomiting, neutropenia, and febrile neutropenia [6]. Irinotecan and capecitabine combined with radiotherapy for locally advanced rectal cancer, 11 cases of leukopenia, 10 cases of neutropenia, and 12 cases of diarrhea were observed in 20 patients [7]. On the other hand, 5-fluorouracil is a chemotherapeutic drug that is widely used in colorectal cancer, may have adverse reactions including alopecia and leukopenia [8]. The standard chemotherapy regimen for stage III colon cancer is oxaliplatin, with the most common side effects of neutropenia, peripheral neuropathy, vomiting, and diarrhea [9]. Oxaliplatin-induced neurotoxicity is the single major dose limiting factor in the treatment of colorectal cancer, which can lead to peripheral neuropathy, difficulty walking, stinging and numbness in the limbs, and increased pain [10]. The side effects of radiotherapy and chemotherapy affect the health, quality of life, and treatment of patients, thus it is necessary to choose effective drugs.

The herb Huang Qi ((Fisch.) Bge.) was first recorded in the the classical ancient Chinese medicine book entitled(Shennong’s Classic of Materia Medica) (25 C.E.–220 C.E.), which is the earliest extant work on traditional herbs and was written in the Three Kingdoms period of China (220 C.E.–280 C.E.). Huang Qi ((Fisch.) Bge.) was considered as one of the representative herb with the function of tonifying the Qi (one of the vital energies in the traditional Chinese medicine theory that circulates around the body at all times) [11]. Astragalus injection, a Chinese patent medicine approved by the State Food and Drug Administration of China with the serial number of 2001ZFB0171, contains Huang Qi ((Fisch.) Bge.) and other ingredients that are widely used in clinical practice. In addition, Huang Qi ((Fisch.) Bge.) plays an anti-cancer role by regulating immunity, inducing apoptosis of tumor cells, and inhibiting the growth and metastasis of tumor cells [12]. According to the existing evidence, in the course of clinical treatment, colorectal cancer patients have achieved certain clinical efficacy by using Astragalus injection on the basis of Western medicine. However, due to the uneven basic conditions and research indicators of these clinical trials and the inconsistency of radiotherapy and chemotherapy schemes, it is difficult to comprehensively evaluate the effect of Astragalus injection as an adjuvant treatment for colorectal cancer. Therefore, this study aimed to systematically evaluate the efficacy and safety of Astragalus injection as an adjuvant treatment for colorectal cancer.

Materials and methods

Search strategy

The Cochrane Library, VIP database, Wanfang database, and Chinese Academic Journal Full Text database were searched for potentially eligible articles from inception to December 15, 2018. The following search keywords were used: (Astragalus injection OR(Fisch.) Bge. injection OR Huang Qi injection OR Astragalus) AND (rectal cancer OR colon cancer OR intestinal cancer OR colorectal cancer). Only studies in Chinese and English language were included. Further, the authors hand-searched the reference lists to look for relevant literatures.

Inclusion criteria

(i) Randomized controlled trial;

(ii) Colorectal cancer patients based on pathological/cytological diagnosis (adenocarcinoma, etc.) [13],no contraindication of chemotherapy, no obvious abnormality of liver and kidney function before treatment;

(iii) Interventions: patients in the control group received chemotherapy alone or combined with other drugs, or chemotherapy combined with radiotherapy. Patients in the experimental group were treated with Astragalus injection combined with interventions in the control group. Chemotherapies in the 2 groups were consistent.

(iv) Outcomes: the primary outcomes were effective rate (complete remission and partial remission according to the WHO criteria for evaluating the efficacy of solid tumors) and the Karnofsky Performance Status (KPS) score [14]. The secondary outcomes were adverse reactions, including bone marrow suppression, nausea and vomiting, and neurotoxicity.

Outcome measurement indexes

Effectiveness. The tumor response probability was calculated as the number of patients experiencing any response (complete response plus partial response) divided by the total number of patients in each treatment group (complete response plus partial response plus no change plus progressive disease).

KPS score. The KPS score is a scale for assessing physical condition with a range from zero to 100 points. The higher the score, the better the health is.

Adverse reactions. Bone marrow suppression (decreased white blood cell and platelet counts), digestive tract reaction, and neurotoxicity. The evaluation of the WHO criteria for acute and subacute toxicity of anticancer drugs is divided into 0–IV grades [15]. The proportion of adverse reactions is equal to the total number of patients with any adverse reactions (I + II + III + IV) divided by the total number of patients in each treatment group (0 + I + II + III + IV).

Literature screening and data extraction

All eligible articles were imported into the NoteExpress document management software for the first time, and the 2 researchers screened the records and extracted data, respectively. Any differences in this process were resolved through discussion or consultation with the third reviewer. The information included the following: name of the first author, year of publication, sample size, interventions, and outcomes.

Assessment of the quality of the included trials

According to the Cochrane Handbook for Systematic Reviews of Interventions Manual 5.1.0, the 2 researchers independently assessed the risk of bias for all involved records. Seven items recommended by the Cochrane manual were as follows: generation of random sequence, assignment concealment, double blindness of implementer and participant, blindness in outcome evaluation, incomplete outcome data, selective outcome report, and other bias sources.

Statistical analysis

The RevMan 5.3 software was used for statistical analysis. The continuous variables were represented by the standardized mean difference (SMD) and 95% confidence interval (CI) and the binary variables were represented by risk ratio (RR) and 95% CI. The statistical heterogeneity across the studies was evaluated using a chi-square test.＞ 0.1 and I2＜ 50% indicated that the heterogeneity was negligible across the studies and a meta-analysis was conducted with the fixed-effect model. On the other hand,＜ 0.1 or I2＞ 50% indicated that the heterogeneity was serious across the studies, and a meta-analysis was conducted with the random-effect model. In addition, a qualitative analysis of publication bias was conducted using funnel diagrams provided by RevMan 5.3 software.

Results

Publication selection

A total of 72 related articles were retrieved, and reduplicated papers were deleted. After reading the title and abstract, 18 articles that did not meet the criteria were excluded. After reading the full texts, 12 articles were excluded, and eight articles that met the inclusion criteria were finally excluded (Figure 1).

Basic characteristics of inclusion studies

A total of 8 articles were included, including 583 patients: 292 in the experimental group and 291 in the control group. The basic information includes the author's name, the year of publication, the number of research samples, the age of patients, the intervention measures, and the judgment criteria. Four articles were treated with FOLFOX regimen, 1 article was treated with FOLFOX/XELOX regimen, 1 with the retitraxel+oxaliplatin regimen, and 2 with neoadjuvant chemotherapy. The criteria included at least the effectiveness, KPS score, and adverse reactions: leukopenia and thrombocytopenia, nausea and vomiting, and neurotoxicity (Table 1).

Bias risk assessment results of the included studies

The quality of the literature included in this study was acceptable (Figure 2).

Clinical efficacy analysis

Effectiveness. Five studies, with a total sample size of 383, reported efficiency [16–20]. Heterogeneity test (= 0.84, I2= 0%) supported the direct synthesis of efficiency. Therefore, fixed-effect model combined effect analysis. Meta-analysis showed that Astragalus injection combined with chemotherapy could improve the treatment efficiency of colorectal cancer patients compared with chemotherapy alone. There was a significant difference between the 2 groups (RR=1.18,95％CI(1.01, 1.38),=0.03)(Figure 3).

Improvement of quality of life. A total of 3 studies reported improvement of KPS [20–22]. Ninety cases in the experimental group and 90 cases in the control group were tested for heterogeneity (= 0.33, I2= 11%) using the fixed-effect model. Meta-analysis showed that Astragalus injection combined with chemotherapysignificantlyimprovedthequalityof life of colorectal cancer patients compared with chemotherapy alone. There were significant differences between the 2 groups(SMD= 1.18, 95％ CI (0.86, 1.50),< 0.001) (figure 4).

Figure 1 Document retrieval process

Adverse reactions

Platelet counts. Four studies, with a sample size of 323, reported changes in platelet count before and after treatment [16–18, 20] using the heterogeneity test (= 0.90, I2= 0%). Therefore, fixed-effect model analysis was used, but the statistical results showed no significant difference (RR = 0.74, 95％ CI (0.55, 1.01),= 0.06), likely associated with too few studies included (figure 5).

Leukocyte counts. Six studies reported leukopenia [16–20, 23] with 232 cases in the experimental group, 231 cases in the control group and heterogeneity test (= 0.42, I2= 0%). The results showed that Astragalus injection could inhibit the adverse reaction of leukopenia (RR = 0.55, 95％ CI (0.42, 0.71),< 0.001), through fixed-effect model analysis (Figure 5).

Neurotoxicity. Five studies reported neurotoxicity [18–22] with 333 samples and heterogeneity test (= 0.95, I2= 0%). Consequently, using the fixed-effect model analysis, the results showed that the adjuvant treatment of Astragalus injection could reduce the adverse reactions of neurotoxicity (RR = 0.43, 95％ CI (0.34, 0.56),< 0.001) (figure 5).

Nausea and vomiting. Six studies reported nausea and vomiting [16–20, 22] with a sample size of 443 cases and heterogeneity test (= 0.82, I2= 0%), therefore, using the fixed effect model analysis, the results showed that the adjuvant treatment of Astragalus injection can reduce the adverse reactions of nausea and vomiting (RR = 0.67, 95％ CI (0.55, 0.80),< 0.001) (figure 5).

Discussion

Radiotherapy and chemotherapy, as the main treatment of malignant tumors, play a significant role in inhibiting the development of tumors, controlling the recurrence and metastasis of tumors as well as consolidating curative effect and improving survival rate. However, due to its non-recognition of the normal and pathological tissues of the human body, cancer patients cannot tolerate serious toxic and side effects after receiving chemotherapy. Such adverse reactions have serious adverse effects on the quality of life of patients with malignant tumors. In addition, patients with malignant tumors are in critical conditions and have a long disease course. Tumor consumptionleadstothedecline ofimmunityand unfavorable physical changes of patients. Therefore, the incidence and severity of adverse reactions of radiotherapy and chemotherapy have increased. It may even lead some patients to treatment termination because of intolerance, which seriously affects the therapeutic effect of patients with malignant tumors. Hence, it is necessary to take effective measures to improve efficiency and reduce toxicity.

Table 1 Basic features of the study

T, experimental group; C, control group; NA, not mentioned; HQ, Astragalus injection; FOLFOX, oxaliplatin + calcium folinate +5-fluorouracil; XELOX, oxaliplatin + capecitabine; ①, white blood cell count; ②, efficiency; ③, platelet count; ④, nausea and vomiting; ⑤, neurotoxicity; ⑥, Karnofsky Performance Status score improvement.

Figure 2 Risk of bias graph

Figure 3 Meta-analysis of clinical efficacy in the two groups. CI, confidence interval.

Figure 4 Meta-analysis of KPS improvement in the two groups. CI, confidence interval.

This study find that Astragalus injection combined with chemotherapy can improve the efficiency of the conventional Western medicine in colorectal cancer patients, indicating that it can play a synergistic role in the treatment of colorectal cancer. The KPS score assesses the patient's health status according to the patient's condition, self-care level, and whether normal exercise products are available. The KPS score increase indicates the improvement of patients' quality of life, which is helpful to reduce patients' pain and improve the clinical cure rate. Through meta-analysis of the safety and efficacy of Astragalus injection in the adjuvant treatment of colorectal cancer, the results show that it can improve the KPS score of colorectal cancer patients. Astragalus injection can not only improve the quality of life of patients and play a synergistic role; however, it can also reduce the side effects of bone marrow suppression. A meta-analysis of hemogram shows that Astragalus injection assisted treatment of colorectal cancer can inhibit the decline of white blood cells and alleviate bone marrow suppression and can further reduce the occurrence of adverse reactions such as digestive tract reaction and neurotoxicity, thereby improving the prognosis of patients. Therefore, the adjuvant treatment of Astragalus injection for colorectal cancer is of great significance to reduce the adverse reactions of patients.

This study is consistent with the current research of Astragalus injection in the field of oncology. For instance, a study has shown that Astragalus can reduce nausea and vomiting caused by oxaliplatin in the treatment of colorectal cancer [24]. Astragalus injection combined with Shengmai injection can effectively reduce the bone marrow suppression level caused by radiotherapy and chemotherapy, and improve the physical condition and the quality of life of patients [25]. Astragalus injection is effective in preventing and treating neurotoxicity caused by oxaliplatin chemotherapy, which can reduce the overall incidence and severity of neurotoxicity [26]. Furthermore, studies have shown that Astragalus injection regulates the development of colon cancer by controlling the expression of calmodulin-mediated glucose regulatory proteins [27]. Lastly, the Astragalus polysaccharide inhibits 5-fluorouracil-induced cardiomyocyte apoptosis mainly by relieving oxidative stress [28].

Conclusion

In conclusion, Astragalus injection can play a synergistic and attenuating role in the adjuvant treatment of colorectal cancer, thereby providing a clinicalmedicationreference;however,larger samples and more high-quality studies are needed to further confirm the efficacy. In addition, we can do further research on the therapeutic effect of Astragalus injection on colorectal cancer patients in the future.

Figure 5 Meta-analysis of adverse reactions. CI, confidence interval.

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This work was supported by a grant from the National Natural Science Foundation of China Regional Science Fund Project (81673862, 81660833, 81760814), Guizhou Provincial Department of Education Project (Qian Jiao Yan He GZS ZI (2016) 08), Guizhou Postgraduate Workstation Program (Educational Hall) Project (Qian Jiao Yan He JYSZ ZI (2014) 018), Guizhou Science and Technology Department Project (Qian Ke he Ren Cai (2016) 4032) and Guizhou Provincial Organization Department Project (Qian Ren Ban Fa (2018) No.3).

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KPS, Karnofsky Performance Status; SMD, standardized mean difference; CI, confidence interval; RR, risk ratio;

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The authors declare that they have no conflict of interest. The authors alone are responsible for the content of the paper.

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Jia Wang, Zhu Yang, Fengxi Long, et al. Astragalus injection as an adjuvant treatment for colorectal cancer: a meta-analysis. Traditional Medicine Research 2020, 5 (1): 53–61.

: Xiaohong Sheng

: 8 December 2019,

27 Decembe 2019,

:30 December 2019.

Dongxin Tang. First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No.71 Baoshan North Road, Yunyan District, Guiyang, 550001, China. E-mail: tangdongxin@sina.com.