# Efficacy of Traditional Chinese Medicine Injection in Preventing Oxaliplatin-Induced Peripheral Neurotoxicity: An Analysis of Evidence from 3598 Patients

Authors: Zhi-Ying Chen; Yue Liu; Yuan Wei; Lin-Yao Deng; Qiang Zhang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2022)

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## Abstract

Background. Oxaliplatin is an effective chemotherapeutic agent for the treatment of malignant tumors. However, severe oxaliplatin-induced peripheral neurotoxicity (OIPN) has been well documented. Traditional Chinese medicine injections (TCMIs) have shown significant efficacy in preventing OIPN. However, it is difficult for clinicians to determine the differences in the efficacy of various TCMIs in preventing OIPN. The aim of this study was to compare the efficacy of various TCMIs in preventing OIPN through a network meta-analysis (NMA) to further inform clinical decision-making. Methods. The Chinese Journal Full Text Database, Chinese Biomedical Literature Database, Wanfang Data Knowledge Service Platform, Chinese Science and Technology Journal Full Text Database, the Cochrane Library, Web of Science, PubMed, and Embase databases were searched for randomized controlled trials (RCTs) of TCMIs for OIPN prevention. The retrieval time was from the establishment of the database to April 12, 2021. NMA was performed using Stata 14.0 software after 2 evaluators independently screened the literature, extracted information, and evaluated the risk of bias of the included studies. Results. A total of 45 eligible RCTs involving 3598 cancer patients and 13 TCMIs were included. The 13 TCMIs included Xiaoaiping injection (XAPI), compound kushen injection (CKSI), Aidi injection (ADI), Brucea javanica oil emulsion injection (BJOEI), Shenmai injection (SMI), Kangai injection (KAI), Astragalus injection (AI), elemene emulsion injection (EEI), Shenfu injection (SFI), Shenqi Fuzheng injection (SIFZI), Kanglaite injection (KLEI), Huachansu injection (HCSI), and lentinan injection (LI). NMA results showed that AI was superior to AD and SIFZI was superior to ADI in reducing the incidence of grade I neurotoxicity. SIFZI was superior to EEI and ADI, and BJOEI was superior to chemotherapy alone in reducing the incidence of grade II neurotoxicity. SMI was superior to LI and CKSI in reducing the incidence of grade III neurotoxicity. SIFZI was superior to LI, BJOEI, XAPI, EEI, SMI, chemotherapy alone, HCSI, KLEI, and ADI in reducing the total incidence of grade I–IV neurotoxicity. SFI was superior to ADI. Based on the SUCRA values, AI was the most likely intervention to reduce the incidence of grade I neurotoxicity, SIFZI was the most likely intervention to reduce the total incidence of grade II and I–IV neurotoxicity, and SMI was the most likely intervention to reduce the incidence of grade III and IV neurotoxicity. Conclusion. TCMIs can prevent OIPN to some extent, among which SIFZI, SMI, and AI may be the most promising TCMIs. However, given the limitations of current studies, more well-designed, high-quality clinical trials will be needed in the future to validate the benefits of TCMIs.


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## Body

## 1. Introduction

Oxaliplatin belongs to the third generation of platinum-based antitumor drugs and is the main treatment for many gastrointestinal cancers, especially colorectal cancer [1]. However, up to 40–50% of patients receiving this drug develop oxaliplatin-induced peripheral neurotoxicity (OIPN) [2, 3]. OIPN has a clinically significant impact on the quality of life of patients with cancer and is a dose-limiting toxicity [4, 5]. Up to 90% of patients on oxaliplatin-based regimens with doses ranging from 85 to 130 mg/m2 will experience certain degree of acute OIPN [6]. It is characterized by rapid onset of sensory abnormalities and sensory disturbances in the hands, feet, and perioral region, and is essentially reversible within a week [7]. However, about 20–50% of patients develop severe chronic OIPN, and a significant proportion of patients have long-term residual neurotoxicity that severely affects their quality of life [5, 8]. Therefore, how to effectively prevent peripheral neurotoxicity caused by oxaliplatin-containing chemotherapy regimens and mitigate peripheral nervous system injury has become an urgent clinical problem.At present, there is no specific method for the prevention and treatment of this kind of peripheral neurotoxicity, and symptomatic treatment of Western medicine is mainly used, such as nerve nutrition, nerve growth factor supplementation, and antioxidant treatment with reduced glutathione [9–11]. In fact, the latest oncology guidelines on OIPN acknowledge that despite the large number of trials available, there is no convincing evidence that any interventions are effective in preventing OIPN [12, 13].OIPN belongs to the category of “paralysis” and “impotence” in Chinese medicine. Many studies have shown that Chinese medicine injections (TCMIs) such asAstragalus injection and Shenmai injection have shown good clinical effects in preventing the occurrence of OIPN [14–16]. However, direct comparisons of clinical trials of various TCMIs for OIPN prevention are lacking, and traditional pairwise comparison meta-analyses do not enable comparisons among multiple interventions, making it difficult to assess which intervention has the best efficacy. Compared with traditional pairwise comparison meta-analyses, network meta-analysis (NMA) can not only summarize direct comparative evidence, but also perform indirect comparisons among multiple interventions based on common comparison groups, ranking the efficacy of each intervention, and providing evidence-based medical evidence for clinical drug selection [17, 18]. This study used NMA method to compare the efficacy of TCMIs in OIPN prevention, in order to provide reference for clinical application.


## 2. Methods

NMA was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [19].


### 2.1. Inclusion and Exclusion Criteria

#### 2.1.1. Types of Studies

Randomized controlled trials(RCTs) were included.


#### 2.1.2. Participants

Patients with a diagnosis of malignancy confirmed by histopathology and/or cytology or imaging. Treatment with oxaliplatin or oxaliplatin-containing chemotherapy regimens was specified in the chemotherapy regimen.


#### 2.1.3. Interventions and Comparisons

The control group was given chemotherapy alone or chemotherapy with placebo. The experimental group used TCMIs in addition to chemotherapy, and the type, dose, and frequency of TCMIs were not limited.


#### 2.1.4. Outcomes

The incidence of OIPN includes the incidence of grade I neurotoxicity, grade II neurotoxicity, grade III neurotoxicity, grade IV neurotoxicity, and the total incidence of grade I–IV neurotoxicity.


### 2.2. Exclusion Criteria

(i)
Republished literature(ii)
Literature with incomplete data(iii)
Both groups used other Chinese medical treatments such as traditional Chinese medicine decoction, Chinese patent medicine, or acupuncture(iv)
Nonrandomized controlled trial


### 2.3. Search Strategy

The Chinese Journal Full Text Database, Chinese Biomedical Literature Database, Wanfang Data Knowledge Service Platform, Chinese Science and Technology Journal Full Text Database, the Cochrane Library, Web of Science, PubMed, and Embase databases were searched for randomized controlled trials (RCTs) of TCMIs for OIPN prevention. The retrieval time was from the establishment of the database to April 12, 2021. Search terms included oxaliplatin, neurotoxicity, names of included TCMIs, RCTs, and their synonyms. The search strategy was developed according to the criteria of the Cochrane systematic review handbook. Taking PubMed database as an example, detailed search strategies are shown in supplementary materials (TableS1).


### 2.4. Data Extraction

Two researchers independently screened the literature, extracted information, and cross-checked it according to inclusion and exclusion criteria. In case of any disagreement, it was resolved through discussion or referred to a third party for negotiation. The data extraction included (1) basic information of the included studies, including study title, first author, journal of publication, and time; (2) baseline characteristics of the study population, including sample size of each group, age of patients, population origin, and tumor type; (3) specific details of the interventions, including the TCMIs used and the type of chemotherapeutic agents; (4) key elements of bias risk assessment; and (5) outcome indicators and outcome measures of interest, including the measurement tools for OIPN and the incidence of OIPN.


### 2.5. Quality Assessment

The risk of bias for RCTs was evaluated by 2 investigators according to the Cochrane systematic review handbook [20]. Evaluation elements included randomization method, concealment of grouping scheme, blinding, completeness of outcome data, selective reporting of study results, and other sources of bias. These elements were assessed as “low risk,” “high risk,” and “unclear.”


### 2.6. Data Analysis

Count data were analyzed with relative risk (RR) and 95% confidence interval (95% CI) as efficacy statistics.I2 was used to quantitatively determine the magnitude of heterogeneity. If I2 < 50% and P>0.1, meta-analysis was performed using a fixed-effects model. If I2 ≥ 50% and P<0.1, meta-analysis was performed using a random-effects model. Since this study was an indirect comparison of various TCMIs combined with chemotherapy based on chemotherapy, no consistency test was required. Network group commands were used for data preprocessing in NMA. Network evidence plots and “corrected-comparison” funnel plots were drawn for each outcome indicator, and pairwise comparisons of different interventions were performed. Efficacy was ranked according to the surface under the cumulative ranking curve (SUCRA). Stata 14.0 was used for direct comparison meta-analysis, NMA, and graph drawing.


## 2.1. Inclusion and Exclusion Criteria

### 2.1.1. Types of Studies

Randomized controlled trials(RCTs) were included.


### 2.1.2. Participants

Patients with a diagnosis of malignancy confirmed by histopathology and/or cytology or imaging. Treatment with oxaliplatin or oxaliplatin-containing chemotherapy regimens was specified in the chemotherapy regimen.


### 2.1.3. Interventions and Comparisons

The control group was given chemotherapy alone or chemotherapy with placebo. The experimental group used TCMIs in addition to chemotherapy, and the type, dose, and frequency of TCMIs were not limited.


### 2.1.4. Outcomes

The incidence of OIPN includes the incidence of grade I neurotoxicity, grade II neurotoxicity, grade III neurotoxicity, grade IV neurotoxicity, and the total incidence of grade I–IV neurotoxicity.


## 2.1.1. Types of Studies

Randomized controlled trials(RCTs) were included.


## 2.1.2. Participants

Patients with a diagnosis of malignancy confirmed by histopathology and/or cytology or imaging. Treatment with oxaliplatin or oxaliplatin-containing chemotherapy regimens was specified in the chemotherapy regimen.


## 2.1.3. Interventions and Comparisons

The control group was given chemotherapy alone or chemotherapy with placebo. The experimental group used TCMIs in addition to chemotherapy, and the type, dose, and frequency of TCMIs were not limited.


## 2.1.4. Outcomes

The incidence of OIPN includes the incidence of grade I neurotoxicity, grade II neurotoxicity, grade III neurotoxicity, grade IV neurotoxicity, and the total incidence of grade I–IV neurotoxicity.


## 2.2. Exclusion Criteria

(i)
Republished literature(ii)
Literature with incomplete data(iii)
Both groups used other Chinese medical treatments such as traditional Chinese medicine decoction, Chinese patent medicine, or acupuncture(iv)
Nonrandomized controlled trial


## 2.3. Search Strategy

The Chinese Journal Full Text Database, Chinese Biomedical Literature Database, Wanfang Data Knowledge Service Platform, Chinese Science and Technology Journal Full Text Database, the Cochrane Library, Web of Science, PubMed, and Embase databases were searched for randomized controlled trials (RCTs) of TCMIs for OIPN prevention. The retrieval time was from the establishment of the database to April 12, 2021. Search terms included oxaliplatin, neurotoxicity, names of included TCMIs, RCTs, and their synonyms. The search strategy was developed according to the criteria of the Cochrane systematic review handbook. Taking PubMed database as an example, detailed search strategies are shown in supplementary materials (TableS1).


## 2.4. Data Extraction

Two researchers independently screened the literature, extracted information, and cross-checked it according to inclusion and exclusion criteria. In case of any disagreement, it was resolved through discussion or referred to a third party for negotiation. The data extraction included (1) basic information of the included studies, including study title, first author, journal of publication, and time; (2) baseline characteristics of the study population, including sample size of each group, age of patients, population origin, and tumor type; (3) specific details of the interventions, including the TCMIs used and the type of chemotherapeutic agents; (4) key elements of bias risk assessment; and (5) outcome indicators and outcome measures of interest, including the measurement tools for OIPN and the incidence of OIPN.


## 2.5. Quality Assessment

The risk of bias for RCTs was evaluated by 2 investigators according to the Cochrane systematic review handbook [20]. Evaluation elements included randomization method, concealment of grouping scheme, blinding, completeness of outcome data, selective reporting of study results, and other sources of bias. These elements were assessed as “low risk,” “high risk,” and “unclear.”


## 2.6. Data Analysis

Count data were analyzed with relative risk (RR) and 95% confidence interval (95% CI) as efficacy statistics.I2 was used to quantitatively determine the magnitude of heterogeneity. If I2 < 50% and P>0.1, meta-analysis was performed using a fixed-effects model. If I2 ≥ 50% and P<0.1, meta-analysis was performed using a random-effects model. Since this study was an indirect comparison of various TCMIs combined with chemotherapy based on chemotherapy, no consistency test was required. Network group commands were used for data preprocessing in NMA. Network evidence plots and “corrected-comparison” funnel plots were drawn for each outcome indicator, and pairwise comparisons of different interventions were performed. Efficacy was ranked according to the surface under the cumulative ranking curve (SUCRA). Stata 14.0 was used for direct comparison meta-analysis, NMA, and graph drawing.


## 3. Results

### 3.1. Literature Screening Result

A total of 4692 literature were retrieved through electronic databases, and 1038 duplicates were removed. 3568 literature were excluded by reading the titles and abstracts. The remaining 246 literature were read through the full text, and finally 45 literature [14–16, 21–62] were included. The literature selection process is illustrated in Figure 1.Figure 1
Flowchart of the literature screening process.


### 3.2. Basic Characteristics of Included Studies

The 45 RCTs [14–16, 21–49, 51–62] were included in two-arm trials, including 3598 patients with cancer. A total of 13 TCMIs were included, including Xiaoaiping injection (4 items) [34, 42, 45, 48], Astragalus injection (3 items) [14, 16, 30], Aidi injection (10 items) [23, 26, 27, 33, 39, 46, 48, 53, 56, 57], Brucea javanica oil emulsion injection (3 items) [22, 40, 50], compound kushen injection (8 items) [25, 35–37, 51, 54, 55, 59], elemene emulsion injection (1 items) [24], Huachansu injection (2 items) [28, 49], Kangai injection (3 items) [21, 29, 31], Kanglaite injection (1 items) [43], lentinan injection (1 items) [38], Shenfu injection (3 items) [32, 47, 62], Shenmai injection (4 items) [15, 58, 60, 61], and Shenqi Fuzheng injection (2 items) [44, 52]. All trials were conducted in China. The included tumor types were basically gastric and colorectal cancers. The measurement tools of OIPN included WHO classification criteria for acute and subacute toxicity of anticancer drugs, the National Cancer Institute Common Terminology Criteria for Adverse Events, and Oxaliplatin Levi-specific sensory neurotoxicity grading. The details of the study characteristics are depicted in Table 1.Table 1
Characteristics of included studies.
StudyStataSample sizeAgeTraditional Chinese medicine injectionChemotherapy drugsTumor typeNo. of patients (start)No. of patients (end)Neurotoxicity assessment toolExperimental group/control groupExperimental groupControl groupWang et al. [45]China46/3632∼74Xiaoaiping injectionOxaliplatin + capecitabine tabletsColorectal cancer8282WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [35]China77/7558 ± 2.461 ± 1.3Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer152152WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [33]China28/2842∼7535∼76Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer5656WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [34]China28/2828∼70Xiaoaiping injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer5656The National Cancer Institute Common Terminology Criteria for Adverse EventsLiu et al. [36]China68/6861.4 ± 12.361.8 ± 12.6Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer136136WHO classification criteria for acute and subacute toxicity of anticancer drugsBao et al. [22]China63/6262.0 ± 9.463.0 ± 7.5Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer130125The National Cancer Institute Common Terminology Criteria for Adverse EventsZhan et al. [55]China64/6462.1 ± 11.662.4 ± 11.8Compound kushen injectionOxaliplatin+5-fluorouracil + Calcium folinateColorectal cancer128128WHO classification criteria for acute and subacute toxicity of anticancer drugsXiang et al. [51]China39/3939.8 ± 7.343.7 ± 6.2Compound kushen injectionRaltitrexed + oxaliplatinColorectal cancer7878WHO classification criteria for acute and subacute toxicity of anticancer drugsLv et al. [37]China33/305861Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer6363WHO classification criteria for acute and subacute toxicity of anticancer drugsZhou et al. [59]China41/4353.8 ± 8.158.3 ± 5.2Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8484WHO classification criteria for acute and subacute toxicity of anticancer drugsZhou et al. [60]China40/4028∼67Shenmai injectionOxaliplatinGastric cancer, Colorectal cancer8075Oxaliplatin Levi-specific sensory neurotoxicity gradingAn et al. [21]China38/3245∼7544∼71Kangai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer7070WHO classification criteria for acute and subacute toxicity of anticancer drugsChang et al. [25]China53/5363.74 ± 7.8564.63 ± 8.25Compound kushen injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer106106WHO classification criteria for acute and subacute toxicity of anticancer drugsZhang et al. [57]China50/5056.7 ± 5.355.6 ± 3.4Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleColorectal cancer100100WHO classification criteria for acute and subacute toxicity of anticancer drugsZhang et al. [56]China43/4361.9 ± 3.962.1 ± 3.9Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8686WHO classification criteria for acute and subacute toxicity of anticancer drugsXu et al. [53]China47/4753.42 ± 3.9654.29 ± 4.11Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer9494WHO classification criteria for acute and subacute toxicity of anticancer drugsFang et al. [15]China46/5054∼8049∼78Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, colorectal cancer9696Oxaliplatin Levi-specific sensory neurotoxicity gradingJin et al. [30]China52/5258.12 ± 7.6958.34 ± 7.25Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer104104WHO classification criteria for acute and subacute toxicity of anticancer drugsCao et al. [23]China35/3548.51 ± 11.8548.4 ± 11.85Aidi injectionOxaliplatin+5-fluorouracil + Calcium folinateGastric cancer7070WHO classification criteria for acute and subacute toxicity of anticancer drugsZeng et al. [24]China25/2431∼7532∼74Elemene emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer4949WHO classification criteria for acute and subacute toxicity of anticancer drugsZhu et al. [61]China46/4129∼73Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8787Oxaliplatin Levi-specific sensory neurotoxicity gradingZhu et al. [62]China40/4052.150.8Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsGastric cancer, colorectal cancer8080Oxaliplatin Levi-specific sensory neurotoxicity gradingLi et al. [32]China40/4032∼7631∼75Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, colorectal cancer8080Oxaliplatin Levi-specific sensory neurotoxicity gradingTang et al. [44]China31/3060.69 ± 3.1359.16 ± 3.15Shenqi Fuzheng injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer6161WHO classification criteria for acute and subacute toxicity of anticancer drugsShen et al. [43]China54/5031∼75Kanglaite injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer104104WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [48]China38/3632∼74Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer7474WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [49]China36/3240∼72Huachansu injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer6868WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [50]China24/2331∼7532∼74Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer4747WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [46]China32/3161.2 ± 3.862.1 ± 3.5Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6363WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [47]China40/4051.451.4Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsGastric cancer, colorectal cancer8080WHO classification criteria for acute and subacute toxicity of anticancer drugsDou et al. [27]China34/3458.4 ± 12.959.2 ± 18.3Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleColorectal cancer6868WHO classification criteria for acute and subacute toxicity of anticancer drugsDou et al. [28]China36/3657.0 ± 3.256.3 ± 2.4Huachansu injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer7272WHO classification criteria for acute and subacute toxicity of anticancer drugsMiao et al. [39]China41/4365Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer8484WHO classification criteria for acute and subacute toxicity of anticancer drugsNie et al. [40]China30/3030∼7327∼75Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsHu et al. [29]China18/1850∼8060∼85Kangai injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer3636The National Cancer Institute Common Terminology Criteria for Adverse EventsXing et al. [52]China45/4554.1 ± 8.453.3 ± 8.5Shenqi Fuzheng injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer9090WHO classification criteria for acute and subacute toxicity of anticancer drugsZhong et al. [58]China30/3062.5 ± 10.760.5 ± 9.2Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, duodenal carcinoma, colorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsYan et al. [54]China41/4155.1 ± 6.853.6 ± 6.1Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8282WHO classification criteria for acute and subacute toxicity of anticancer drugsRuan et al. [42]China42/4236∼7438∼76Xiaoaiping injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer8484The National Cancer Institute Common Terminology Criteria for Adverse EventsChen et al. [14]China30/3053.8 ± 14.452.5 ± 12.6Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsChen et al. [26]China45/4546.93 ± 6.9146.77 ± 6.83Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer9090WHO classification criteria for acute and subacute toxicity of anticancer drugsLei et al. [31]China30/3031∼75Kangai injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsRao et al. [41]China30/3031∼7434∼72Xiaoaiping injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsMa et al. [38]China41/3761.6 ± 8.1963.41 ± 7.43Lentinan injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer7878WHO classification criteria for acute and subacute toxicity of anticancer drugsLuo et al. [16]China30/3046∼7342∼74Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugs


### 3.3. Risk of Bias Assessment

14 studies were considered low risk for randomization, 4 studies were assessed as high risk because they had incorrect methods of random sequence generation, and the randomization of the remaining 27 studies was unclear. The method of allocation concealment was unclear for all studies. Due to the specificity of TCMIs, it is difficult to do blinding. The blinding method for all studies was unclear. For incomplete outcome data, one study showed high risk of bias. Details of the risk of bias assessment are shown in Figure2.


### 3.4. Directly Compared Meta-Analysis Results

A meta-analysis of direct comparisons of TCMIs combined with chemotherapy compared to chemotherapy alone was conducted. The results showed that AI can reduce incidence of grade I neurotoxicity (P<0.05) compared with chemotherapy; SFI and AI could reduce incidence of grade II neurotoxicity (P<0.05); SFI and SMI could reduce incidence of grade III neurotoxicity (P<0.05); ADI, SFI, SMI, SIFZI, CKSI, HCSI, AI, KLEI, LI, and XAPI could reduce total incidence of grade I ∼ IV neurotoxicity (P<0.05). Results of direct comparative meta-analyses are shown in Table 2.Table 2
Direct comparison of meta-analysis results.
Outcome indexComparison categoryNumber of studiesHeterogeneityMeta-analysis resultsI2PRR, 95%CIPIncidence of grade I neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.79 (0.19, 3.30)0.743SFI + chemotherapy vs chemotherapy30%0.9980.73 (0.53, 1.00)0.05SMI + chemotherapy vs chemotherapy451.30%0.1040.72 (0.42, 1.26)0.253SIFZI + chemotherapy vs chemotherapy1NANA0.81 (0.44, 1.49)0.5CKSI + chemotherapy vs chemotherapy1NANA0.89 (0.37, 2.13)0.791AI + chemotherapy vs chemotherapy30%0.9350.59 (0.36, 0.98)0.042KAI + chemotherapy vs chemotherapy280.30%0.0240.67 (0.19, 2.36)0.531EEI + chemotherapy vs chemotherapy1NANA0.48 (0.10, 2.38)0.369LI + chemotherapy vs chemotherapy1NANA0.41 (0.16, 1.07)0.069XAPI + chemotherapy vs chemotherapy278.60%0.0310.43 (0.10, 1.78)0.531BJOEI + chemotherapy vs chemotherapy1NANA0.75 (0.18, 3.07)0.689Incidence of grade II neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.17 (0.02, 1.34)0.099SFI + chemotherapy vs chemotherapy30%0.9660.43 (0.24, 0.79)0.006SMI + chemotherapy vs chemotherapy433.90%0.2090.68 (0.43, 1.07)0.095SIFZI + chemotherapy vs chemotherapy1NANA0.77 (0.38, 1.570)0.471CKSI + chemotherapy vs chemotherapy1NANA0.86 (0.31, 2.38)0.767AI + chemotherapy vs chemotherapy30%0.9020.39 (0.19, 0.81)0.011KAI + chemotherapy vs chemotherapy1NANA0.17 (0.01, 3.40)0.246EEI + chemotherapy vs chemotherapy1NANA0.96 (0.15, 6.28)0.966LI + chemotherapy vs chemotherapy1NANA0.60 (0.11, 3.40)0.566XAPI + chemotherapy vs chemotherapy20%0.3280.54 (0.23, 1.31)0.173BJOEI + chemotherapy vs chemotherapy1NANA0.75 (0.18, 3.07)0.689Incidence of grade III neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.15 (0.01, 2.81)0.204SFI + chemotherapy vs chemotherapy30%0.9490.16 (0.03, 0.87)0.034SMI + chemotherapy vs chemotherapy47.40%0.3560.38 (0.20, 0.75)0.005SIFZI + chemotherapy vs chemotherapy1NANA0.25 (0.03, 2.15)0.207CKSI + chemotherapy vs chemotherapy1NANA1.00 (0.26, 3.79)1AI + chemotherapy vs chemotherapy30%0.8250.26 (0.07, 1.04)0.056LI + chemotherapy vs chemotherapy1NANA0.18 (0.01, 3.65)0.265XAPI + chemotherapy vs chemotherapy1NANA0.52 (0.09, 2.96)0.462Incidence of grade IV neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.35 (0.02, 8.34)0.516SMI + chemotherapy vs chemotherapy20%0.7180.51 (0.22, 1.22)0.129AI + chemotherapy vs chemotherapy1NANA0.33 (0.01, 8.00)0.498Incidence of grade I∼IV neurotoxicityADI + chemotherapy vs chemotherapy1013.50%0.3190.42 (0.31, 0.57)<0.0001SFI + chemotherapy vs chemotherapy30%0.9730.57 (0.46, 0.71)<0.0001SMI + chemotherapy vs chemotherapy467.80%0.0250.56 (0.40, 0.78)0.001SIFZI + chemotherapy vs chemotherapy20%0.5070.68 (0.52, 0.89)0.005CKSI + chemotherapy vs chemotherapy817.70%0.290.56 (0.45, 0.71)<0.0001HCSI + chemotherapy vs chemotherapy20%0.8740.45 (0.30, 0.69)<0.0001AI + chemotherapy vs chemotherapy30%0.9970.47 (0.33, 0.66)<0.0001KAI + chemotherapy vs chemotherapy382.20%0.0040.45 (0.11, 1.79)0.254KLEI + chemotherapy vs chemotherapy1NANA0.66 (0.45, 0.97)0.034EEI + chemotherapy vs chemotherapy1NANA0.64 (0.21, 1.99)0.441LI + chemotherapy vs chemotherapy1NANA0.40 (0.18, 0.85)0.018XAPI + chemotherapy vs chemotherapy454.70%0.0850.59 (0.38, 0.92)0.019BJOEI + chemotherapy vs chemotherapy30%0.8090.84 (0.58, 1.21)0.346NA, data not available; RR, relative risk; CI, confidence interval; XAPI, Xiaoaiping injection; CKSI, compound kushen injection; ADI, Aidi injection; BJOEI, Brucea javanica oil emulsion injection; SMI, Shenmai injection; KAI, Kangai injection; AI,Astragalus injection; EEI, elemene emulsion injection; SFI, Shenfu injection; SIFZI, Shenqi Fuzheng injection; KLEI, Kanglaite injection; HCSI, Huachansu injection; LI, lentinan injection.Figure 2
Risk of bias graph of the included RCTs. (a) Risk of bias summary; (b) risk of bias graph.
(a)(b)


### 3.5. Comparison Results of Network Meta-Analysis

#### 3.5.1. Evidence Network Diagram

The evidence network diagram is illustrated in Figure3. Each dot represents a drug, and the direct connection between the two points indicated a direct comparison between the two drugs. The thicker the line between the two dots, the greater the number of paired studies, the larger the node, and the larger the sample size of studies involved in the intervention.Figure 3
Network diagrams for different outcomes. (a) Incidence of grade I neurotoxicity; (b) incidence of grade II neurotoxicity; (c) incidence of grade III neurotoxicity; (d) incidence of grade IV neurotoxicity; (e) total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


#### 3.5.2. Incidence of Grade I Neurotoxicity

Incidence of grade I neurotoxicity was reported in 20 studies involving 11 TCMIs and 1522 patients. The results of the NMA showed that the differences were statistically significant for AI versus ADI (RR:0.48; 95%CI (0.26, 0.87)), and SIFZI versus ADI (RR:0.53; 95%CI (0.34, 0.84)), and there were no significant differences in other interventions (Figure4(a)).Figure 4
Pooled estimates of the network meta-analysis. (a) Pooled relative risk (95% confidence intervals) for the incidence of grade I neurotoxicity; (b) pooled relative risk (95% confidence intervals) for the incidence of grade II neurotoxicity; (c) pooled relative risk (95% confidence intervals) for the incidence of grade III neurotoxicity; (d) pooled relative risk (95% confidence intervals) for the incidence of grade IV neurotoxicity; (e) pooled relative risk (95% confidence intervals) for the total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


#### 3.5.3. Incidence of Grade II Neurotoxicity

Incidence of grade II neurotoxicity was reported in 19 studies involving 11 TCMIs and 1462 patients. The results of the NMA showed statistically significant differences for SIFZI versus EEI (RR:0.44; 95%CI (0.24, 0.79)), SIFZI versus ADI (RR:0.39; 95%CI (0.19, 0.81)), and BJOEI versus chemotherapy alone (RR:0.32; 95%CI (0.03, 3.07)), and the difference between the remaining interventions was not statistically significant (Figure4(b)).


#### 3.5.4. Incidence of Grade III Neurotoxicity

Incidence of grade III neurotoxicity was reported in 15 studies involving 8 TCMIs and 1227 patients. The results of the NMA showed statistically significant differences in SMI versus LI (RR:0.47; 95%CI (0.24, 0.93)), and SMI versus CKSI (RR:0.16; 95%CI (0.03, 0.90)), and the difference between the remaining interventions was not statistically significant (Figure4(c)).


#### 3.5.5. Incidence of Grade IV Neurotoxicity

Incidence of grade IV neurotoxicity was reported in 4 studies involving 3 TCMIs and 355 patients. The results of the NMA showed no statistically significant differences in the comparison of the interventions (Figure4(d)).


#### 3.5.6. Total Incidence of Grade I ∼ IV Neurotoxicity

Total incidence of grade I ∼ IV neurotoxicity was reported in 45 studies involving 13 TCMIs and 3598 patients. The results of the NMA showed that the differences were statistically significant for SIFZI versus LI (RR:0.67; 95%CI (0.46, 0.98)), SIFZI versus BJOEI (RR:0.59; 95%CI (0.42, 0.84)), SIFZI versus XAPI (RR:0.57; 95%CI (0.44, 0.75)), SIFZI versus EEI (RR:0.57; 95%CI (0.42, 0.78)), SIFZI versus SMI (RR:0.58; 95%CI (0.44, 0.77)), SIFZI versus chemotherapy (RR:0.47; 95%CI (0.31, 0.70)), SIFZI versus HCSI (RR:0.45; 95%CI (0.27, 0.75)), SIFZI versus KLEI (RR:0.39; 95%CI (0.17, 0.93)), SIFZI versus ADI (RR:0.44; 95%CI (0.32, 0.62)), and SFI versus ADI (RR:0.53; 95%CI (0.31, 0.93)), and the differences between the remaining interventions were not statistically significant (Figure4(e)).


### 3.6. Rank Probabilities

The SUCRA cumulative probability ranking showed that AI was most likely to be the best intervention to reduce the incidence of grade I neurotoxicity. Ranking results of incidence of grade I neurotoxicity were AI (SUCRA = 84.1%) > SIFZI (SUCRA = 78.4%) > SMI (SUCRA = 64.2%) > LI (SUCRA = 58.5%) > chemotherapy (SUCRA = 54.5%)>SFI (SUCRA = 52.5%)>EEI (SUCRA = 49.7%)>XAPI (SUCRA = 44.8)>BJOEI (SUCRA = 34.6%)>CKSI (SUCRA = 33.7%)>ADI (SUCRA = 26.4%)>KAI (SUCRA = 18.6%) (Figure5(a)). SIFZI was the most likely intervention to reduce the incidence of grade II neurotoxicity. Ranking results of incidence of grade II neurotoxicity were SIFZI (SUCRA = 81.2%) > CKSI (SUCRA = 68.5%) > SMI (SUCRA = 67.8%) > LI (SUCRA = 63.6%) > SFI (SUCRA = 60.8%) > XAPI (SUCRA = 58.8%) > KAI (SUCRA = 51.9%) > BJOEI (SUCRA = 45.1%) > EEI (SUCRA = 32.3%) > ADI (SUCRA = 29.8%) > AI (SUCRA = 22.8%) > chemotherapy (SUCRA = 17.4%) (Figure 5(b)). SMI was the most likely intervention to reduce the incidence of grade III neurotoxicity. Ranking results of incidence of grade III neurotoxicity were SMI (SUCRA = 85.6%) > SFI (SUCRA = 81.2%) > XAPI (SUCRA = 59.5%) > LI (SUCRA = 55.9%) > ADI (SUCRA = 39.5%) > AI (SUCRA = 38.3%) > SIFZI (SUCRA = 34.2%) > chemotherapy (SUCRA = 30.4%)>CKSI (SUCRA = 25.4%) (Figure 5(c)). SMI was the most likely intervention to reduce the incidence of grade IV neurotoxicity. Ranking results of incidence of grade IV neurotoxicity were SMI (SUCRA = 80.7%) > AI (SUCRA = 42.5%) > ADI (SUCRA = 39.2%) > chemotherapy (SUCRA = 37.6%) (Figure 5(d)). SIFZI was the most likely intervention to reduce the incidence of grade I ∼ IV neurotoxicity. Ranking results of incidence of grade I ∼ IV neurotoxicity were SIFZI (SUCRA = 94.5%) > SFI (SUCRA = 79.4%) > AI (SUCRA = 75.0%) > LI (SUCRA = 62.0%) > KAI (SUCRA = 59.0%) > CKSI (SUCRA = 53.1%) > BJOEI (SUCRA = 50.2%) > XAPI (SUCRA = 45.5%) > EEI (SUCRA = 45.0%) > SMI (SUCRA = 47.7%) > chemotherapy (SUCRA = 24.6%)>HCSI (SUCRA = 23.4%)>KLEI (SUCRA = 21.2%)>ADI (SUCRA = 19.2%) (Figure 5(e)).Figure 5
The surface under the cumulative ranking curve (SUCRA) plots for different outcomes. (a) Incidence of grade I neurotoxicity; (b) incidence of grade II neurotoxicity; (c) incidence of grade III neurotoxicity; (d) incidence of grade IV neurotoxicity; (e) total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


### 3.7. Small-Sample Effect Estimation

If no less than 10 studies were included, comparison-corrected funnel plots were drawn to identify the possibility of small-sample effects in the intervention network. The resulting funnel plot was slightly asymmetric, considering the possibility of a small-sample effect or publication bias between studies (Figure6).Figure 6
Publication bias. (a) Incidence of grade I neurotoxicity comparison-correction funnel chart; (b) incidence of grade II neurotoxicity comparison-correction funnel chart; (c) incidence of grade III neurotoxicity comparison-correction funnel chart; (d) total incidence of grade I ∼ IV neurotoxicity comparison-correction funnel chart.
(a)(b)(c)(d)


### 3.8. Sensitivity Analysis

We performed sensitivity analyses for outcome indicators that included at least 3 or more literature. Sensitivity analysis showed that SMI plus chemotherapy versus chemotherapy reversed the results of the meta-analysis in terms of incidence of grade I neurotoxicity and incidence of grade II neurotoxicity. The results of the meta-analysis were reversed for AI plus chemotherapy versus chemotherapy in terms of incidence of grade II neurotoxicity. KAI plus chemotherapy versus chemotherapy and XAPI plus chemotherapy versus chemotherapy were reversed for incidence of grade I ∼ IV neurotoxicity. The results of the meta-analysis were reversed for neurotoxicity. No reversal was found for the remaining outcome indicators. The results are presented in the Supplementary Material (FiguresS1–S17).


## 3.1. Literature Screening Result

A total of 4692 literature were retrieved through electronic databases, and 1038 duplicates were removed. 3568 literature were excluded by reading the titles and abstracts. The remaining 246 literature were read through the full text, and finally 45 literature [14–16, 21–62] were included. The literature selection process is illustrated in Figure 1.Figure 1
Flowchart of the literature screening process.


## 3.2. Basic Characteristics of Included Studies

The 45 RCTs [14–16, 21–49, 51–62] were included in two-arm trials, including 3598 patients with cancer. A total of 13 TCMIs were included, including Xiaoaiping injection (4 items) [34, 42, 45, 48], Astragalus injection (3 items) [14, 16, 30], Aidi injection (10 items) [23, 26, 27, 33, 39, 46, 48, 53, 56, 57], Brucea javanica oil emulsion injection (3 items) [22, 40, 50], compound kushen injection (8 items) [25, 35–37, 51, 54, 55, 59], elemene emulsion injection (1 items) [24], Huachansu injection (2 items) [28, 49], Kangai injection (3 items) [21, 29, 31], Kanglaite injection (1 items) [43], lentinan injection (1 items) [38], Shenfu injection (3 items) [32, 47, 62], Shenmai injection (4 items) [15, 58, 60, 61], and Shenqi Fuzheng injection (2 items) [44, 52]. All trials were conducted in China. The included tumor types were basically gastric and colorectal cancers. The measurement tools of OIPN included WHO classification criteria for acute and subacute toxicity of anticancer drugs, the National Cancer Institute Common Terminology Criteria for Adverse Events, and Oxaliplatin Levi-specific sensory neurotoxicity grading. The details of the study characteristics are depicted in Table 1.Table 1
Characteristics of included studies.
StudyStataSample sizeAgeTraditional Chinese medicine injectionChemotherapy drugsTumor typeNo. of patients (start)No. of patients (end)Neurotoxicity assessment toolExperimental group/control groupExperimental groupControl groupWang et al. [45]China46/3632∼74Xiaoaiping injectionOxaliplatin + capecitabine tabletsColorectal cancer8282WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [35]China77/7558 ± 2.461 ± 1.3Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer152152WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [33]China28/2842∼7535∼76Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer5656WHO classification criteria for acute and subacute toxicity of anticancer drugsLiu et al. [34]China28/2828∼70Xiaoaiping injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer5656The National Cancer Institute Common Terminology Criteria for Adverse EventsLiu et al. [36]China68/6861.4 ± 12.361.8 ± 12.6Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer136136WHO classification criteria for acute and subacute toxicity of anticancer drugsBao et al. [22]China63/6262.0 ± 9.463.0 ± 7.5Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer130125The National Cancer Institute Common Terminology Criteria for Adverse EventsZhan et al. [55]China64/6462.1 ± 11.662.4 ± 11.8Compound kushen injectionOxaliplatin+5-fluorouracil + Calcium folinateColorectal cancer128128WHO classification criteria for acute and subacute toxicity of anticancer drugsXiang et al. [51]China39/3939.8 ± 7.343.7 ± 6.2Compound kushen injectionRaltitrexed + oxaliplatinColorectal cancer7878WHO classification criteria for acute and subacute toxicity of anticancer drugsLv et al. [37]China33/305861Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer6363WHO classification criteria for acute and subacute toxicity of anticancer drugsZhou et al. [59]China41/4353.8 ± 8.158.3 ± 5.2Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8484WHO classification criteria for acute and subacute toxicity of anticancer drugsZhou et al. [60]China40/4028∼67Shenmai injectionOxaliplatinGastric cancer, Colorectal cancer8075Oxaliplatin Levi-specific sensory neurotoxicity gradingAn et al. [21]China38/3245∼7544∼71Kangai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer7070WHO classification criteria for acute and subacute toxicity of anticancer drugsChang et al. [25]China53/5363.74 ± 7.8564.63 ± 8.25Compound kushen injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer106106WHO classification criteria for acute and subacute toxicity of anticancer drugsZhang et al. [57]China50/5056.7 ± 5.355.6 ± 3.4Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleColorectal cancer100100WHO classification criteria for acute and subacute toxicity of anticancer drugsZhang et al. [56]China43/4361.9 ± 3.962.1 ± 3.9Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8686WHO classification criteria for acute and subacute toxicity of anticancer drugsXu et al. [53]China47/4753.42 ± 3.9654.29 ± 4.11Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer9494WHO classification criteria for acute and subacute toxicity of anticancer drugsFang et al. [15]China46/5054∼8049∼78Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, colorectal cancer9696Oxaliplatin Levi-specific sensory neurotoxicity gradingJin et al. [30]China52/5258.12 ± 7.6958.34 ± 7.25Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer104104WHO classification criteria for acute and subacute toxicity of anticancer drugsCao et al. [23]China35/3548.51 ± 11.8548.4 ± 11.85Aidi injectionOxaliplatin+5-fluorouracil + Calcium folinateGastric cancer7070WHO classification criteria for acute and subacute toxicity of anticancer drugsZeng et al. [24]China25/2431∼7532∼74Elemene emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer4949WHO classification criteria for acute and subacute toxicity of anticancer drugsZhu et al. [61]China46/4129∼73Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8787Oxaliplatin Levi-specific sensory neurotoxicity gradingZhu et al. [62]China40/4052.150.8Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsGastric cancer, colorectal cancer8080Oxaliplatin Levi-specific sensory neurotoxicity gradingLi et al. [32]China40/4032∼7631∼75Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, colorectal cancer8080Oxaliplatin Levi-specific sensory neurotoxicity gradingTang et al. [44]China31/3060.69 ± 3.1359.16 ± 3.15Shenqi Fuzheng injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer6161WHO classification criteria for acute and subacute toxicity of anticancer drugsShen et al. [43]China54/5031∼75Kanglaite injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer104104WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [48]China38/3632∼74Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer7474WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [49]China36/3240∼72Huachansu injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer6868WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [50]China24/2331∼7532∼74Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer4747WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [46]China32/3161.2 ± 3.862.1 ± 3.5Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6363WHO classification criteria for acute and subacute toxicity of anticancer drugsWang et al. [47]China40/4051.451.4Shenfu injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsGastric cancer, colorectal cancer8080WHO classification criteria for acute and subacute toxicity of anticancer drugsDou et al. [27]China34/3458.4 ± 12.959.2 ± 18.3Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleColorectal cancer6868WHO classification criteria for acute and subacute toxicity of anticancer drugsDou et al. [28]China36/3657.0 ± 3.256.3 ± 2.4Huachansu injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer7272WHO classification criteria for acute and subacute toxicity of anticancer drugsMiao et al. [39]China41/4365Aidi injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer8484WHO classification criteria for acute and subacute toxicity of anticancer drugsNie et al. [40]China30/3030∼7327∼75Brucea javanica oil emulsion injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsHu et al. [29]China18/1850∼8060∼85Kangai injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer3636The National Cancer Institute Common Terminology Criteria for Adverse EventsXing et al. [52]China45/4554.1 ± 8.453.3 ± 8.5Shenqi Fuzheng injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer9090WHO classification criteria for acute and subacute toxicity of anticancer drugsZhong et al. [58]China30/3062.5 ± 10.760.5 ± 9.2Shenmai injectionOxaliplatin+5-fluorouracil + calcium folinateGastric cancer, duodenal carcinoma, colorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsYan et al. [54]China41/4155.1 ± 6.853.6 ± 6.1Compound kushen injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer8282WHO classification criteria for acute and subacute toxicity of anticancer drugsRuan et al. [42]China42/4236∼7438∼76Xiaoaiping injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer8484The National Cancer Institute Common Terminology Criteria for Adverse EventsChen et al. [14]China30/3053.8 ± 14.452.5 ± 12.6Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsChen et al. [26]China45/4546.93 ± 6.9146.77 ± 6.83Aidi injectionOxaliplatin + tegafur-gimeracil-oteracil potassium capsuleGastric cancer9090WHO classification criteria for acute and subacute toxicity of anticancer drugsLei et al. [31]China30/3031∼75Kangai injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsRao et al. [41]China30/3031∼7434∼72Xiaoaiping injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugsMa et al. [38]China41/3761.6 ± 8.1963.41 ± 7.43Lentinan injectionOxaliplatin+5-fluorouracil + calcium folinateColorectal cancer7878WHO classification criteria for acute and subacute toxicity of anticancer drugsLuo et al. [16]China30/3046∼7342∼74Astragalus injectionOxaliplatin+5-fluorouracil + calcium folinate, oxaliplatin + capecitabine tabletsColorectal cancer6060WHO classification criteria for acute and subacute toxicity of anticancer drugs


## 3.3. Risk of Bias Assessment

14 studies were considered low risk for randomization, 4 studies were assessed as high risk because they had incorrect methods of random sequence generation, and the randomization of the remaining 27 studies was unclear. The method of allocation concealment was unclear for all studies. Due to the specificity of TCMIs, it is difficult to do blinding. The blinding method for all studies was unclear. For incomplete outcome data, one study showed high risk of bias. Details of the risk of bias assessment are shown in Figure2.


## 3.4. Directly Compared Meta-Analysis Results

A meta-analysis of direct comparisons of TCMIs combined with chemotherapy compared to chemotherapy alone was conducted. The results showed that AI can reduce incidence of grade I neurotoxicity (P<0.05) compared with chemotherapy; SFI and AI could reduce incidence of grade II neurotoxicity (P<0.05); SFI and SMI could reduce incidence of grade III neurotoxicity (P<0.05); ADI, SFI, SMI, SIFZI, CKSI, HCSI, AI, KLEI, LI, and XAPI could reduce total incidence of grade I ∼ IV neurotoxicity (P<0.05). Results of direct comparative meta-analyses are shown in Table 2.Table 2
Direct comparison of meta-analysis results.
Outcome indexComparison categoryNumber of studiesHeterogeneityMeta-analysis resultsI2PRR, 95%CIPIncidence of grade I neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.79 (0.19, 3.30)0.743SFI + chemotherapy vs chemotherapy30%0.9980.73 (0.53, 1.00)0.05SMI + chemotherapy vs chemotherapy451.30%0.1040.72 (0.42, 1.26)0.253SIFZI + chemotherapy vs chemotherapy1NANA0.81 (0.44, 1.49)0.5CKSI + chemotherapy vs chemotherapy1NANA0.89 (0.37, 2.13)0.791AI + chemotherapy vs chemotherapy30%0.9350.59 (0.36, 0.98)0.042KAI + chemotherapy vs chemotherapy280.30%0.0240.67 (0.19, 2.36)0.531EEI + chemotherapy vs chemotherapy1NANA0.48 (0.10, 2.38)0.369LI + chemotherapy vs chemotherapy1NANA0.41 (0.16, 1.07)0.069XAPI + chemotherapy vs chemotherapy278.60%0.0310.43 (0.10, 1.78)0.531BJOEI + chemotherapy vs chemotherapy1NANA0.75 (0.18, 3.07)0.689Incidence of grade II neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.17 (0.02, 1.34)0.099SFI + chemotherapy vs chemotherapy30%0.9660.43 (0.24, 0.79)0.006SMI + chemotherapy vs chemotherapy433.90%0.2090.68 (0.43, 1.07)0.095SIFZI + chemotherapy vs chemotherapy1NANA0.77 (0.38, 1.570)0.471CKSI + chemotherapy vs chemotherapy1NANA0.86 (0.31, 2.38)0.767AI + chemotherapy vs chemotherapy30%0.9020.39 (0.19, 0.81)0.011KAI + chemotherapy vs chemotherapy1NANA0.17 (0.01, 3.40)0.246EEI + chemotherapy vs chemotherapy1NANA0.96 (0.15, 6.28)0.966LI + chemotherapy vs chemotherapy1NANA0.60 (0.11, 3.40)0.566XAPI + chemotherapy vs chemotherapy20%0.3280.54 (0.23, 1.31)0.173BJOEI + chemotherapy vs chemotherapy1NANA0.75 (0.18, 3.07)0.689Incidence of grade III neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.15 (0.01, 2.81)0.204SFI + chemotherapy vs chemotherapy30%0.9490.16 (0.03, 0.87)0.034SMI + chemotherapy vs chemotherapy47.40%0.3560.38 (0.20, 0.75)0.005SIFZI + chemotherapy vs chemotherapy1NANA0.25 (0.03, 2.15)0.207CKSI + chemotherapy vs chemotherapy1NANA1.00 (0.26, 3.79)1AI + chemotherapy vs chemotherapy30%0.8250.26 (0.07, 1.04)0.056LI + chemotherapy vs chemotherapy1NANA0.18 (0.01, 3.65)0.265XAPI + chemotherapy vs chemotherapy1NANA0.52 (0.09, 2.96)0.462Incidence of grade IV neurotoxicityADI + chemotherapy vs chemotherapy1NANA0.35 (0.02, 8.34)0.516SMI + chemotherapy vs chemotherapy20%0.7180.51 (0.22, 1.22)0.129AI + chemotherapy vs chemotherapy1NANA0.33 (0.01, 8.00)0.498Incidence of grade I∼IV neurotoxicityADI + chemotherapy vs chemotherapy1013.50%0.3190.42 (0.31, 0.57)<0.0001SFI + chemotherapy vs chemotherapy30%0.9730.57 (0.46, 0.71)<0.0001SMI + chemotherapy vs chemotherapy467.80%0.0250.56 (0.40, 0.78)0.001SIFZI + chemotherapy vs chemotherapy20%0.5070.68 (0.52, 0.89)0.005CKSI + chemotherapy vs chemotherapy817.70%0.290.56 (0.45, 0.71)<0.0001HCSI + chemotherapy vs chemotherapy20%0.8740.45 (0.30, 0.69)<0.0001AI + chemotherapy vs chemotherapy30%0.9970.47 (0.33, 0.66)<0.0001KAI + chemotherapy vs chemotherapy382.20%0.0040.45 (0.11, 1.79)0.254KLEI + chemotherapy vs chemotherapy1NANA0.66 (0.45, 0.97)0.034EEI + chemotherapy vs chemotherapy1NANA0.64 (0.21, 1.99)0.441LI + chemotherapy vs chemotherapy1NANA0.40 (0.18, 0.85)0.018XAPI + chemotherapy vs chemotherapy454.70%0.0850.59 (0.38, 0.92)0.019BJOEI + chemotherapy vs chemotherapy30%0.8090.84 (0.58, 1.21)0.346NA, data not available; RR, relative risk; CI, confidence interval; XAPI, Xiaoaiping injection; CKSI, compound kushen injection; ADI, Aidi injection; BJOEI, Brucea javanica oil emulsion injection; SMI, Shenmai injection; KAI, Kangai injection; AI,Astragalus injection; EEI, elemene emulsion injection; SFI, Shenfu injection; SIFZI, Shenqi Fuzheng injection; KLEI, Kanglaite injection; HCSI, Huachansu injection; LI, lentinan injection.Figure 2
Risk of bias graph of the included RCTs. (a) Risk of bias summary; (b) risk of bias graph.
(a)(b)


## 3.5. Comparison Results of Network Meta-Analysis

### 3.5.1. Evidence Network Diagram

The evidence network diagram is illustrated in Figure3. Each dot represents a drug, and the direct connection between the two points indicated a direct comparison between the two drugs. The thicker the line between the two dots, the greater the number of paired studies, the larger the node, and the larger the sample size of studies involved in the intervention.Figure 3
Network diagrams for different outcomes. (a) Incidence of grade I neurotoxicity; (b) incidence of grade II neurotoxicity; (c) incidence of grade III neurotoxicity; (d) incidence of grade IV neurotoxicity; (e) total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


### 3.5.2. Incidence of Grade I Neurotoxicity

Incidence of grade I neurotoxicity was reported in 20 studies involving 11 TCMIs and 1522 patients. The results of the NMA showed that the differences were statistically significant for AI versus ADI (RR:0.48; 95%CI (0.26, 0.87)), and SIFZI versus ADI (RR:0.53; 95%CI (0.34, 0.84)), and there were no significant differences in other interventions (Figure4(a)).Figure 4
Pooled estimates of the network meta-analysis. (a) Pooled relative risk (95% confidence intervals) for the incidence of grade I neurotoxicity; (b) pooled relative risk (95% confidence intervals) for the incidence of grade II neurotoxicity; (c) pooled relative risk (95% confidence intervals) for the incidence of grade III neurotoxicity; (d) pooled relative risk (95% confidence intervals) for the incidence of grade IV neurotoxicity; (e) pooled relative risk (95% confidence intervals) for the total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


### 3.5.3. Incidence of Grade II Neurotoxicity

Incidence of grade II neurotoxicity was reported in 19 studies involving 11 TCMIs and 1462 patients. The results of the NMA showed statistically significant differences for SIFZI versus EEI (RR:0.44; 95%CI (0.24, 0.79)), SIFZI versus ADI (RR:0.39; 95%CI (0.19, 0.81)), and BJOEI versus chemotherapy alone (RR:0.32; 95%CI (0.03, 3.07)), and the difference between the remaining interventions was not statistically significant (Figure4(b)).


### 3.5.4. Incidence of Grade III Neurotoxicity

Incidence of grade III neurotoxicity was reported in 15 studies involving 8 TCMIs and 1227 patients. The results of the NMA showed statistically significant differences in SMI versus LI (RR:0.47; 95%CI (0.24, 0.93)), and SMI versus CKSI (RR:0.16; 95%CI (0.03, 0.90)), and the difference between the remaining interventions was not statistically significant (Figure4(c)).


### 3.5.5. Incidence of Grade IV Neurotoxicity

Incidence of grade IV neurotoxicity was reported in 4 studies involving 3 TCMIs and 355 patients. The results of the NMA showed no statistically significant differences in the comparison of the interventions (Figure4(d)).


### 3.5.6. Total Incidence of Grade I ∼ IV Neurotoxicity

Total incidence of grade I ∼ IV neurotoxicity was reported in 45 studies involving 13 TCMIs and 3598 patients. The results of the NMA showed that the differences were statistically significant for SIFZI versus LI (RR:0.67; 95%CI (0.46, 0.98)), SIFZI versus BJOEI (RR:0.59; 95%CI (0.42, 0.84)), SIFZI versus XAPI (RR:0.57; 95%CI (0.44, 0.75)), SIFZI versus EEI (RR:0.57; 95%CI (0.42, 0.78)), SIFZI versus SMI (RR:0.58; 95%CI (0.44, 0.77)), SIFZI versus chemotherapy (RR:0.47; 95%CI (0.31, 0.70)), SIFZI versus HCSI (RR:0.45; 95%CI (0.27, 0.75)), SIFZI versus KLEI (RR:0.39; 95%CI (0.17, 0.93)), SIFZI versus ADI (RR:0.44; 95%CI (0.32, 0.62)), and SFI versus ADI (RR:0.53; 95%CI (0.31, 0.93)), and the differences between the remaining interventions were not statistically significant (Figure4(e)).


## 3.5.1. Evidence Network Diagram

The evidence network diagram is illustrated in Figure3. Each dot represents a drug, and the direct connection between the two points indicated a direct comparison between the two drugs. The thicker the line between the two dots, the greater the number of paired studies, the larger the node, and the larger the sample size of studies involved in the intervention.Figure 3
Network diagrams for different outcomes. (a) Incidence of grade I neurotoxicity; (b) incidence of grade II neurotoxicity; (c) incidence of grade III neurotoxicity; (d) incidence of grade IV neurotoxicity; (e) total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


## 3.5.2. Incidence of Grade I Neurotoxicity

Incidence of grade I neurotoxicity was reported in 20 studies involving 11 TCMIs and 1522 patients. The results of the NMA showed that the differences were statistically significant for AI versus ADI (RR:0.48; 95%CI (0.26, 0.87)), and SIFZI versus ADI (RR:0.53; 95%CI (0.34, 0.84)), and there were no significant differences in other interventions (Figure4(a)).Figure 4
Pooled estimates of the network meta-analysis. (a) Pooled relative risk (95% confidence intervals) for the incidence of grade I neurotoxicity; (b) pooled relative risk (95% confidence intervals) for the incidence of grade II neurotoxicity; (c) pooled relative risk (95% confidence intervals) for the incidence of grade III neurotoxicity; (d) pooled relative risk (95% confidence intervals) for the incidence of grade IV neurotoxicity; (e) pooled relative risk (95% confidence intervals) for the total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


## 3.5.3. Incidence of Grade II Neurotoxicity

Incidence of grade II neurotoxicity was reported in 19 studies involving 11 TCMIs and 1462 patients. The results of the NMA showed statistically significant differences for SIFZI versus EEI (RR:0.44; 95%CI (0.24, 0.79)), SIFZI versus ADI (RR:0.39; 95%CI (0.19, 0.81)), and BJOEI versus chemotherapy alone (RR:0.32; 95%CI (0.03, 3.07)), and the difference between the remaining interventions was not statistically significant (Figure4(b)).


## 3.5.4. Incidence of Grade III Neurotoxicity

Incidence of grade III neurotoxicity was reported in 15 studies involving 8 TCMIs and 1227 patients. The results of the NMA showed statistically significant differences in SMI versus LI (RR:0.47; 95%CI (0.24, 0.93)), and SMI versus CKSI (RR:0.16; 95%CI (0.03, 0.90)), and the difference between the remaining interventions was not statistically significant (Figure4(c)).


## 3.5.5. Incidence of Grade IV Neurotoxicity

Incidence of grade IV neurotoxicity was reported in 4 studies involving 3 TCMIs and 355 patients. The results of the NMA showed no statistically significant differences in the comparison of the interventions (Figure4(d)).


## 3.5.6. Total Incidence of Grade I ∼ IV Neurotoxicity

Total incidence of grade I ∼ IV neurotoxicity was reported in 45 studies involving 13 TCMIs and 3598 patients. The results of the NMA showed that the differences were statistically significant for SIFZI versus LI (RR:0.67; 95%CI (0.46, 0.98)), SIFZI versus BJOEI (RR:0.59; 95%CI (0.42, 0.84)), SIFZI versus XAPI (RR:0.57; 95%CI (0.44, 0.75)), SIFZI versus EEI (RR:0.57; 95%CI (0.42, 0.78)), SIFZI versus SMI (RR:0.58; 95%CI (0.44, 0.77)), SIFZI versus chemotherapy (RR:0.47; 95%CI (0.31, 0.70)), SIFZI versus HCSI (RR:0.45; 95%CI (0.27, 0.75)), SIFZI versus KLEI (RR:0.39; 95%CI (0.17, 0.93)), SIFZI versus ADI (RR:0.44; 95%CI (0.32, 0.62)), and SFI versus ADI (RR:0.53; 95%CI (0.31, 0.93)), and the differences between the remaining interventions were not statistically significant (Figure4(e)).


## 3.6. Rank Probabilities

The SUCRA cumulative probability ranking showed that AI was most likely to be the best intervention to reduce the incidence of grade I neurotoxicity. Ranking results of incidence of grade I neurotoxicity were AI (SUCRA = 84.1%) > SIFZI (SUCRA = 78.4%) > SMI (SUCRA = 64.2%) > LI (SUCRA = 58.5%) > chemotherapy (SUCRA = 54.5%)>SFI (SUCRA = 52.5%)>EEI (SUCRA = 49.7%)>XAPI (SUCRA = 44.8)>BJOEI (SUCRA = 34.6%)>CKSI (SUCRA = 33.7%)>ADI (SUCRA = 26.4%)>KAI (SUCRA = 18.6%) (Figure5(a)). SIFZI was the most likely intervention to reduce the incidence of grade II neurotoxicity. Ranking results of incidence of grade II neurotoxicity were SIFZI (SUCRA = 81.2%) > CKSI (SUCRA = 68.5%) > SMI (SUCRA = 67.8%) > LI (SUCRA = 63.6%) > SFI (SUCRA = 60.8%) > XAPI (SUCRA = 58.8%) > KAI (SUCRA = 51.9%) > BJOEI (SUCRA = 45.1%) > EEI (SUCRA = 32.3%) > ADI (SUCRA = 29.8%) > AI (SUCRA = 22.8%) > chemotherapy (SUCRA = 17.4%) (Figure 5(b)). SMI was the most likely intervention to reduce the incidence of grade III neurotoxicity. Ranking results of incidence of grade III neurotoxicity were SMI (SUCRA = 85.6%) > SFI (SUCRA = 81.2%) > XAPI (SUCRA = 59.5%) > LI (SUCRA = 55.9%) > ADI (SUCRA = 39.5%) > AI (SUCRA = 38.3%) > SIFZI (SUCRA = 34.2%) > chemotherapy (SUCRA = 30.4%)>CKSI (SUCRA = 25.4%) (Figure 5(c)). SMI was the most likely intervention to reduce the incidence of grade IV neurotoxicity. Ranking results of incidence of grade IV neurotoxicity were SMI (SUCRA = 80.7%) > AI (SUCRA = 42.5%) > ADI (SUCRA = 39.2%) > chemotherapy (SUCRA = 37.6%) (Figure 5(d)). SIFZI was the most likely intervention to reduce the incidence of grade I ∼ IV neurotoxicity. Ranking results of incidence of grade I ∼ IV neurotoxicity were SIFZI (SUCRA = 94.5%) > SFI (SUCRA = 79.4%) > AI (SUCRA = 75.0%) > LI (SUCRA = 62.0%) > KAI (SUCRA = 59.0%) > CKSI (SUCRA = 53.1%) > BJOEI (SUCRA = 50.2%) > XAPI (SUCRA = 45.5%) > EEI (SUCRA = 45.0%) > SMI (SUCRA = 47.7%) > chemotherapy (SUCRA = 24.6%)>HCSI (SUCRA = 23.4%)>KLEI (SUCRA = 21.2%)>ADI (SUCRA = 19.2%) (Figure 5(e)).Figure 5
The surface under the cumulative ranking curve (SUCRA) plots for different outcomes. (a) Incidence of grade I neurotoxicity; (b) incidence of grade II neurotoxicity; (c) incidence of grade III neurotoxicity; (d) incidence of grade IV neurotoxicity; (e) total incidence of grade I ∼ IV neurotoxicity.
(a)(b)(c)(d)(e)


## 3.7. Small-Sample Effect Estimation

If no less than 10 studies were included, comparison-corrected funnel plots were drawn to identify the possibility of small-sample effects in the intervention network. The resulting funnel plot was slightly asymmetric, considering the possibility of a small-sample effect or publication bias between studies (Figure6).Figure 6
Publication bias. (a) Incidence of grade I neurotoxicity comparison-correction funnel chart; (b) incidence of grade II neurotoxicity comparison-correction funnel chart; (c) incidence of grade III neurotoxicity comparison-correction funnel chart; (d) total incidence of grade I ∼ IV neurotoxicity comparison-correction funnel chart.
(a)(b)(c)(d)


## 3.8. Sensitivity Analysis

We performed sensitivity analyses for outcome indicators that included at least 3 or more literature. Sensitivity analysis showed that SMI plus chemotherapy versus chemotherapy reversed the results of the meta-analysis in terms of incidence of grade I neurotoxicity and incidence of grade II neurotoxicity. The results of the meta-analysis were reversed for AI plus chemotherapy versus chemotherapy in terms of incidence of grade II neurotoxicity. KAI plus chemotherapy versus chemotherapy and XAPI plus chemotherapy versus chemotherapy were reversed for incidence of grade I ∼ IV neurotoxicity. The results of the meta-analysis were reversed for neurotoxicity. No reversal was found for the remaining outcome indicators. The results are presented in the Supplementary Material (FiguresS1–S17).


## 4. Discussion

OIPN is the primary dose-limiting toxicity of oxaliplatin and is characterized by specific somatosensory features, including cold and mechanical abnormal pain [63]. The pathogenesis of OIPN is still unclear, and there are several theories of its pathogenesis: ion channel theory, axonal neuropathy theory, central neuro-sensitive theory, neuronal cell death theory, etc. [64–67]. The main therapeutic drugs in Western medicine are sodium channel blockers, calcium-magnesium combination, reduced glutathione, gangliosides, and venlafaxine [68–73]. However, based on the current evidence, particularly the results of an NMA, there is insufficient certainty to support that any Western drug is effective in preventing OIPN [4]. TCMIs are the product of modernization of Chinese medicine, and compared with other herbal dosage forms, the injectable form has the characteristics of high bioavailability, precise efficacy, and rapid action, and is mostly used for preventive treatment in clinical practice. In this study, we performed NMA on 13 TCMIs and combined the results to determine which TCMIs are the best choice for clinical treatment and to provide reference for clinicians to prevent the occurrence of OIPN.The NMA evaluated the efficacy of 13 TCMIs for the prevention of OIPN in 3598 cancer patients. 13 TCMIs include XAPI, CKSI, ADI, BJOEI, SMI, KAI, AI, EEI, SFI, SIFZI, KLEI, HCSI, and LI. The NMA results showed that AI was better than ADI and SIFZI was better than ADI in preventing the incidence of grade I neurotoxicity, and the probability ranking showed that AI > SIFZI > SMI > LI > chemotherapy > SFI > EEI > XAPI > BJOEI > CKSI > ADI > KAI. SIFZI was superior to EEI and ADI, and BJOEI was superior to chemotherapy alone in preventing the incidence of grade II neurotoxicity. The probability ranking results showed that SIFZI > CKSI > SMI > LI > SFI > XAPI > KAI > BJOEI > EEI > ADI > AI > chemotherapy. SMI was superior to LI and CKSI in preventing the incidence of grade III neurotoxicity. Probability ranking results show that SMI > SFI > XAPI > LI > ADI > AI > SIFZI > chemotherapy > CKSI. There was no statistically significant difference between the interventions in preventing the incidence of grade IV neurotoxicity. The probability ranking results showed that SMI > AI > ADI > chemotherapy. SIFZI was superior to LI, BJOEI, XAPI, EEI, SMI, chemotherapy alone, HCSI, KLEI, and ADI in preventing grade I ∼ IV neurotoxicity; SFI was superior to ADI. The probability ranking results showed that SIFZI > SFI > AI > LI > KAI > CKSI > BJOEI > XAPI > EEI > SMI > chemotherapy > HCSI > KLEI > ADI. SIFZI, SMI, and AI had the largest SUCRA values and were most likely to be the best treatment options. Considering the moderate quality of the included studies and the limited number of included studies, the probability ranking results are for clinicians’ reference only.In vitro and in vivo studies suggest that extracts ofAstragalus may be a potential nerve growth-promoting factor that helps promote the growth of peripheral nerve axons [74]. Astragaloside IV, an active component of Astragalus, attenuates OIPN by modulating neuroinflammation and oxidative stress and downregulating the expression of TNF-α, IL-6, and IL-1β [75, 76]. A study by Luo et al. [16] showed that AI reduced the overall incidence of OIPN. In addition, the results of a meta-analysis showed that Astragalus-based herbal medicines helped to alleviate OIPN [77]. Therefore, Astragalus-based TCMIs (e.g., AI and SIFZI) may be a direction for future research. However, based on the probability ranking results, AI is the best intervention to reduce the incidence of grade I neurotoxicity and SIFZI is most likely to be the best intervention to reduce the total incidence of grade II and I ∼ IV neurotoxicity. This may be because codonopsis can regulate immunity, increase bone marrow hematopoiesis, inhibit platelet aggregation, improve microcirculation of surrounding tissues, and protect nerve function [44]. From the perspective of the theory of traditional Chinese medicine, if qi and blood are not running smoothly, the skin will be numb if it is not nourishing, and SIFZI has the effect of nourishing qi to support the righteousness. SMI is purified from ginseng and Ophiopogon japonicus. It contains ginsenosides, which can regulate the metabolism of neurons and promote the repair of damaged neurons [15, 78]. Ophiopogon japonicus is a natural antioxidant agent, which can directly reduce the production of oxygen-free radicals, reduce the lipid peroxidation of cells, and enhance the antioxidant function of the body [79]. The meta-analysis of direct comparisons in this study found that SMI reduced the total incidence of grade I ∼ IV neurotoxicity. Probability ranking results suggest that SMI is most likely to be the best intervention for reducing the incidence of grade III and IV neurotoxicity. SIFZI, SMI, and AI may be the most promising TCMIs in preventing the occurrence of OIPN.In this study, NMA was used for the first time to compare the clinical efficacy of different TCMIs in the prevention of OIPN, with a large number of included studies and a large sample size, showing high statistical efficacy. However, there were also certain limitations: (i) the included studies were all in Chinese, which may have language bias; (ii) the quality of the included studies was average, and most of them did not mention allocation concealment and blinding, which may affect the reliability of the results; (iii) there was some heterogeneity in some results, which may be related to the clinical characteristics of the included studies such as different tumor types and chemotherapy regimens. (iv) The included RCTs were compared on the basis of chemotherapy combined with TCMIs and chemotherapy alone, and there was a lack of direct comparison between TCMI. This may have weakened the strength of the evidence supporting the results. Therefore, future high-quality randomized controlled trials are needed to assess the clinical efficacy of TCMIs for the prevention of OIPN.In summary, the application of TCMIs on top of oxaliplatin-containing chemotherapy regimens can prevent the occurrence of OIPN to some extent. Among them, AI focused on reducing grade I neurotoxic reactions, SIFZI focused on reducing grade II and I ∼ IV neurotoxic reactions, and SMI focused on reducing grade III and IV neurotoxic reactions. However, based on the limitations of this study, the efficacy ranking does not fully indicate the clinical efficacy, and the results of this ranking should be viewed with caution.



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*Source: 6875253-2022-07-22.xml*