# Radix Astragali-Based Chinese Herbal Medicine for Oxaliplatin-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis

Authors: Bo Deng; Liqun Jia; Zhiqiang Cheng
Journal: Evidence-Based Complementary and Alternative Medicine
 (2016)

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## Abstract

Background. Treatment of chemotherapy-induced peripheral neuropathy (CIPN) remains a big challenge for oncologists. The aim of this study is to evaluate the effects of Radix Astragali- (RA-) based Chinese herbal medicine in the prevention and treatment of oxaliplatin-induced peripheral neuropathy, including the incidence and grading of neurotoxicity, effective percentage, and nerve conduction velocity.Methods. All randomized controlled trials (RCTs) were found using PubMed, Cochrane, Springer, China National Knowledge Infrastructure (CNKI), and Wanfang Database of China Science Periodical Database (CSPD) by keyword search. Meta-analysis was conducted using RevMan 5.0.Results. A total of 1552 participants were included in 24 trials. Meta-analysis showed the incidence of all-grade neurotoxicity was significantly lower in experimental groups and high-grade neurotoxicity was also significantly less. Effective percentage was significantly higher and sensory nerve conduction velocity was improved significantly, but changes in motor nerve conduction velocity were not statistically significant. No adverse events associated with RA-based intervention were reported.Conclusion. RA-based intervention may be beneficial in relieving oxaliplatin-induced peripheral neuropathy. However, more double-blind, multicenter, large-scale RCTs are needed to support this theory.Trial Registration. PROSPERO International prospective register of systematic reviews has registration number  CRD42015019903.


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## Body

## 1. Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) results from toxic effects of chemotherapy drugs predominantly affecting the peripheral nervous system. The associated pain of CIPN can be extremely disabling, with a marked impact on quality of life (Qol), functions of daily living, and increases the risks of noncompliance with cancer treatment [1]. Oxaliplatin (OXAL), a third-generation platinum-based compound, has become pivotal for the therapy of metastatic colorectal cancer and other malignancies including lung, breast, and ovarian cancers [2, 3]. However, OXAL induced chronic neurotoxicity occurs in 63.6% or more of patients, which limited the dosing of OXAL [4].Radix Astragali (the root ofAstragalus mongholicus Bge.orAstragalus membranaceus Bge.) has been used as one of the primary tonic herbs in traditional Chinese and Japanese Kampo medicine. Recently, Radix Astragali (Huangqi, in Chinese) is being widely used, orally or topically, and alone or in combination with western conventional medicine to relieve CIPN. Multiple randomized clinical trials have suggested that Radix Astragali- (RA-) based intervention can reduce symptoms, improve Qol and immunologic function, increase plasma nerve growth factor (NGF) levels, and delay the progression of CIPN [5–28].In vivo RA-based prescription (Huangqi Guizhi Wuwu Decoction) can effectively relieve pain and improve sciatic nerve conduction velocity and function in rats with CIPN [29, 30]. Its mechanism may be related to downregulating NR2B expression in L4–6 lumbar spinal segments and upregulating pNF-H protein levels in dorsal root ganglia [30]. However, no systematic review to date has reported effects of RA-based intervention on OXAL induced peripheral neuropathy. In this meta-analysis, the effectiveness and safety of RA-based intervention for preventing and treating OXAL induced peripheral neuropathy are evaluated for the first time.


## 2. Methods

Ethics data for this study were acquired through previously published work; no patient or hospital data were accessed. Therefore, written consent and institutional ethical review were not required for this research.


### 2.1. Database and Search Strategies

The electronic databases of MEDLINE (1982–2015), Cochrane Controlled Trials (2015, Issue 12), Springer (1997–2015), China National Knowledge Infrastructure (CNKI) database (1997–2015), and Wanfang Database of China Science Periodical Database (CSPD) (1998–2015) were searched by using keywords of “Neurotoxicity”, “Oxaliplatin” “Astragali”, or “Huangqi”, without language limitation. Reference lists from trials selected by electronic searching were hand searched. All of those searches ended before January 2016.


### 2.2. Inclusion Criteria

All randomized controlled trials (RCTs) investigating the effects of RA-based Chinese herbal medicine for preventing and treating OXAL induced peripheral neuropathy will be eligible for inclusion.


#### 2.2.1. Types of Participants

All adult patients (18 years and older, no upper age limit) with a treatment of OXAL will be considered for this review. The participants had to conform to the following diagnostic criteria.(1)
The patient was clearly diagnosed malignant by pathology or cytology.(2)
The patient was treated by OXAL, FOLFOX (OXAL + 5-fluorouracil + calcium folinate), or XELOX (OXAL + capecitabine).(3)
Age, gender, stages, and pathological types between the groups were balanced and comparable.


#### 2.2.2. Types of Interventions

RA-based interventions included single herb (including extracts from RA) and a compound of several herbs, irrespective of dosage form (e.g., oral decoction or lotion). The mode of delivery (e.g., oral, topical administration or intravenous) was not restricted. Relative high dose RA (monarch drug) should be included in the prescription and regimen of herbs was not restricted.The control interventions were placebo, no intervention, or conventional treatment such as mecobalamin, Ca/Mg infusions, or reduced glutathione. We also included trials of RA-based prescription plus conventional medicine versus the same conventional medicine alone.


### 2.3. Types of Outcome Measures

Grading of CIPN. Primary outcome was the grading of CIPN in at least 1 chemotherapy cycle, but preferably in 4 cycles of chemotherapy. We considered Levi’s grade [31], World Health Organization (WHO) grade [32] or National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) for the clinical grading of CIPN [33] (Table 1).Table 1
Grading scales used to evaluate oxaliplatin-induced peripheral neuropathy.
Grade 1 Grade 2 Grade 3 Grade 4 Levi et al. [31] Paresthesia or insensitive, complete relief in 1 week Paresthesia or insensitive, complete relief in 14 days Paresthesia or insensitive, complete relief in 21 days Paresthesia or insensitive,combined with functional abnormality  Miller et al. [32] Paresthesias and/or decreased tendon reflex Severe paresthesia and/or mild anergia Intolerable paresthesia and/or marked motor loss Paralysis  CTCAE 4.03 [33] Asymptomatic; loss of deep tendon reflexes or paresthesia Moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self-care ADL Life-threatening consequences; urgent intervention indicatedClinical Effectiveness. Clinical effectiveness was assessed according to what is previously described [32, 34].Complete Remission (CR). The patients felt completely free from all symptoms, with the grading of CIPN reduced to grade 0.Partial Remission (PR). Symptoms abated obviously, and the grading of CIPN reduced ≥1 grade.Nonperceptible (NP). Compared with before treatment symptoms have not abated, and the grading of CIPN did not reduce.(1)RemissionRate=CR+PR.Nerve Conduction Velocity. Changes in values of sensory nerve conduction velocity (SNCV) or motor sensory nerve conduction velocity (MNCV) were measured by validated methods after 1 week of RA treatment or more.Quality of Life (Qol) and Adverse Events. We extracted Qol, measured as Karnofsky (KPS) scale or Eastern Cooperative Oncology Group (ECOG) scale. Adverse events were also extracted.


### 2.4. Exclusion Criteria

We excluded studies with unclear diagnostic criteria and without the use of RA. Combinations of herbs and other forms of treatment (e.g., acupuncture or moxibustion) were excluded.


### 2.5. Data Extraction and Quality Assessment

Data were entered into an electronic database by two authors (Bo Deng and Liqun Jia) independently. Where differences in opinion existed, they were resolved by a third party. Improved Jadad scale was used to assess the quality of RCTs, including randomization, blinding of participants, personnel, and outcome assessors, incomplete outcome data, and other threats to validity [35]. High quality is 4–7 points. Low quality is 1–3 points.


### 2.6. Data Synthesis

Review Manager (RevMan) 5.0 software, provided by the Cochrane Collaboration (UK), was used to analyze the results of the trials. Dichotomous data were expressed as odds ratio (OR). Continuous data were expressed as mean difference (MD). Heterogeneity between results of different trials was tested, and heterogeneity was presented as significant whenI2 is over 50% or P<0.1. Random effect model was used for the meta-analysis if there was significant heterogeneity and fixed effect model was used when the heterogeneity was not significant [35]. Publication bias was explored via a funnel plot analysis.


## 2.1. Database and Search Strategies

The electronic databases of MEDLINE (1982–2015), Cochrane Controlled Trials (2015, Issue 12), Springer (1997–2015), China National Knowledge Infrastructure (CNKI) database (1997–2015), and Wanfang Database of China Science Periodical Database (CSPD) (1998–2015) were searched by using keywords of “Neurotoxicity”, “Oxaliplatin” “Astragali”, or “Huangqi”, without language limitation. Reference lists from trials selected by electronic searching were hand searched. All of those searches ended before January 2016.


## 2.2. Inclusion Criteria

All randomized controlled trials (RCTs) investigating the effects of RA-based Chinese herbal medicine for preventing and treating OXAL induced peripheral neuropathy will be eligible for inclusion.


### 2.2.1. Types of Participants

All adult patients (18 years and older, no upper age limit) with a treatment of OXAL will be considered for this review. The participants had to conform to the following diagnostic criteria.(1)
The patient was clearly diagnosed malignant by pathology or cytology.(2)
The patient was treated by OXAL, FOLFOX (OXAL + 5-fluorouracil + calcium folinate), or XELOX (OXAL + capecitabine).(3)
Age, gender, stages, and pathological types between the groups were balanced and comparable.


### 2.2.2. Types of Interventions

RA-based interventions included single herb (including extracts from RA) and a compound of several herbs, irrespective of dosage form (e.g., oral decoction or lotion). The mode of delivery (e.g., oral, topical administration or intravenous) was not restricted. Relative high dose RA (monarch drug) should be included in the prescription and regimen of herbs was not restricted.The control interventions were placebo, no intervention, or conventional treatment such as mecobalamin, Ca/Mg infusions, or reduced glutathione. We also included trials of RA-based prescription plus conventional medicine versus the same conventional medicine alone.


## 2.2.1. Types of Participants

All adult patients (18 years and older, no upper age limit) with a treatment of OXAL will be considered for this review. The participants had to conform to the following diagnostic criteria.(1)
The patient was clearly diagnosed malignant by pathology or cytology.(2)
The patient was treated by OXAL, FOLFOX (OXAL + 5-fluorouracil + calcium folinate), or XELOX (OXAL + capecitabine).(3)
Age, gender, stages, and pathological types between the groups were balanced and comparable.


## 2.2.2. Types of Interventions

RA-based interventions included single herb (including extracts from RA) and a compound of several herbs, irrespective of dosage form (e.g., oral decoction or lotion). The mode of delivery (e.g., oral, topical administration or intravenous) was not restricted. Relative high dose RA (monarch drug) should be included in the prescription and regimen of herbs was not restricted.The control interventions were placebo, no intervention, or conventional treatment such as mecobalamin, Ca/Mg infusions, or reduced glutathione. We also included trials of RA-based prescription plus conventional medicine versus the same conventional medicine alone.


## 2.3. Types of Outcome Measures

Grading of CIPN. Primary outcome was the grading of CIPN in at least 1 chemotherapy cycle, but preferably in 4 cycles of chemotherapy. We considered Levi’s grade [31], World Health Organization (WHO) grade [32] or National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) for the clinical grading of CIPN [33] (Table 1).Table 1
Grading scales used to evaluate oxaliplatin-induced peripheral neuropathy.
Grade 1 Grade 2 Grade 3 Grade 4 Levi et al. [31] Paresthesia or insensitive, complete relief in 1 week Paresthesia or insensitive, complete relief in 14 days Paresthesia or insensitive, complete relief in 21 days Paresthesia or insensitive,combined with functional abnormality  Miller et al. [32] Paresthesias and/or decreased tendon reflex Severe paresthesia and/or mild anergia Intolerable paresthesia and/or marked motor loss Paralysis  CTCAE 4.03 [33] Asymptomatic; loss of deep tendon reflexes or paresthesia Moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self-care ADL Life-threatening consequences; urgent intervention indicatedClinical Effectiveness. Clinical effectiveness was assessed according to what is previously described [32, 34].Complete Remission (CR). The patients felt completely free from all symptoms, with the grading of CIPN reduced to grade 0.Partial Remission (PR). Symptoms abated obviously, and the grading of CIPN reduced ≥1 grade.Nonperceptible (NP). Compared with before treatment symptoms have not abated, and the grading of CIPN did not reduce.(1)RemissionRate=CR+PR.Nerve Conduction Velocity. Changes in values of sensory nerve conduction velocity (SNCV) or motor sensory nerve conduction velocity (MNCV) were measured by validated methods after 1 week of RA treatment or more.Quality of Life (Qol) and Adverse Events. We extracted Qol, measured as Karnofsky (KPS) scale or Eastern Cooperative Oncology Group (ECOG) scale. Adverse events were also extracted.


## 2.4. Exclusion Criteria

We excluded studies with unclear diagnostic criteria and without the use of RA. Combinations of herbs and other forms of treatment (e.g., acupuncture or moxibustion) were excluded.


## 2.5. Data Extraction and Quality Assessment

Data were entered into an electronic database by two authors (Bo Deng and Liqun Jia) independently. Where differences in opinion existed, they were resolved by a third party. Improved Jadad scale was used to assess the quality of RCTs, including randomization, blinding of participants, personnel, and outcome assessors, incomplete outcome data, and other threats to validity [35]. High quality is 4–7 points. Low quality is 1–3 points.


## 2.6. Data Synthesis

Review Manager (RevMan) 5.0 software, provided by the Cochrane Collaboration (UK), was used to analyze the results of the trials. Dichotomous data were expressed as odds ratio (OR). Continuous data were expressed as mean difference (MD). Heterogeneity between results of different trials was tested, and heterogeneity was presented as significant whenI2 is over 50% or P<0.1. Random effect model was used for the meta-analysis if there was significant heterogeneity and fixed effect model was used when the heterogeneity was not significant [35]. Publication bias was explored via a funnel plot analysis.


## 3. Results

### 3.1. Description of Studies and Methodological Quality (Figure1 and Table 2)

Our primary searches identified 841 references from the above databases. After duplicates, animal studies, case reports, reviews, and obvious ineligibility were removed, we retrieved a total of 110 references for further assessment. After full-text reviews, 24 trials were included [5–28]. Included trials were published from 2009 to 2015, with the years 2011 to 2015 having a larger number of trials (20 trials, 85.70% patients) than other years. All trials were conducted in mainland China. Since all included trials were assessed to be of high quality (improved Jadad score of 4 or 5 points), the risk of bias in this systematic review was low. All 24 trials employed computer software or random number tables for randomization. Nine trials used conventional medicine as control, and only one trial performed double-blinding.Figure 1
Flow chart of included studies in this systematic review.Table 2
Characteristics of studies included in this systematic review.
Author Year Samplesize Mean age (year)(median/range) % men Chemotherapy Radix Astragali intervention Control Cui et al. [5] 2009 40 60 57.5 FOLFOX Single herb extract No intervention Feng [6] 2011 40 28 ～ 55 67.5 FOLFOX Compound prescription No intervention Huang et al. [7] 2013 61 62.3 62.3 FOLFOX Compound prescription No intervention Huang et al. [8] 2010 60 46 71.7 FOLFOX Compound prescription No intervention Jin et al. [9] 2015 77 47.2 48.1 FOLFOX Compound prescription No intervention Kong [10] 2012 40 40 ～ 60 52.5 OXAL Compound prescription No intervention Li et al. [11] 2013 60 50.1 31.7 FOLFOX Compound prescription GSH Liang et al. [12] 2012 84 32 ～ 73 70.2 FOLFOX Compound prescription No intervention Liang et al. [13] 2015 135 47.8 67.4 FOLFOX Compound prescription No intervention Lin and Luo [14] 2011 90 51 54.4 FOLFOX Compound prescription No intervention Liu   et al. [15] 2011 60 61.5 64.3 FOLFOX, OXAL Compound prescription Mecobalamin Liu [16] 2009 68 31 ～ 70 60.3 FOLFOX Compound prescription No intervention Lv [17] 2015 90 53.0 53.3 OXAL Compound prescription Mecobalamin Qin and Sun [18] 2015 42 55 61.9 FOLFOX Compound prescription Mecobalamin Qin et al. [19] 2012 68 57.2 47.1 OXAL, TAX Compound prescription Cobamamide Shen et al. [20] 2015 60 59.7 65.0 OXAL Compound prescription Mecobalamin Sun et al. [21] 2010 60 55.3 63.3 FOLFOX, XELOX, TAX + 5-Fu Compound prescription Mecobalamin Tan and Qi [22] 2015 63 31 ～ 70 60.3 OXAL Compound prescription Mecobalamin Wang [23] 2015 60 52.3 50.0 FOLFOX Compound prescription Ca/Mg infusions Wu et al. [24] 2015 89 49.2 70.8 Platinum, TAX, Compound prescription No intervention Wu et al. [25] 2012 60 23 ～ 71 65.8 FOLFOX Compound prescription No intervention Wu et al. [26] 2015 60 59.7 65.6 Platinum, TAX, VCR Compound prescription No intervention Xu et al. [27] 2011 40 ∗ 45.0 OXAL Compound prescription No intervention Zhang and Lu [28] 2013 70 31–77 65.7 FOLFOX Single herb extract +thioctic acid No intervention FOLFOX: oxaliplatin + 5-fluorouracil + calcium folinate. 5-Fu: 5-fluorouracil. GSH: glutathione. OXAL: oxaliplatin. TAX: taxol. VCR: vincristine. XELOX: oxaliplatin + capecitabine.


### 3.2. Participants

In total, 1552 participants with OXAL treatment were included in these 24 trials. The average size of the trials was 66 participants, ranging from 40 to 135 per trial. Eleven trials enrolled only inpatients (n=689 patients, 44.39%). The remaining 13 trials did not specify the setting (n=863 patients, 55.61%). All trials included both adult male and female patients, with 58.63% participants being male. Types of cancer in participants included colorectal cancer (n=1033 patients), gastric cancer (n=399 patients), and lung cancer/breast cancer/other cancers (n=52 patients). The cancers of 68 patients were not specified. Accumulated OXAL dose varied from 130 mg/m2 to 800 mg/m2, with 260–600 mg/m2 (11 trials) being the most common. Eighteen trials used Levi’s grading of CIPN, 3 used CTCAE criteria of CIPN, and 3 used WHO criteria of CIPN.


### 3.3. Intervention Comparisons (Tables3 and 4)

Sixteen trials (n=1060 patients) compared RA-based intervention with no intervention. Three trials (n=159 patients) tested RA-based prescriptions against mecobalamin. Another 5 trials (n=333 patients) tested RA-based prescriptions in combination treatment remedies compared to the same western medications for CIPN management. Three types of administration methods were employed in these 24 trials, including oral administration (10 trials), topical administration (12 trials), and intravenous drip (1 trial). One trial employed oral administration combined with topical administration. The most popular prescriptions were modified Huangqi Guizhi Wuwu Decoction (7 trials) and modified Buyang Huanwu Decoction (5 trials). Prescriptions composed by the investigators themselves were combined and modified from these 2 prescriptions (10 trials). More than 50% of RA-based prescriptions included Danggui, Guizhi, Baishao, Jixueteng, Chuanxiong, and Honghua. These herbs may augment the effects of RA intervention on CIPN. Doses of RA ranged from 15 g to 180 g but most fell in the range of 30 to 50 g (12 trials). The duration of treatment varied mostly from 2 weeks to 8 chemotherapy cycles. Regarding topical administration, the temperature of decoction ranged from 35°C to 42°C, but most were in the range of 38–42°C (6 trials).Table 3
Characteristics of Radix Astragali-based interventions.
Author Year Radix Astragali prescription Administration Course of treatment (d) Dose (g) Jadad score CIPN grade Curative effect NCV Cui et al. [5] 2009 Huangqi Injection i.v. 7 30 mL 4 +   5 Feng [6] 2011 Buyang Huanwu Decoction ad us. ext 5∗ 6 chemotherapeutic cycles 120 4 +   6 Huang et al. [7] 2013 Huangqi Guizhi Wuwu Decoction p.o. 5∗ 4 chemotherapeutic cycles 30 4 +   7 Huang et al. [8] 2010 Huangqi Guizhi Wuwu Decoction ad us. ext 5∗ 4 chemotherapeutic cycles 100 4 +  + 8 Jin et al. [9] 2015 Self-made prescription ad us. ext 10∗ 4 chemotherapeutic cycles 15 4 +   9 Kong [10] 2012 Self-made prescription ad us. ext 6∗ 3 chemotherapeutic cycles 30 4 +   10 Li et al. [11] 2013 Self-made prescription p.o. 5∗ 6 chemotherapeutic cycles 30 4 +   11 Liang et al. [12] 2012 Buyang Huanwu Decoction p.o. 28 40 4 +   12 Liang et al. [13] 2015 Buyang Huanwu Decoction p.o 28 30 4 +   13 Lin and Luo [14] 2011 Huangqi Guizhi Wuwu Decoction ad us. ext 84 ≥15 4 +   14 Liu et al. [15] 2011 Huangqi Guizhi Wuwu Decoction p.o. 42 30 4 +  + 15 Liu [16] 2009 Self-made prescription ad us. ext 14 ≥15 4 +   16 Lv [17] 2015 Self-made prescription ad us. ext 7 50 5  + + 17 Qin and Sun [18] 2015 Self-made prescription p.o.+ ad us. ext 14∗ 5 chemotherapeutic cycles 30 4 +   18 Qin et al. [19] 2012 Self-made prescription ad us. ext 14 20 4  +  19 Shen et al. [20] 2015 Huangqi Guizhi Wuwu Decoction ad us. ext 14 50 4  +  20 Sun et al. [21] 2010 Buyang Huanwu Decoction ad us. ext 14 180 4  + + 21 Tan and Qi [22] 2015 Self-made prescription p.o. 10∗ 2 chemotherapeutic cycles 45 4  +  22 Wang [23] 2015 Huangqi Guizhi Wuwu Decoction ad us. ext 3∗ 8 chemotherapeutic cycles 45 4 +   23 Wu et al. [24] 2015 Huangqi Guizhi Wuwu Decoction p.o. 5∗ 4 chemotherapeutic cycles 30 4 +   23 Wu et al. [25] 2012 Buyang Huanwu Decoction p.o. 112 60 4 +  + 25 Wu et al. [26] 2015 Self-made prescription p.o. 7∗ 2 chemotherapeutic cycles ≥15 4 +   26 Xu et al. [27] 2011 Self-made prescription ad us. ext 5∗ 2 chemotherapeutic cycles 30 4 +   27 Zhang and Lu [28] 2013 Huang qijing oral liquid p.o. 5∗ 8 chemotherapeutic cycles 20 4 +  + 28Table 4
Chinese herbs combination in Radix Astragali-based prescriptions.
Latin name English name Chinese name Counts Frequency (%) Angelica sinensis (Oliv.) Diels Radix Angelicae sinensis Danggui 19 86.36 Cinnamomum cassia Presl Ramulus Cinnamomi Guizhi 17 77.27 Paeonia lactiflora Pall. Radix Paeoniae Alba Baishao 16 72.73 Spatholobus suberectus Dunn Caulis spatholobi Jixueteng 13 59.09 Ligusticum chuanxiong Hort. Rhizoma Chuanxiong Chuanxiong 12 54.55 Carthamus tinctorius L. Flos Carthami Honghua 10 50.00 Prunus persica (L.) Batsch Semen persicae Taoren 9 40.91 Ziziphus jujuba Mill. Fructus Jujubae Dazao 8 36.36 Salvia miltiorrhiza Bge. Radix Salviae Miltiorrhizae Danshen 7 31.82 Zingiber officinale Rosc. Rhizoma Zingiberis (recens) Jiang 7 31.82 Pheretima aspergillum (E. Perrier) Pheretima Dilong 7 31.82


### 3.4. Effects of Interventions

#### 3.4.1. Incidence of All-Grade CIPN (Figure2)

Eighteen trials reported incidence of all-grade (grades 1–4) CIPN. Five trials included CIPN patients and reported curative effects of RA-based prescriptions. And 1 trial only reported incidence of high-grade CIPN. Fifteen trials compared RA-based intervention to no intervention. RA-based intervention significantly reduced CIPN occurrence (n=993 patients; OR, 0.19, 95% CI, 0.14 to 0.25, P<0.01). One trial compared RA-based prescription to mecobalamin. RA-based prescription significantly reduced CIPN occurrence (n=42 patients; OR, 0.17, 95% CI, 0.03 to 0.94, P<0.05). Two trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. RA-based prescriptions in combined remedies significantly reduced CIPN occurrence (n=120 patients; OR, 0.42, 95% CI, 0.18 to 0.97, P<0.05).Figure 2
Forest plot of comparison: incidence of all-grade oxaliplatin-induced peripheral neuropathy.


#### 3.4.2. Incidence of High-Grade CIPN (Figure3)

Nineteen trials reported incidence of high-grade (grades 3-4) CIPN. No patients develop high-grade CIPN in 1 trial. Therefore 18 trials were included in a forest plot. Fourteen trials compared RA-based intervention to no intervention, mostly by using Levi’s grading (11 trials). RA-based intervention significantly reduced high-grade CIPN (n=931 patients; OR, 0.17, 95% CI, 0.09 to 0.31, P<0.01). However, 2 trials compared modified RA-based prescriptions to mecobalamin, and 2 trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. In these trials, there was no statistical difference between groups.Figure 3
Forest plot of comparison: incidence of high-grade oxaliplatin-induced peripheral neuropathy.


#### 3.4.3. Curative Effect of RA-Based Prescriptions (Figure4)

Five trials included 341 patients that had already developed CIPN and reported curative effects of RA-based prescriptions. The total effective rate of RA-based prescriptions was 79.07%, compared with 54.44% in the control group. Three trials compared curative effects of RA-based prescriptions plus mecobalamin to mecobalamin alone, where RA-based prescriptions were significantly more effective in relieving CIPN (n=213 patients; OR, 4.84, 95% CI, 2.38 to 9.83, P<0.01). However, 1 trial compared RA-based prescription to mecobalamin, and 1 trial compared RA-based prescription to no treatment. In these trials, there was no statistical difference between groups.Figure 4
Forest plot of comparison: curative effects of Radix Astragali-based prescriptions on oxaliplatin-induced peripheral neuropathy.


#### 3.4.4. SNCV and MNCV (Figures5 and 6)

Six trials reported RA-based interventions significantly improved SNCV (MD 4.42 m/s, 95% CI 3.27 to 5.57,P<0.01). However, regarding MNCV, there was no statistical difference between groups.Figure 5
Forest plot of comparison: sensory nerve conduction velocity.Figure 6
Forest plot of comparison: motor nerve conduction velocity.


#### 3.4.5. Safety, Quality of Life, and Publication Bias

Among the 24 articles incorporated in the meta-analysis, no adverse events associated with RA-based interventions were reported. Nineteen trials reported Qol (KPS score > 60 or ECOG score ≤ 2) before RA intervention, and 2 trials reported Qol improvement. One trial reported the percentage of patients with Qol improvement while the other reported the increased level of KPS score. Therefore, the results of these 2 trials could not be combined in the meta-analysis. Exploration of the funnel plots (Figure7) for all-grade CIPN, high-grade CIPN, and curative effects between RA-based interventions and control suggested near symmetry. No significant publication bias was found.Figure 7
Funnel plot analysis of risk of bias. (a) Funnel plot analysis of incidence of all-grade chemotherapy-induced peripheral neuropathy (CIPN). (b) Funnel plot analysis of incidence high-grade CIPN (grades 3-4). (c) Funnel plot analysis of curative effects of Radix Astragali-based prescriptions on CIPN.
(a) (b) (c)


## 3.1. Description of Studies and Methodological Quality (Figure1 and Table 2)

Our primary searches identified 841 references from the above databases. After duplicates, animal studies, case reports, reviews, and obvious ineligibility were removed, we retrieved a total of 110 references for further assessment. After full-text reviews, 24 trials were included [5–28]. Included trials were published from 2009 to 2015, with the years 2011 to 2015 having a larger number of trials (20 trials, 85.70% patients) than other years. All trials were conducted in mainland China. Since all included trials were assessed to be of high quality (improved Jadad score of 4 or 5 points), the risk of bias in this systematic review was low. All 24 trials employed computer software or random number tables for randomization. Nine trials used conventional medicine as control, and only one trial performed double-blinding.Figure 1
Flow chart of included studies in this systematic review.Table 2
Characteristics of studies included in this systematic review.
Author Year Samplesize Mean age (year)(median/range) % men Chemotherapy Radix Astragali intervention Control Cui et al. [5] 2009 40 60 57.5 FOLFOX Single herb extract No intervention Feng [6] 2011 40 28 ～ 55 67.5 FOLFOX Compound prescription No intervention Huang et al. [7] 2013 61 62.3 62.3 FOLFOX Compound prescription No intervention Huang et al. [8] 2010 60 46 71.7 FOLFOX Compound prescription No intervention Jin et al. [9] 2015 77 47.2 48.1 FOLFOX Compound prescription No intervention Kong [10] 2012 40 40 ～ 60 52.5 OXAL Compound prescription No intervention Li et al. [11] 2013 60 50.1 31.7 FOLFOX Compound prescription GSH Liang et al. [12] 2012 84 32 ～ 73 70.2 FOLFOX Compound prescription No intervention Liang et al. [13] 2015 135 47.8 67.4 FOLFOX Compound prescription No intervention Lin and Luo [14] 2011 90 51 54.4 FOLFOX Compound prescription No intervention Liu   et al. [15] 2011 60 61.5 64.3 FOLFOX, OXAL Compound prescription Mecobalamin Liu [16] 2009 68 31 ～ 70 60.3 FOLFOX Compound prescription No intervention Lv [17] 2015 90 53.0 53.3 OXAL Compound prescription Mecobalamin Qin and Sun [18] 2015 42 55 61.9 FOLFOX Compound prescription Mecobalamin Qin et al. [19] 2012 68 57.2 47.1 OXAL, TAX Compound prescription Cobamamide Shen et al. [20] 2015 60 59.7 65.0 OXAL Compound prescription Mecobalamin Sun et al. [21] 2010 60 55.3 63.3 FOLFOX, XELOX, TAX + 5-Fu Compound prescription Mecobalamin Tan and Qi [22] 2015 63 31 ～ 70 60.3 OXAL Compound prescription Mecobalamin Wang [23] 2015 60 52.3 50.0 FOLFOX Compound prescription Ca/Mg infusions Wu et al. [24] 2015 89 49.2 70.8 Platinum, TAX, Compound prescription No intervention Wu et al. [25] 2012 60 23 ～ 71 65.8 FOLFOX Compound prescription No intervention Wu et al. [26] 2015 60 59.7 65.6 Platinum, TAX, VCR Compound prescription No intervention Xu et al. [27] 2011 40 ∗ 45.0 OXAL Compound prescription No intervention Zhang and Lu [28] 2013 70 31–77 65.7 FOLFOX Single herb extract +thioctic acid No intervention FOLFOX: oxaliplatin + 5-fluorouracil + calcium folinate. 5-Fu: 5-fluorouracil. GSH: glutathione. OXAL: oxaliplatin. TAX: taxol. VCR: vincristine. XELOX: oxaliplatin + capecitabine.


## 3.2. Participants

In total, 1552 participants with OXAL treatment were included in these 24 trials. The average size of the trials was 66 participants, ranging from 40 to 135 per trial. Eleven trials enrolled only inpatients (n=689 patients, 44.39%). The remaining 13 trials did not specify the setting (n=863 patients, 55.61%). All trials included both adult male and female patients, with 58.63% participants being male. Types of cancer in participants included colorectal cancer (n=1033 patients), gastric cancer (n=399 patients), and lung cancer/breast cancer/other cancers (n=52 patients). The cancers of 68 patients were not specified. Accumulated OXAL dose varied from 130 mg/m2 to 800 mg/m2, with 260–600 mg/m2 (11 trials) being the most common. Eighteen trials used Levi’s grading of CIPN, 3 used CTCAE criteria of CIPN, and 3 used WHO criteria of CIPN.


## 3.3. Intervention Comparisons (Tables3 and 4)

Sixteen trials (n=1060 patients) compared RA-based intervention with no intervention. Three trials (n=159 patients) tested RA-based prescriptions against mecobalamin. Another 5 trials (n=333 patients) tested RA-based prescriptions in combination treatment remedies compared to the same western medications for CIPN management. Three types of administration methods were employed in these 24 trials, including oral administration (10 trials), topical administration (12 trials), and intravenous drip (1 trial). One trial employed oral administration combined with topical administration. The most popular prescriptions were modified Huangqi Guizhi Wuwu Decoction (7 trials) and modified Buyang Huanwu Decoction (5 trials). Prescriptions composed by the investigators themselves were combined and modified from these 2 prescriptions (10 trials). More than 50% of RA-based prescriptions included Danggui, Guizhi, Baishao, Jixueteng, Chuanxiong, and Honghua. These herbs may augment the effects of RA intervention on CIPN. Doses of RA ranged from 15 g to 180 g but most fell in the range of 30 to 50 g (12 trials). The duration of treatment varied mostly from 2 weeks to 8 chemotherapy cycles. Regarding topical administration, the temperature of decoction ranged from 35°C to 42°C, but most were in the range of 38–42°C (6 trials).Table 3
Characteristics of Radix Astragali-based interventions.
Author Year Radix Astragali prescription Administration Course of treatment (d) Dose (g) Jadad score CIPN grade Curative effect NCV Cui et al. [5] 2009 Huangqi Injection i.v. 7 30 mL 4 +   5 Feng [6] 2011 Buyang Huanwu Decoction ad us. ext 5∗ 6 chemotherapeutic cycles 120 4 +   6 Huang et al. [7] 2013 Huangqi Guizhi Wuwu Decoction p.o. 5∗ 4 chemotherapeutic cycles 30 4 +   7 Huang et al. [8] 2010 Huangqi Guizhi Wuwu Decoction ad us. ext 5∗ 4 chemotherapeutic cycles 100 4 +  + 8 Jin et al. [9] 2015 Self-made prescription ad us. ext 10∗ 4 chemotherapeutic cycles 15 4 +   9 Kong [10] 2012 Self-made prescription ad us. ext 6∗ 3 chemotherapeutic cycles 30 4 +   10 Li et al. [11] 2013 Self-made prescription p.o. 5∗ 6 chemotherapeutic cycles 30 4 +   11 Liang et al. [12] 2012 Buyang Huanwu Decoction p.o. 28 40 4 +   12 Liang et al. [13] 2015 Buyang Huanwu Decoction p.o 28 30 4 +   13 Lin and Luo [14] 2011 Huangqi Guizhi Wuwu Decoction ad us. ext 84 ≥15 4 +   14 Liu et al. [15] 2011 Huangqi Guizhi Wuwu Decoction p.o. 42 30 4 +  + 15 Liu [16] 2009 Self-made prescription ad us. ext 14 ≥15 4 +   16 Lv [17] 2015 Self-made prescription ad us. ext 7 50 5  + + 17 Qin and Sun [18] 2015 Self-made prescription p.o.+ ad us. ext 14∗ 5 chemotherapeutic cycles 30 4 +   18 Qin et al. [19] 2012 Self-made prescription ad us. ext 14 20 4  +  19 Shen et al. [20] 2015 Huangqi Guizhi Wuwu Decoction ad us. ext 14 50 4  +  20 Sun et al. [21] 2010 Buyang Huanwu Decoction ad us. ext 14 180 4  + + 21 Tan and Qi [22] 2015 Self-made prescription p.o. 10∗ 2 chemotherapeutic cycles 45 4  +  22 Wang [23] 2015 Huangqi Guizhi Wuwu Decoction ad us. ext 3∗ 8 chemotherapeutic cycles 45 4 +   23 Wu et al. [24] 2015 Huangqi Guizhi Wuwu Decoction p.o. 5∗ 4 chemotherapeutic cycles 30 4 +   23 Wu et al. [25] 2012 Buyang Huanwu Decoction p.o. 112 60 4 +  + 25 Wu et al. [26] 2015 Self-made prescription p.o. 7∗ 2 chemotherapeutic cycles ≥15 4 +   26 Xu et al. [27] 2011 Self-made prescription ad us. ext 5∗ 2 chemotherapeutic cycles 30 4 +   27 Zhang and Lu [28] 2013 Huang qijing oral liquid p.o. 5∗ 8 chemotherapeutic cycles 20 4 +  + 28Table 4
Chinese herbs combination in Radix Astragali-based prescriptions.
Latin name English name Chinese name Counts Frequency (%) Angelica sinensis (Oliv.) Diels Radix Angelicae sinensis Danggui 19 86.36 Cinnamomum cassia Presl Ramulus Cinnamomi Guizhi 17 77.27 Paeonia lactiflora Pall. Radix Paeoniae Alba Baishao 16 72.73 Spatholobus suberectus Dunn Caulis spatholobi Jixueteng 13 59.09 Ligusticum chuanxiong Hort. Rhizoma Chuanxiong Chuanxiong 12 54.55 Carthamus tinctorius L. Flos Carthami Honghua 10 50.00 Prunus persica (L.) Batsch Semen persicae Taoren 9 40.91 Ziziphus jujuba Mill. Fructus Jujubae Dazao 8 36.36 Salvia miltiorrhiza Bge. Radix Salviae Miltiorrhizae Danshen 7 31.82 Zingiber officinale Rosc. Rhizoma Zingiberis (recens) Jiang 7 31.82 Pheretima aspergillum (E. Perrier) Pheretima Dilong 7 31.82


## 3.4. Effects of Interventions

### 3.4.1. Incidence of All-Grade CIPN (Figure2)

Eighteen trials reported incidence of all-grade (grades 1–4) CIPN. Five trials included CIPN patients and reported curative effects of RA-based prescriptions. And 1 trial only reported incidence of high-grade CIPN. Fifteen trials compared RA-based intervention to no intervention. RA-based intervention significantly reduced CIPN occurrence (n=993 patients; OR, 0.19, 95% CI, 0.14 to 0.25, P<0.01). One trial compared RA-based prescription to mecobalamin. RA-based prescription significantly reduced CIPN occurrence (n=42 patients; OR, 0.17, 95% CI, 0.03 to 0.94, P<0.05). Two trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. RA-based prescriptions in combined remedies significantly reduced CIPN occurrence (n=120 patients; OR, 0.42, 95% CI, 0.18 to 0.97, P<0.05).Figure 2
Forest plot of comparison: incidence of all-grade oxaliplatin-induced peripheral neuropathy.


### 3.4.2. Incidence of High-Grade CIPN (Figure3)

Nineteen trials reported incidence of high-grade (grades 3-4) CIPN. No patients develop high-grade CIPN in 1 trial. Therefore 18 trials were included in a forest plot. Fourteen trials compared RA-based intervention to no intervention, mostly by using Levi’s grading (11 trials). RA-based intervention significantly reduced high-grade CIPN (n=931 patients; OR, 0.17, 95% CI, 0.09 to 0.31, P<0.01). However, 2 trials compared modified RA-based prescriptions to mecobalamin, and 2 trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. In these trials, there was no statistical difference between groups.Figure 3
Forest plot of comparison: incidence of high-grade oxaliplatin-induced peripheral neuropathy.


### 3.4.3. Curative Effect of RA-Based Prescriptions (Figure4)

Five trials included 341 patients that had already developed CIPN and reported curative effects of RA-based prescriptions. The total effective rate of RA-based prescriptions was 79.07%, compared with 54.44% in the control group. Three trials compared curative effects of RA-based prescriptions plus mecobalamin to mecobalamin alone, where RA-based prescriptions were significantly more effective in relieving CIPN (n=213 patients; OR, 4.84, 95% CI, 2.38 to 9.83, P<0.01). However, 1 trial compared RA-based prescription to mecobalamin, and 1 trial compared RA-based prescription to no treatment. In these trials, there was no statistical difference between groups.Figure 4
Forest plot of comparison: curative effects of Radix Astragali-based prescriptions on oxaliplatin-induced peripheral neuropathy.


### 3.4.4. SNCV and MNCV (Figures5 and 6)

Six trials reported RA-based interventions significantly improved SNCV (MD 4.42 m/s, 95% CI 3.27 to 5.57,P<0.01). However, regarding MNCV, there was no statistical difference between groups.Figure 5
Forest plot of comparison: sensory nerve conduction velocity.Figure 6
Forest plot of comparison: motor nerve conduction velocity.


### 3.4.5. Safety, Quality of Life, and Publication Bias

Among the 24 articles incorporated in the meta-analysis, no adverse events associated with RA-based interventions were reported. Nineteen trials reported Qol (KPS score > 60 or ECOG score ≤ 2) before RA intervention, and 2 trials reported Qol improvement. One trial reported the percentage of patients with Qol improvement while the other reported the increased level of KPS score. Therefore, the results of these 2 trials could not be combined in the meta-analysis. Exploration of the funnel plots (Figure7) for all-grade CIPN, high-grade CIPN, and curative effects between RA-based interventions and control suggested near symmetry. No significant publication bias was found.Figure 7
Funnel plot analysis of risk of bias. (a) Funnel plot analysis of incidence of all-grade chemotherapy-induced peripheral neuropathy (CIPN). (b) Funnel plot analysis of incidence high-grade CIPN (grades 3-4). (c) Funnel plot analysis of curative effects of Radix Astragali-based prescriptions on CIPN.
(a) (b) (c)


## 3.4.1. Incidence of All-Grade CIPN (Figure2)

Eighteen trials reported incidence of all-grade (grades 1–4) CIPN. Five trials included CIPN patients and reported curative effects of RA-based prescriptions. And 1 trial only reported incidence of high-grade CIPN. Fifteen trials compared RA-based intervention to no intervention. RA-based intervention significantly reduced CIPN occurrence (n=993 patients; OR, 0.19, 95% CI, 0.14 to 0.25, P<0.01). One trial compared RA-based prescription to mecobalamin. RA-based prescription significantly reduced CIPN occurrence (n=42 patients; OR, 0.17, 95% CI, 0.03 to 0.94, P<0.05). Two trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. RA-based prescriptions in combined remedies significantly reduced CIPN occurrence (n=120 patients; OR, 0.42, 95% CI, 0.18 to 0.97, P<0.05).Figure 2
Forest plot of comparison: incidence of all-grade oxaliplatin-induced peripheral neuropathy.


## 3.4.2. Incidence of High-Grade CIPN (Figure3)

Nineteen trials reported incidence of high-grade (grades 3-4) CIPN. No patients develop high-grade CIPN in 1 trial. Therefore 18 trials were included in a forest plot. Fourteen trials compared RA-based intervention to no intervention, mostly by using Levi’s grading (11 trials). RA-based intervention significantly reduced high-grade CIPN (n=931 patients; OR, 0.17, 95% CI, 0.09 to 0.31, P<0.01). However, 2 trials compared modified RA-based prescriptions to mecobalamin, and 2 trials compared RA-based prescriptions plus reduced glutathione or Ca/Mg infusions with the same conventional medications. In these trials, there was no statistical difference between groups.Figure 3
Forest plot of comparison: incidence of high-grade oxaliplatin-induced peripheral neuropathy.


## 3.4.3. Curative Effect of RA-Based Prescriptions (Figure4)

Five trials included 341 patients that had already developed CIPN and reported curative effects of RA-based prescriptions. The total effective rate of RA-based prescriptions was 79.07%, compared with 54.44% in the control group. Three trials compared curative effects of RA-based prescriptions plus mecobalamin to mecobalamin alone, where RA-based prescriptions were significantly more effective in relieving CIPN (n=213 patients; OR, 4.84, 95% CI, 2.38 to 9.83, P<0.01). However, 1 trial compared RA-based prescription to mecobalamin, and 1 trial compared RA-based prescription to no treatment. In these trials, there was no statistical difference between groups.Figure 4
Forest plot of comparison: curative effects of Radix Astragali-based prescriptions on oxaliplatin-induced peripheral neuropathy.


## 3.4.4. SNCV and MNCV (Figures5 and 6)

Six trials reported RA-based interventions significantly improved SNCV (MD 4.42 m/s, 95% CI 3.27 to 5.57,P<0.01). However, regarding MNCV, there was no statistical difference between groups.Figure 5
Forest plot of comparison: sensory nerve conduction velocity.Figure 6
Forest plot of comparison: motor nerve conduction velocity.


## 3.4.5. Safety, Quality of Life, and Publication Bias

Among the 24 articles incorporated in the meta-analysis, no adverse events associated with RA-based interventions were reported. Nineteen trials reported Qol (KPS score > 60 or ECOG score ≤ 2) before RA intervention, and 2 trials reported Qol improvement. One trial reported the percentage of patients with Qol improvement while the other reported the increased level of KPS score. Therefore, the results of these 2 trials could not be combined in the meta-analysis. Exploration of the funnel plots (Figure7) for all-grade CIPN, high-grade CIPN, and curative effects between RA-based interventions and control suggested near symmetry. No significant publication bias was found.Figure 7
Funnel plot analysis of risk of bias. (a) Funnel plot analysis of incidence of all-grade chemotherapy-induced peripheral neuropathy (CIPN). (b) Funnel plot analysis of incidence high-grade CIPN (grades 3-4). (c) Funnel plot analysis of curative effects of Radix Astragali-based prescriptions on CIPN.
(a) (b) (c)


## 4. Discussion

CIPN is not recorded in classic TCM books, so it remains a big challenge for TCM oncologists. Based on syndrome differentiation and treatment, TCM oncologists believe that CIPN falls under the category of Bi syndrome in TCM. The pathogenesis of CIPN is believed to be asthenia of qi and blood, qi stagnation and blood stasis. These lead to tendon and vessel malnutrition and stasis in collaterals. The treatment includes benefiting qi and nourishing blood, regulating ying and wei, and promoting blood circulation to remove meridian obstruction.RA is one of the most commonly used herbs tonifying qi.In vitro andin vivo studies suggest RA extract can be a potential nerve growth-promoting factor, being salutary in encouraging the growth of axons in peripheral nerves [36]. Astragaloside IV, an active ingredient in RA, contributed to sciatic nerve regeneration and functional recovery in mice. The mechanism underlying this effect may be associated with the upregulation of growth-associated protein-43 expression [37]. RA extract promoted neural-directed differentiation of mesenchymal stem cells into nerve cellsin vitroand also had neuroprotective effects on the central nervous system [38, 39].This review identified a relatively large amount of evidence on the effectiveness of RA-based interventions, either tested alone or tested in combined remedies, for the prevention and treatment of OXAL induced peripheral neuropathy. Compared with no intervention or conventional western medicine, RA-based interventions have the potential of being more effective in relieving CIPN. RA-based interventions also lead to improvement of SNCV. No adverse event was reported and 2 trials reported Qol improvement after RA-based interventions. In China, there is a general perception that it could improve Qol for various conditions. However, clinical trials need to monitor and report Qol improvement.Most of RA-based prescriptions included Danggui, Guizhi, Baishao, Jixueteng, Chuanxiong, and Honghua. These herbs may improve the effects of RA intervention on CIPN. Individualized treatment in TCM requires the modification of herbs with various symptoms in different patients. So the herbs included in RA-based prescriptions were heterogeneous. There were variations in the formulation, dosage, administration, and duration of treatment in the included trials. Even for herbal intervention of the same name, there were still differences in the specific composition or dose of included Chinese herbal medicine. Information about quality control was lacking on the development of the herbal preparations or the manufacture of herbal products. Future trials should provide information about standardization, including composition, quality control, and detailed regimens. The majority of trials compared RA-based intervention with no intervention; others used western conventional medicine as controls. Only 1 trial used a formal placebo control, so the positive effect should be interpreted conservatively.This review has its limitations. We only included studies published in journals. Dissertations and conference papers were not included. Only high quality (improved Jadad score ≥ 4 points) trials were included. We excluded 38 trials with low quality or insufficient information for assessing risk of bias. Therefore, it may not be possible to achieve a complete summary of all existent evidence. Quantitative subgroup analysis exploring the effects of age, disease history, and duration could not be performed due to insufficient data. No multicenter, large-scale RCTs were identified. Most trials focused on short-term rather than long-term outcomes. Future trials should assure adequate concealment of allocation and blinding of outcome assessors.


## 5. Conclusions

From our study, we found that RA-based intervention may have clinical effectiveness for relieving OXAL induced peripheral neuropathy and lead to improvement of SNCV. However, the evidence is not sufficient. In the future, results from double-blind, multicenter, large-scale RCTs are needed to draw more definitive conclusions.



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*Source: 2421876-2016-10-04.xml*