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

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.


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 of Astragalus mongholicus Bge. or Astragalus 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 . 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 metaanalysis, the effectiveness and safety of RA-based intervention for preventing and treating OXAL induced peripheral neuropathy are evaluated for the first time.

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.

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.

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.
(3) Age, gender, stages, and pathological types between the groups were balanced and comparable.

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.

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).
Clinical Effectiveness. Clinical effectiveness was assessed according to what is previously described [32,34].

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.

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 when 2 is over 50% or < 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. (Figure 1 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 . 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.

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 ( = 689 patients, 44.39%). The remaining 13 trials did not specify the setting ( = 863 patients, 55.61%). All trials included both adult male and female patients, with 58.63% participants being male.
The cancers of 68 patients were not specified. Accumulated OXAL dose varied from 130 mg/m 2 to 800 mg/m 2 , with 260-600 mg/m 2 (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. (Tables 3 and 4). Sixteen trials ( = 1060 patients) compared RA-based intervention with no intervention. Three trials ( = 159 patients) tested RAbased prescriptions against mecobalamin. Another 5 trials ( = 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  Evidence-Based Complementary and Alternative Medicine  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). Figure 2). 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 RAbased intervention to no intervention. RA-based intervention significantly reduced CIPN occurrence ( = 993 patients; OR, 0.19, 95% CI, 0.14 to 0.25, < 0.01). One trial compared RA-based prescription to mecobalamin. RA-based prescription significantly reduced CIPN occurrence ( = 42 patients; OR, 0.17, 95% CI, 0.03 to 0.94, < 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 ( = 120 patients; OR, 0.42, 95% CI, 0.18 to 0.97, < 0.05). Grade CIPN (Figure 3). 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 ( = 931 patients; OR, 0.17, 95% CI, 0.09 to 0.31, < 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 4). 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 ( = 213 patients; OR, 4.84, 95% CI, 2.38 to 9.83, < 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. (Figures 5 and 6). Six trials reported RA-based interventions significantly improved SNCV (MD 4.42 m/s, 95% CI 3.27 to 5.57, < 0.01). However, regarding MNCV, there was no statistical difference between groups.

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 (Figure 7) 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.  Test for overall effect: Z = 2.03 (P = 0.04) Test for overall effect: Z = 11.55 (P < 0.00001)

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 and in 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].

RA in combined remedies
Li et al. 2013

Total events
Test for subgroup differences: not applicable   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 cells in vitro and 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 RAbased 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.

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.