Evidence-Based Complementary and Alternative Medicine
Volume 2019 (2019), Article ID 8423037, 15 pages
https://doi.org/10.1155/2019/8423037

Review Article

Kangai Injection, a Traditional Chinese Medicine, Improves Efficacy and Reduces Toxicity of Chemotherapy in Advanced Colorectal Cancer Patients: A Systematic Review and Meta-Analysis

Siqi Huang,¹ Weijun Peng,¹ Dan Mao,¹ Shaofan Zhang,² PanPan Xu,¹ PengJi Yi,¹ and Sifang Zhang¹

¹Department of Integrated Traditional Chinese and Western Internal Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, China
²Department of Oncology, Yueyang Hospital of Traditional Chinese Medicine, Yueyang, Hunan 414000, China

Correspondence should be addressed to Sifang Zhang; sifangzhang2005@csu.edu.cn

Received 27 March 2019; Revised 1 June 2019; Accepted 17 June 2019; Published 15 July 2019

Academic Editor: Oliver Micke

Copyright © 2019 Siqi Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. To systematically review whether the Kangai injection (KAI), which is commonly used traditional Chinese medicine, can improve the clinical efficacy of chemotherapy and relieve adverse reactions of chemotherapy in advanced colorectal cancer (CRC) patients. Methods. A comprehensive literature search was performed in three English and three Chinese electronic databases until March 2019. The literature was screened by EndNote X8 and data were analysed by RevMan5 and Stata12.0. Results. This meta-analysis consisted of twenty-eight studies, of which 2310 cases were reported. Among the 2310 cases, 1207 cases were treated with KAI combined with chemotherapy and 1103 cases were treated with chemotherapy alone. The results showed that KAI combined with chemotherapy significantly improved tumor response (Risk Ratio (RR) =1.32; 95% confidence interval (CI): 1.22-1.43; p<0.00001); Karnofsky performance status (KPS score) (Risk Ratio (RR) =1.48; 95% CI: 1.36-1.60; p<0.00001); reduced adverse drug reactions (ADRs) such as nausea and vomiting (OR =0.31; 95% CI: 0.24-0.41; p <0.00001), diarrhea (OR =0.36; 95% CI: 0.25-0.52; p<0.00001), leukopenia (OR =2.97; 95% CI:2.27-3.88; p<0.00001), thrombocytopenia (OR =0.53; 95% CI: 0.38-0.74; p<0.0002), liver dysfunction (OR =0.29; 95% CI: 0.20-0.44; p<0.00001), neurotoxicity (OR =0.51; 95% CI: 0.36-0.71; p = 0.0004); increased immune function (CD3⁺: MD=6.34; 95% CI: 5.52-7.16; p < 0.00001, CD4⁺: MD=-5.99; 95% CI: 5.20-6.78; p < 0.00001; and CD4⁺/CD8⁺: MD=0.34; 95% CI: 0.14-0.54; p < 0.0009), and prolonged survival time (OR =1.77; 95% CI: 1.25-2.50; p = 0.001). Renal dysfunction caused by chemotherapy was not affected by KAI treatment (Odds Ratio (OR) =0.53; 95%IC: 0.25-1.12; p = 0.10). Conclusion. KAI can increase clinical effectiveness, improve quality of life, alleviate ADRs, and prolong survival time in advanced colorectal (CRC) patients receiving chemotherapy.

1. Introduction

Colorectal cancer (CRC), including colon and rectal cancers, is the third most common diagnosed malignancy and the second most common cause of cancer-related deaths in the world [1]. Over 1.8 million new CRC cases and 881,000 deaths were estimated to occur in 2018 [1]. The incidence and mortality rates of CRC have been increasing in China and have become a major public health problem in the country [2–6]. Moreover, the incidence rate of younger patients with CRC was rising [7]. Currently, the treatment for CRC mainly includes surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and comprehensive treatment [8]. For patients with an early stage, surgery is the main effective treatment. However, more than 50% patients were diagnosed until they enter into advanced stages; therefore, the operation was generally not suitable [9–12]. Although chemotherapy intervention is the mainstay of unresectable metastatic CRC treatment, many factors, such as lack of selectivity for tumor cells, insufficient drug concentration in tumor tissues, drug resistance, and systemic toxicity, affect the efficacy of chemotherapy and quality of patients life [5, 13]. Therefore, a more effective therapy is still necessary and urgent.

Traditional Chinese medicine (TCM), which is a promising alternative therapy for the treatment of CRC, has evolved over thousands of years in China and has been known to prevent tumorigenesis, minimize toxicity, reinforce the treatment effect, improve quality of life, and revert multidrug resistance[14–17]. Increasing evidence [18–21] has demonstrated that TCM combined with chemotherapy could significantly increase efficacy, improve quality of life, and alleviate the toxicity of chemotherapy. The Kangai injection (KAI), a TCM, consisting of Ginseng, Astragali radix and Kushen, has been widely applied as auxiliary treatment for multiple tumor in the clinic, and it has been demonstrated that it can enhance immunity, strengthen the effect of chemotherapy, improve quality of life, and alleviate adverse drug reactions (ADRs) [22, 23]. However, KAI as an adjuvant drug to increase efficacy, improve quality of life, and alleviate the ADRs of CRC patients receiving chemotherapy has not been systemically reviewed thus far.

Therefore, a systematic review and meta-analysis were conducted to compare the clinical effective rate, quality of life, ADRs, and survival time of patients who were treated with KAI combined with chemotherapy versus those who were treated with chemotherapy alone.

2. Methods

2.1. Databases and Search Strategy

Various databases were searched from the database inception to March 2019, including English databases PubMed, the Cochrane Library, Web of Science and the Chinese databases China National Knowledge Infrastructure (CNKI), the VIP information resource integration service platform (VIP), and Wanfang Data knowledge service platform (Wanfang Data). The English terms used were (“colorectal cancer” OR “colorectal carcinoma” OR “carcinoma of large intestine” OR “colorectal neoplasm”) AND (“kangai injection” OR “kang’ai injection” OR “traditional Chinese medicine” OR “Chinese medicine” OR “Chinese herbs”) AND (“chemotherapy” OR “chemotherapeutic” OR “infusion chemotherapy” OR “chemical therapy” OR “chemotherapy combined”). The Chinese terms used were “kangai zhusheye”, “kangai zhusheji”, “zhongyao”, “dachangai”, “jiechangai”, “jiezhichangai”, “zhichangai” and “lianhehualiao”. Two reviewers (Siqi Huang and Shaofan Zhang) independently retrieved articles from the databases using the same search terms. All identified literatures were screened after duplication checking with EndNote X8.1.

2.2. Inclusion Criteria

Included studies met the following criteria: (1) patients were diagnosed and confirmed as advanced CRC; (2) randomized controlled trial (RCT); (3) KAI was the only Chinese patent medicine used in RCTs; (4) KAI combined with chemotherapy treatment served as the experimental group, and chemotherapy treatment alone served as control group; (5) two or more of the following outcomes were measured: clinical effective rate, performance status (the Karnofsky performance scale, KPS), ADRs including nausea and vomiting, diarrhea, leukopenia, thrombocytopenia, liver dysfunction, renal dysfunction, peripheral neuropathy, and survival time.

2.3. Exclusion Criteria

Studies were excluded based on the following criteria: (1) reviews, meeting abstracts, and animal experiments; (2) the clinical stage of CRC was not advanced stage or was not clear; (3) patients had other tumors in addition to CRC; (4) treatment was combined with other traditional Chinese herbs; (5) incomplete or missing data; (6) the presence of less than two of the abovementioned outcomes.

2.4. Quality Assessment and Data Extraction

The quality of the included studies was evaluated according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions [24]. Selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome data), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias were assessed according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. The three biases of judgment were low risk, high risk, and unclear. Two reviewers (PengJi Yi and PanPan Xu) independently screened and extracted data from the texts. Any disagreements were ultimately resolved by two senior authors (Dan Mao and Weijun Peng). The following information was extracted: authors, year of publication, median age, sample size, gender, study design, KAI, details of intervention, and outcomes (tumor response, KPS, ADRs, and so on).

2.5. Statistical Analysis

(1) All the meta-analyses were performed using the Cochrane Collaboration software (RevMan 5.3). (2) The Odds Ratio (OR) or the Risk Ratio (RR) was used to analysis dichotomous variables such as clinical efficacy, KPS, and ADRs. If the 95% confidence interval (CI) did not include the value 1, the OR or RR point estimate was considered statistically significant at the p value less than 0.05. The weighted mean difference (WMD) was used to analysis continuous variables. If the 95% confidence interval (CI) did not include the value 0, the WMD point estimate was considered statistically significant at the p value less than 0.05. (3) The heterogeneity of the data assessed by the Chi² test and I² test. The combined data were considered as having heterogeneity if p < 0.1 or I² > 50% and a random-effects model was used; otherwise, a fixed-effects model was used. Sensitivity was used for the heterogeneity. (4) Begg’s test and funnel plot analyses were used to determine the publication bias of articles by Stata12.0. A two-tailed p value less than 0.05 was considered significant.

3. Results

3.1. Search Results and Study Characteristics

A total of 739 publications were identified using the predefined search strategy through several electronic databases. After excluding duplicates by EndNote X8, 670 studies were selected for analysis of the title and abstracts, and 43 studies were selected for through text reading. Fourteen studies did not meet the inclusion criteria or met the exclusion criteria: 5 articles included other tumors in addition to CRC; 3 articles included clinical stages of CRC that were not advanced stage; 1 article included other Chinese medicine; and 5 articles had no target outcomes. Finally, twenty-eight studies [25–52] were identified to meet the inclusion criteria. In this study, there were a total of 2310 cases, including 1207 cases for chemotherapy combined with KAI and 1103 cases for chemotherapy alone (Figure 1). The baseline characteristics for each study are shown in Table 1.

Table 1: Notes. E/C: experiment group and control group. F/M: female and male. N: not mentioned. ①: tumor response. ②: KPS. ③: nausea and vomiting. ④: diarrhea. ⑤: leukopenia. ⑥: thrombocytopenia. ⑦: liver dysfunction. ⑧: renal dysfunction. ⑨: neurotoxicity. ⑩: immune function. ⑪: survival time.

Study ID
Sample size (E/C)
Gender (F/M)
Median age(E/C)
Study design(E/C)
Intervention
KAI dosage (ml/day)
Outcomes

E
C

Cai 2015 [25]
45/45
49/41
50.24±2.4
Parallel-group
FOLFIRI+KAI
FOLFIRI
40
①③④⑥⑦⑧

Chen 2008 [26]
26/26
24/28
59
Parallel-group
FOLFOX4+KAI
FOLFOX4
60
①②③④⑤⑦⑧⑨

Chen 2016 [27]
46/46
34/58
61.2±11.7/62.1±11.4
Parallel-group
FOLFOX4+KAI
FOLFOX4
40
①③④⑤

Ding 2012 [28]
32/32
25/39
54/53
Parallel-group
FOLFOX4+KAI
FOLFOX4
40
①③④⑤⑥

Ding 2017 [29]
32/30
24/38
60/58
Parallel-group
XELOX+KAI
XELOX
40
①②⑪

Guo 2015 [30]
50/50
45/55
58.2±1.2/58.4±2.6
Parallel-group
FOLFOX4+KAI
FOLFOX4
60
①③④⑤⑦⑨

Guo 2016 [31]
46/46
41/51
59.7±1.5/59.9±1.2
Parallel-group
FOLFOX4+KAI
FOLFOX4
50
③⑥

Han 2010 [32]
60/60
45/75
52/51
Parallel-group
FOLFOX+KAI
FOLFOX
40
②③④⑤⑥⑨

Jiang 2011[33]
30/30
18/42
52.7/54.3
Parallel-group
FOLFIRI+KAI
FOLFIRI
40
①②③⑤

Lei 2011 [34]
30/30
25/35
N
Parallel-group
FOLFOX4+KAI
FOLFOX4
50
②③④⑤⑥⑨

Li 2008 [35]
87/61
65/83
55
Parallel-group
5FU+CF+KAI
5FU+CF
40
①②③

Li 2014 [36]
48/49
42/55
58.9±1.58/59.2±1.62
Parallel-group
FOLFIRI+KAI
FOLFIRI
40-60
①②③④⑤⑥⑦⑧⑩

Li 2015 [37]
45/48
41/52
57.13±7.05/56.72±7.24
Parallel-group
XELOX+KAI
XELOX
40
①⑪

Liang 2015[38]
31/31
24/38
53.8±6.4
Parallel-group
FOLFOX+KAI
FOLFOX
40
①②⑦⑧

Liu 2010[39]
46/40
32/54
65
Parallel-group
FOLFOX4+KAI
FOLFOX4
60
①②③⑤⑨

Ma 2016[40]
30/30
18/42
55±2.5
Parallel-group
mFOLFOX6+KAI
mFOLFOX6
40
②③④⑦⑧

Qiao 2015[41]
25/25
17/33
54.4/56.2
Parallel-group
FOLFOX+KAI
FOLFOX
40
①②⑤⑦⑧⑨

Qiu 2011[42]
21/22
16/27
52.7/56.9
Parallel-group
FOLFOX4+KAI
FOLFOX4
40
①②③⑤

Ruan 2014[43]
33/34
34/33
N
Parallel-group
XELOX+KAI
XELOX
40
①②③⑤⑥⑦

Wang 2016[44]
50/50
46/54
56.4±4.9/56.8±4.6
Parallel-group
FOLFOX+KAI
FOLFOX
50
①②⑤⑥⑦⑨

Xiao 2008 [45]
51/109
48/112
56/53.5
Parallel-group
FOLFOX+KAI
FOLFOX
40
②③⑨⑪

Xiao 2017 [46]
26/24
26/24
55
Parallel-group
mFOLFOX6+KAI
mFOLFOX6
50
②⑩

Xu 2018 [47]
68/68
63/73
56.5/57
Parallel-group
FOLFOX+KAI
FOLFOX
40
①⑩⑪

Yang 2007[48]
24/24
18/30
56
Parallel-group
FOLFOX+KAI
FOLFOX
50
①②⑤

Yang 2016[49]
41/41
44/38
71
Parallel-group
FOLFOX4+KAI
FOLFOX4
40
②⑩

Yu 2018[50]
50/50
33/67
55.4±5.8/54.6±6.1
Parallel-group
FOLFOX+KAI
FOLFOX
60
①⑨⑩

Zhang 2011[51]
22/23
15/30
42-71/45-73
Parallel-group
L-OHP+5FU+KAI
L-OHP+5FU
40
①②

Zhou 2011[52]
30/30
42/19
60.0±1.5/61.0±1.0
Parallel-group
FOLFOX+KAI
FOLFOX
60
①②⑤⑥⑦⑨⑪

Figure 1: PRISMA flow diagram.

3.2. Risk of Bias

The quality of the included studies was generally low. Only eleven studies described the special randomization method, although all studies mentioned the random sequence generation. Four of the twenty-eight studies mentioned allocation concealment. One study provided information about the blinding of participants and personnel, blinding of outcome assessment, and selective reporting. The risk of bias is shown in Figures 2 and 3.

Figure 2: Risk of bias summary.

Figure 3: Risk of bias.

3.3. Results

3.3.1. Tumor Response

In this meta-analysis, 22 [25–31, 33, 35–44, 47, 48, 50–52] studies that assessed complete response (CR) or partial response (PR) in 1715 patients showed significant differences between KAI combined with chemotherapy group and chemotherapy alone group (Risk Ratio (RR) =1.32; 95% CI: 1.22-1.43; p<0.00001) (Figure 4(a)). There was no heterogeneity between two groups (Chi²=25.26, p =0.24; I² =17%) and fixed-effects model was used to analyse the data. No significant publication bias was detected by Begg’s test (p=0.099) (Figure 4(b)).

(a) Forest plot and meta-analysis of tumor response

(b) Funnel plot of tumor response

Figure 4

3.3.2. Performance Status

There were 17 [26, 29, 32–34, 36, 38, 39, 41–46, 48, 51, 52] studies that assessed KPS scores in the meta-analysis. No significantly heterogeneity between two groups (Chi² = 21.59, p = 0.16; I² = 26%) and we used fixed-effects models to analysis. The results showed that there was a statistically significant difference between the two groups (Risk Ratio (RR) =1.48; 95% CI: 1.36-1.60; p<0.00001). This result indicated that KAI combined with chemotherapy significantly improved KPS when compared with chemotherapy alone (Figure 5(a)). The Begg’s test detected publication bias (p = 0.001) (Figure 5(b)).

(a) Forest plot and meta-analysis of KSP

(b) Funnel plot of KSP

Figure 5

3.3.3. Adverse Drug Reactions

Two stages of nausea and vomiting were reported in these studies. As for toxicity grades III-IV of nausea and vomiting, seven trails [32–35, 42, 43, 45] including 658 cases were assessed. No heterogeneity was found (Chi² =1.87, P = 0.87; I² = 0%), so fixed-effect model was applied to analyse the data. The results showed that KAI can alleviate III-IV nausea and vomiting caused by chemotherapy, despite the effect which was moderate (Odds Ratio (OR) =0.19; 95%CI: 0.08-0.41; p<0.00001) (Figure 6(a)). Sixteen trials [25–28, 30–36, 39, 40, 42, 43, 45] with 1391 cases (741 cases of experimental group and 649 cases of control group) provided the results for nausea and vomiting. The fixed-effect model was applied to analyse the data (Chi² =15.74, P = 0.40; I² = 5%). The results indicated that there was a statistically significant difference between the two groups and KAI combined with chemotherapy can significantly alleviate nausea and vomiting when compared with chemotherapy alone (Odds Ratio (OR) =0.31; 95%CI: 0.24-0.41; p<0.00001) (Figure 6(b)). No publication bias was detected by Begg’s test (p = 0.594) (Figure 6(c)).

(a) Forest plot and meta-analysis of the III-IV grade nausea and vomiting

(b) Forest plot and meta-analysis of I-IV grade nausea and vomiting

(c) Funnel plot of nausea and vomiting

Figure 6

Nine studies [25–28, 30, 32, 34, 36, 40] that assessed 735 patients (368 patients in the experimental group and 367 patients in the control group) reported diarrhea. The fixed-effect model was applied to analysis because there was no heterogeneity (Chi² =9.14, p = 0.33; I² = 12%). The results indicated that there was a statistically significant difference between the two groups and KAI combined with chemotherapy notably improved diarrhea compared with chemotherapy alone (Odds Ratio (OR) =0.36; 95% CI: 0.25-0.52; p<0.00001) (Figure 7). No publication bias was detected by Begg’s test (p = 0.864).

Figure 7: Forest plot and meta-analysis of diarrhea.

Senven studies [28, 32–34, 36, 42, 43] that evaluated 511 cases reported leukopenia with the toxicity grades III-IV. The result showed that KAI combined with chemotherapy improve leukopenia which caused by chemotherapy (Odds Ratio (OR) =2.84; 95% CI:1.65-4.89; p<0.0002). The fixed-effect model was performed to analysis because there was no significant heterogeneity ((Chi² =6.45, p= 0.38; I² = 7%) (in Figure 8(a)). Fifteen studies [26–28, 30, 32–34, 36, 39–44, 48, 52] that assessed 1098 patients reported leukopenia with the toxicity grades I-IV. The difference was statistically in favour of KAI combined with chemotherapy (Odds Ratio (OR) =2.97; 95% CI:2.27-3.88; p<0.00001), with no heterogeneity between two groups (Chi² =6.11, p= 0.96; I² = 0%), so the fixed-effect model was used for analysis (in Figure 8(b)). No significant publication bias was detected by Begg’s test (p= 0.224).

(a) Forest plot and meta-analysis of III-IV grade leukopenia

(b) Forest plot and meta-analysis of I-IV grade leukopenia

Figure 8

Nine studies [25, 28, 31, 32, 34, 36, 43, 44, 52] that assessed 750 patients reported thrombocytopenia. The difference was statistically in favour of KAI combined with chemotherapy (Odds Ratio (OR) =0.53; 95% CI: 0.38~0.74; p<0.0002), with no significant heterogeneity between two groups (Chi² =7.12, p= 0.42; I² = 0%), so the fixed-effect model was used for analysis (Figure 9). No publication bias was detected by Begg’s test (p = 0.893).

Figure 9: Forest plot and meta-analysis of thrombocytopenia.

A total of ten publications [25, 26, 30, 36, 38, 40, 41, 43, 44, 52] with 738 patients reported liver dysfunction. No heterogeneity between two groups was observed (Chi² =14.90, P = 0.09; I² = 42%). The fixed-effects model was adopted to analyse data. The results suggested that there was a statistically significant difference between experimental and control groups and KAI combined with chemotherapy notably relived liver toxicity of chemotherapy when compared with chemotherapy alone (Odds Ratio (OR) =0.29; 95% CI: 0.20~0.44; p<0.00001(Figure 10)). No publication bias was detected by Begg’s test (p= 0.326).

Figure 10: Forest plot and meta-analysis of liver dysfunction.

A total of six [25, 26, 37, 38, 40, 41] publications with 411 patients reported renal dysfunction. No heterogeneity between two groups was observed (Chi² =4.75, p = 0.31; I² = 16%) so the fixed-effects model was adopted to analyse data. The results suggested that there was no statistically significant difference between the experimental and control groups, and KAI combined with chemotherapy did not significantly relive the renal toxicity of chemotherapy when compared with chemotherapy alone (Odds Ratio (OR) =0.53; 95% CI: 0.25-1.12; p = 0.10) (Figure 11). No publication bias was detected by Begg’s test (p=0.348).

Figure 11: Forest plot and meta-analysis of renal dysfunction.

Neurotoxicity was reported in ten [26, 30, 32, 34, 39, 41, 44, 45, 50, 52] trails that contained 906 patients. KAI combined with chemotherapy was associated with a better protective effect against chemotherapy than chemotherapy alone, and the result was statistically significant (Odds Ratio (OR) = 0.51; 95% CI: 0.36-0.71; p= 0.0004). There was no heterogeneity, and the data were analysed by fixed-effects model (Chi² = 7.25, p= 0.61; I² = 0) (Figure 12). No publication bias was detected by Begg’s test (p = 0.326).

Figure 12: Forest plot and meta-analysis of neurotoxicity.

3.3.4. Immune Function

A total of five studies [36, 46, 47, 49, 50] reported immune function. Three trials [36, 46, 50] reported CD3⁺, five trials [36, 46, 47, 49, 50] reported CD4⁺, four trials [46, 47, 49, 50] reported CD8⁺, and three trials [36, 46, 50] reported the ratio of CD4⁺/CD8⁺. There was no significant difference in the pretreatment levels of CD3⁺, CD4⁺, CD8⁺, and the ratio of CD4⁺/CD8⁺ cells between the KAI combined with chemotherapy group and chemotherapy alone group (CD3⁺: MD=-0.30; 95% CI: -1.04-0.44; p=0.43.CD4⁺: MD=0.16; 95% CI: -0.55-0.87; p=0.65.CD8⁺: MD=-0.09; 95%IC: -0.78-0.60; p=0.8; the ratio of CD4⁺/CD8⁺: MD=0.03; 95% CI: -0.02-0.07; p=0.21) (Figures 13(a)–13(d)). A fix-effect model was used to analyse the data because heterogeneity was not observed (CD3⁺, CD4⁺, CD8⁺, and the ratio of CD4⁺/CD8⁺: I² = 0).

(a) CD3⁺ of pretreatment

(b) CD4⁺ of pretreatment

(c) CD8⁺ of pretreatment

(d) The ratio of CD4⁺/CD8⁺ of pretreatment

Figure 13

After treatment, the results indicated that KAI combined with chemotherapy can significantly increase the level of CD3⁺ (CD3⁺: MD=6.34; 95% CI: 5.52-7.16; p < 0.00001), CD4⁺ (CD4⁺: MD=-5.99; 95% IC: 5.20-6.78; p < 0.00001), and CD4⁺/CD8⁺ (CD4⁺/CD8⁺: MD=0.34; 95%CI: 0.14-0.54; p < 0.0009) when compared with chemotherapy alone (Figures 14(a)–14(c)). However, the CD8⁺ level was not significantly different between the two groups (CD8⁺: MD=0.38; 95% CI: -2.56-3.32; p = 0.80) (Figure 14(d)). Random-effect model was used to analyse data because heterogeneity of the ratio of CD4⁺/CD8⁺ (Chi² =15.42, p= 0.001; I² = 81%) and CD8⁺ (Chi² =66.25, p< 0.00001; I² = 94%) was high. For CD3⁺ and CD4⁺ fixed-effect model was used to evaluate data with moderate heterogeneity (CD3⁺: I² = 8%; CD4⁺: I² = 45%). No significant publication bias was observed (CD3⁺: p= 0.730; CD4⁺: p= 0.390; CD8⁺: p= 0.118; and the ratio of CD4⁺/CD8⁺: p= 0.130).

(a) CD3⁺ of posttreatment

(b) CD4⁺ of posttreatment

(c) CD4⁺/CD8⁺ of posttreatment

(d) CD8⁺ of posttreatment

Figure 14

3.3.5. Survival Rate

In this meta-analysis, five studies [29, 37, 45, 47, 52] involving 511 participants reported the one-year survival rate. A fixed-effects model was used to analyse the data due to no heterogeneity (Chi² =1.90, p = 0.75; I² = 0%). The results indicated that there was a statistically significant difference between two groups (Odds Ratio (OR) =2.04; 95% CI: 1.26-3.28; p = 0.003) (Figure 15). No publication bias was detected by Begg’s test (p= 0.294).

Figure 15: Forest plot and meta-analysis of survival rate.

4. Discussion

CRC is one of the most common malignancies in the world [3]. More than 50% patients already entered end-stage when diagnosed with CRC and lost the chance of surgery [10]. Despite advances in treatment modalities, the adverse reactions like bone marrow suppression, gastrointestinal reactions, and multidrug resistance are still widespread and seriously affect cancer patient’s quality of life even end treatment [10, 53].

TCM especially Chinese herbs medicines, as an important component of complementary and alternative medicine, has evolved over thousands of years in China with its own unique system of theories, diagnostic, and therapies [54]. KAI, a typical anticancer injection of TCM formula, mainly consists of ginseng, astragali radix, and matrine. (1) The major effective ingredients of Ginseng are Ginsenoside (Ginsenoside Rg1, Ginsenoside Rb1, Ginsenoside Rg3, and Ginsenoside Rf) and Ginseng Polysaccharides; these ingredients can improve immune functions and increase white blood cell (WBC) count after chemotherapy. (2) The major active ingredients of astragali radix is the root of the Leguminous Plant Astragalus, which has inhibitory effect on tumor cell proliferation and induces apoptosis. (3) Matrine and oxymatrine, two kinds of alkaloid form Kushen, have pharmacological activities to selectively kill tumor cells and inhibit tumor growth by changing the molecular sequence of the nucleic acids in cells [23, 55].

Accumulating clinical evidence demonstrated that KAI has played an important role in cancer therapy which can enhance the effect, improve quality of life, strengthen immune function, and reduce adverse reactions. A meta-analysis systematically evaluated the efficacy and safety of KAI combined with chemotherapy for treatment of breast cancer in 2018, and the result showed that KAI combined with chemotherapy for treating Chinese breast cancer can improve quality of life and minimize the adverse reactions [23]. A meta-analysis [56] and a randomized controlled trial [22] evaluated the efficacy and safety of KAI combined with chemotherapy for non-small-cell lung cancer (NSCLC), and the result demonstrated that KAI can enhance the therapy effect, improve quality of life, and reduce reverse reactions when combined with chemotherapy.

To the best of our knowledge, this study was the first time to systematically evaluate the synergistic and detoxifying effects of KAI therapy on advanced CRC patients receiving chemotherapy. This meta-analysis of twenty-eight RCTS including 2310 cases comparing the efficacy and safety of KAI combined with chemotherapy and chemotherapy alone. Our results suggested that KAI plays an important role in enhancing efficacy, improving quality of life, alleviating adverse drug reaction (ADRs), strengthening immune function, and prolonging survival time of CRC patients receiving chemotherapy.

The following limitations of this meta-analysis must be concerned. First, although we searched the PubMed, Web of Science, and the Cochrane Library databases, all of the included studies and all the subjects in the studies were Chinese. Further research is needed to assess the efficacy of KAI in other populations. Second, the quality of the studies included in our meta-analysis was poor. Although most trials performed randomization, four studies referred to allocation concealment, and only one was a double-blinded study. Moreover, all trials were carried out at single a centre. Third, publication bias was found in one of outcomes (KSP), so the results should be interpreted with caution. Fourth, the heterogeneity of the level of CD8⁺ and the ratio of CD4⁺/CD8⁺ were observed to be high. Sensitivity analysis did not eliminate heterogeneity. The high heterogeneity might be due to differences in sample size, patient age, tumor stage and grade, difference doses of KAI, and other factors among the studies. Finally, although the doses of KAI in most studies were the same (40 ml/day), there were still differences (50 ml/day, 60 ml/day). Large doses may favour better results which may result in publication bias.

5. Conclusion

KAI combined with chemotherapy can improve the quality of life, enhance clinical effectiveness rate of chemotherapy, and reduce the chemo-induced toxicity of chemotherapy treatment for advanced colorectal cancer patients. However, the outcomes were evaluated in a purely Chinese population, and the long-term, high-quality studies with a large sample size are needed to confirm the efficacy and tolerability of KAI in other populations.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

All author designed the protocol. Siqi Huang and Shaofan Zhang searched the literature. Siqi Huang, PanPan Xu, and PengJi Yi retrieved data. Siqi Huang, Weijun Peng, and Dan Mao analysed data and wrote and revised this paper. Sifang Zhang edited the paper.

References

F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA: A Cancer Journal for Clinicians, vol. 68, no. 6, pp. 394–424, 2018.

W. Chen, R. Zheng, P. D. Baade et al., “Cancer statistics in China, 2015,” CA: A Cancer Journal for Clinicians, vol. 66, no. 2, pp. 115–132, 2016.

R. L. Siegel, K. D. Miller, S. A. Fedewa et al., “Colorectal cancer statistics,” CA: A Cancer Journal for Clinicians, vol. 67, no. 3, pp. 177–193, 2017.

J. Zhu, Z. Tan, K. Hollis-Hansen, Y. Zhang, C. Yu, and Y. Li, “Epidemiological trends in colorectal cancer in china: an ecological study,” Digestive Diseases and Sciences, vol. 62, no. 1, pp. 235–243, 2017.

S. Qin, J. Li, L. Wang et al., “Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in patients With RAS wild-type metastatic colorectal cancer: the open-label, randomized, Phase III tailor trial,” Journal of Clinical Oncology, vol. 36, no. 30, pp. 3031–3039, 2018.

M. Arnold, M. S. Sierra, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray, “Global patterns and trends in colorectal cancer incidence and mortality,” Gut, vol. 66, no. 4, pp. 683–691, 2017.

L. C. Connell, J. M. Mota, M. I. Braghiroli, and P. M. Hoff, “The rising incidence of younger patients with colorectal cancer: questions about screening, biology, and treatment,” Current Treatment Options in Oncology, vol. 18, no. 4, 2017.

E. J. Kuipers, W. M. Grady, D. Lieberman et al., “Colorectal cancer,” Nature Reviews Disease Primers, vol. 1, 2015.

T. Wang, H. Nan, C. Zhang et al., “Aidi injection combined with FOLFOX4 chemotherapy regimen in the treatment of advanced colorectal carcinoma,” Journal of Cancer Research Therapeutics, vol. 10, 2014.

R. M. McQuade, V. Stojanovska, J. C. Bornstein, and K. Nurgali, “Colorectal cancer chemotherapy: the evolution of treatment and new approaches,” Current Medicinal Chemistry, vol. 24, no. 15, pp. 1537–1557, 2017.

Z. Sun, N. Zhou, Q. Han et al., “MicroRNA-197 influences 5-fluorouracil resistance via thymidylate synthase in colorectal cancer,” Clinical and Translational Oncology, vol. 17, no. 11, pp. 876–883, 2015.

M. G. Lee, C. C. Chiu, C. C. Wang et al., “Trends and outcomes of surgical treatment for colorectal cancer between 2004 and 2012- an analysis using national inpatient database,” Scientific Reports, vol. 7, no. 1, 2016.

F. Geng, Z. Wang, H. Yin, J. Yu, and B. Cao, “Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives,” Cancer Biotherapy and Radiopharmaceuticals, vol. 32, no. 5, pp. 149–160, 2017.

W. Peng, S. Zhang, Z. Zhang et al., “Jianpi Jiedu decoction, a traditional Chinese medicine formula, inhibits tumorigenesis, metastasis, and angiogenesis through the mTOR/HIF-1alpha/VEGF pathway,” Journal of Ethnopharmacology, vol. 224, pp. 140–148, 2018.

K. Y. Tan, C. B. Liu, A. H. Chen, Y. J. Ding, H. Y. Jin, and F. Seow-Choen, “The role of traditional Chinese medicine in colorectal cancer treatment,” Techniques in Coloproctology, vol. 12, no. 1, pp. 1–6, 2008.

F.-X. Lin, L.-F. Tian, C.-Y. Lei, C.-C. Ding, L. Shi, and S.-F. Zhang, “Chinese medicine for outcomes in colorectal cancer patients: a retrospective clinical study,” Chinese Journal of Integrative Medicine, vol. 23, no. 9, pp. 648–653, 2017.

H. Sui, S.-F. Pan, Y. Feng et al., “Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway,” BMC Complementary and Alternative Medicine, vol. 14, article 279, 2014.

R. Xu, L. Lin, Y. Li, and Y. Li, “ShenQi FuZheng Injection combined with chemotherapy in the treatment of colorectal cancer: A meta-analysis,” PLoS ONE, vol. 12, no. 9, 2017.

S. Zhang, L. Shi, and D. Mao, “Use of jianpi jiedu herbs in patients with advanced colorectal cancer: a systematic review and meta-analysis,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 6180810, 13 pages, 2018.

Y.-H. Liao, C.-C. Lin, H.-C. Lai, J.-H. Chiang, J.-G. Lin, and T.-C. Li, “Adjunctive traditional Chinese medicine therapy improves survival of liver cancer patients,” Liver International, vol. 35, no. 12, pp. 2595–2602, 2015.

D. Mao, L. Feng, S. Huang, S. Zhang, W. Peng, and S. Zhang, “Meta-analysis of xihuang pill efficacy when combined with chemotherapy for treatment of breast cancer,” Evidence-Based Complementary and Alternative Medicine, vol. 2019, 14 pages, 2019.

X. He, S. Han, and P. Li, “Injectable Chinese herbal formula Kang'ai for nonsmall cell lung cancer: trial sequential analysis of 2,259 participants from 31 randomized controlled trials,” Journal of Cancer Research and Therapeutics, vol. 12, no. 2, pp. 735–743, 2016.

J. X. Xue, Z. Y. Zhu, W. H. Bian, and C. Yao, “The traditional chinese medicine kangai injection as an adjuvant method in combination with chemotherapy for the treatment of breast cancer in chinese patients: a meta-analysis,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 6305645, 16 pages, 2018.

J. Higgins and S. Green, Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series, 2008.

X.-S. J. G. L. D.-J. Cai, “Efficacy of kang ai injection combined with chemotherapy in 90 patients with advanced colon cancer,” Northern Pharmacy, vol. 12, no. 8, 2015.

X. Chen, J. Huang, Q. Yang, and W. Chen, “Clinical observation of combined chemotherapy with kang-ai injection in treatment of advanced colorectal cancer,” Guangming Traditional Chinese, vol. 23, no. 11, pp. 1745–1747, 2008.

W. P. Chenji-Tao, “the effect of kang'ai injection on IL-17 and IL-10 expression in patients with colon cancer and its clinical efficay,” Chinese Journal of Integrated Traditional and Western Medicine, vol. 24, no. 10, p. 762, 2016.

C. Ding, L. Zhang, and S. Yu, “Clinical observation of Kang ai injection with FOLFOX4 chemotherapy in treating advanced colorectal cancer,” Medical Frontie, 2012.

P. Ding, Z. Lu, W. Wang, and Y. Zhou, “Clinical obseration of Kang'ai injection combined with capecitabine and oxaliplatin scheme in treatment of advanced colon cancer,” Shanxi Journal of Traditional Chinese Medicine, vol. 38, no. 3, pp. 351-352, 2017.

Y.-H. Guo, “Effect observation of chemotherapy combined with kangai injection in advanced colorectal cancer,” Global Traditional Chinese Medicine, vol. 8, no. 5, pp. 620–623, 2015.

L. Guo, “To evaluate the clinical value of kangai injection combined with chemotherapy in the treatment of advanced colon cancer,” Guide of China Medicine, vol. 14, no. 31, pp. 133-134, 2016 (Chinese).

H. Han, L. Zhang, D. Chen, and Y. Wang, “Clinical observation of 60 cases of colorectal cancer treated by kangai injection combined with chemotherapy,” Journal of New Chinese Medicine, vol. 42.3, pp. 42-43, 2010.

Q. Jiang and H. Zhu, “Clinical study of kangai injection combined with forfiri chemotherapy in the treatment of 30 cases of advanced colon cancer,” Journal of Kunming Medical University, vol. 9, pp. 52-53, 2011.

Z. Lei and H. Li, “Clinical observation of combination Kang′ai injection and chemotherapy for patients after colorectal cancer surgery,” Proceeding of Clinical Medicine, vol. 21, no. 6, pp. 403–405, 2012.

W. Li, J. Cao, W. Zhang et al., “Clinical application of kangai injection in the treatment of colorectal cancer,” Journal of Chinese Medicinal Materials, vol. 31, no. 6, pp. 943–945, 2008.

L. Kang, “Observation on Kang'ai injection combined with chemotherapy for advanced colon cancer,” Journal of Liaoning University of Traditional Chinese Medicine, vol. 16, no. 11, pp. 19–21, 2014.

C.-X. Li, “Clinical observation of kangai injection combined with chemotherapy in the treatment of advanced colorectal cancer,” Modern Diagnosis and Treatment, pp. 2741-2742, 2015.

J. Liang and X. Huang, “Clinical observation on the effect of kangai injection on the reduction and enhancement of chemotherapy in postoperative patients with colorectal cancer,” Strait Pharmaceutical Journal, vol. 27, no. 6, pp. 139-140, 2015.

W.-D. Liu, C.-F. Ma, X.-W. Hu et al., “Kangai combined with chemotherapy for advanced colorectal cancer in the elderly,” Journal of Practical Oncology, vol. 24, no. 2, pp. 166-167, 2010.

D. Ma, J. Hou, Z. Wu, and Q. Chen, “Observation on the curative effect of kangai injection combined with chemotherapy on advanced colorectal cancer,” Journal of Clinical Medical, vol. 3, no. 57, pp. 11349-11350, 2016.

J. Qiao, F. Li, J. Qiu, and Z. Zhou, “Evaluation of kangai injection adjuvant chemotherapy for rectal cancer after operation,” West China Medical Journal, vol. 28, no. 9, pp. 1420–1422, 2013.

Z.-C. Qiu, “Kang ai injection combined with chemotherapy in 22 cases of advanced colon cancer,” Shanxi Journal of Traditional Chinese Medicine, vol. 32, no. 1, 2011.

X. J. Ruan, C. Liu, L. Wei, and F. Wang, “Observation on the curative effect of kangai injection combined with XELOX program in the treatment of advanced colorectal cancer,” Modern Journal of Integrated Traditional Chinese and Western Medicine, vol. 23, no. 18, 1983 pages, 2014, 1985.

L. Wang, T. Li, and H.-X. Du, “Clinical observation of kangai injection combined with chemotherapy for advanced colon cancer,” Heilongjiang Medicine Journal, vol. 29, no. 01, pp. 97–99, 2016.

B. Xiao, S. Cui, C. Chen et al., “Observation on the therapeutic effect of Chinese patent medicine combined with 5-fu oxaliplatin in the adjuvant treatment of colorectal cancer after operation,” China Foreign Medical Treatment, vol. 20, pp. 74-75, 2008.

M. Xiao, Y. Liu, W. Tian, and L. Gong, “Kang Ai injection chemotherapy for locally advanced colorectal cancer immune function and the effect of TCM symptoms,” Contemporary Medicine, vol. 27, no. 30, pp. 9–12, 2017.

B. Xu, P. Ruan, T. Xu, and S. Wang, “Effects of Kang'ai injection on immunomodulation and long-term clinical outcome in patients with stage IIB or III colon cancer,” Journal of Practical Oncology, vol. 33, no. 5, pp. 429–432, 2018.

F. Yang, “Effects of kangai injection on chemotherapy of colorectal cancer,” Cancer Research and Clinic, vol. 19, pp. 117-118, 2007.

J. Y. Yang, M. Dan, Z. Ye et al., “Effect of kangai injection on immune function and quality of life in patients with advanced colorectal cancer,” Chinese Journal of Surgical Oncology, vol. 8, no. 2, pp. 120–122, 2016.

X. Yu, L. Jiang, and W. Zhu, “Clinical research of Kangai injection combined with FOLFOX chemotherapy in the treatment of colorectal cancer,” Oncology Progress, vol. 16, no. 5, pp. 650–653, 2018.

X. Zhang and H. Peng, “Efficacy observation of Kang' ai Injection combined with chemotherapy in treating advanced colorectal cancer,” Modern Medicine and Health, vol. 27, no. 10, pp. 1450-1451, 2011.

L.-P. Zhou, “Injection combined with chemotherapy in the treatment of advanced colorectal cancer for 30 cases,” Chinese Medicine Modern Distance Education of China, vol. 14, no. 22, pp. 91-92, 2016.

Q. Shi, W. Li, Q. Le et al., “Attenuated effects of Jianpi Qushi herbs on patients receiving FOLFOX4 after colorectal cancer surgery: a meta-analysis,” Chinese Journal of Integrative Medicine, pp. 1–10, 2016.

P. Wang, Z. Qi, F. Cui et al., “An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics,” Bioscience Trends, vol. 12, no. 3, pp. 220–239, 2018.

Y. Lai, J. Lu, X. Chen, H. Hu, and Y. Wang, “Analysis of anti-cancer traditional chinese medicine injections based on market performance,” World Science and Technology, vol. 14, no. 5, pp. 1958–1962, 2012.

Q. Lu and C. Li, “Therapeutic efficacy and safety of Kang-ai injection combined with platinum-based doublet chemotherapy in advanced NSCLC: a meta-analysis,” Life Sciences, vol. 210, pp. 9–19, 2018.