Protective Effects of Vitamin E on Chemotherapy-Induced Peripheral Neuropathy: A Meta-Analysis of Randomized Controlled Trials

doi:10.21203/rs.2.22123/v1

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Protective Effects of Vitamin E on Chemotherapy-Induced Peripheral Neuropathy: A Meta-Analysis of Randomized Controlled Trials

https://doi.org/10.21203/rs.2.22123/v1

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published 18 Jun, 2021

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Background

Chemotherapy often causes chemotherapy-induced peripheral neuropathy (CIPN), but effective prevention measures are still lacking. Whether vitamin E can prevent peripheral neurotoxicity caused by chemotherapy is inconclusive. Therefore, we collected related randomized controlled trials (RCTs) and conducted a meta-analysis to examine whether vitamin E could prevent CIPN.

Methods

We searched PubMed, EMBASE and the Cochrane databases in November 2019 for eligible trials. Two reviewers conducted the analysis independently when studies were homogeneous enough.

Results

Eight RCTs, involving 555 patients, were identified. Upon pooling these RCTs, patients who received vitamin E supplementation of 600 mg/day had a significantly lower incidence of peripheral neuropathy (RR 0.31; 95% CI 0.14 to 0.65; P = 0.002) induced by chemotherapy compared with the placebo group. Vitamin E played a key role in decreasing the incidence of peripheral neuropathy in the cisplatin chemotherapy group (RR 0.28; 95% CI 0.14 to 0.54; P = 0.0001). With regard to improvements in sural amplitude, vitamin E supplementation significantly decreased patients’ sural amplitude after three rounds of chemotherapy (RR -2.66; 95% CI -5.09 to -0.24; P =0.03) in contrast with that of placebo supplementation, while no significant difference was observed when patients were treated with vitamin E after six rounds of chemotherapy. In addition, the vitamin E group had better improvement in the neurotoxicity score (RR -2.65; 95% CI -4.01to -1.29; P = 0.0001) and a lower incidence of reflexes and distal paraesthesias (RR 0.50; 95% CI 0.29 to 0.87; P = 0.01) compared to the control group.

Conclusion

Available data included in this meta-analysis showed that vitamin E supplementation can confer modest improvement in the prevention of CIPN. However, large-scale, well-designed RCTs are needed to confirm the exact role of vitamin E supplementation in the prevention of CIPN.

Cancer Biology

Oncology

Vitamin E

Peripheral neuropathy

Chemotherapy

Meta-analysis

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of chemotherapeutic agents, limiting the using of many chemotherapy regimens. The prevalence of this disabling pain condition reaches up to 68% in the short term when receiving chemotherapy [1]. The severe pain of CIPN causes the loss of functional abilities and decreases patients’ quality of life. The additional financial burden and waste of medical resources caused by CIPN also cannot be ignored [2].

The neuropathogenesis of CIPN is still unclear. Multifactorial pathological processes may be involved, including oxidative stress, apoptosis, altered calcium homeostasis, immune response, glutamate signalling, ectopic activation of MAP-kinases and nociceptors, and neuroinflammation [3]. Accumulating research has indicated that the production of reactive oxygen species (ROS) is a significant cause of peripheral neuropathy induced by chemotherapy [4], and many researchers have claimed that an antioxidant substance could provide effective protection against peripheral neuropathy [5]. Currently, there are no approaches that have been effective in the prevention of CIPN [6]. Additionally, limited progress has been made in the discovery of agents that show an advantage in the prevention and treatment of CIPN.

Vitamin E is regarded as a treatment for neuropathy and is useful for the alleviation of chemotherapy-related toxicities [7]. It has been shown that the plasma vitamin E levels in cisplatin-treated patients who developed severe CIPN were significantly reduced [8], and vitamin E supplementation ameliorated neurotoxicity in animals receiving cisplatin by eliminating oxygen free radicals [7]. Pace suggested that vitamin E decreases the incidence and severity of cisplatin- and paclitaxel-induced peripheral neurotoxicity from 2003 to 2010 [9, 10]. In the same way, Argyriou attested that vitamin E protects chemotherapy-induced peripheral nerve damage in RCTs in 2006 [11]. In a recent study from 2017, Shamsaei found that vitamin E protects against paclitaxel-induced neuropathy and improves sensory nervous system function [12]. However, Kottschade, Afonseca and Salehi did not report favourable findings for vitamin E in clinical studies from 2011 to 2015 [13, 14, 15]. Thus, whether vitamin E can improve or prevent CIPN is still controversial.

Our study aimed to summarize the currently available evidence, and a meta-analysis was conducted to further study the effect of vitamin E on the prevention of CIPN with the hope of providing convincing medical evidence for clinicians to prevent CIPN.

Search methods for the identification of studies

Two independent reviewers completed a systematic search in PubMed, EMBASE, and the Cochrane databases from the inception dates to 24 November 2019. All disagreements were resolved by discussion between the reviewers. The search was restricted to English publications and human subjects with the following keywords: chemotherapy, neuropathy or peripheral neuropathy or peripheral nerve toxicity or neurotoxicity or CIPN, and vitamin E or tocopherol. There were no language limitations.

Selection and excluded criteria

The titles and abstracts identified from the above databases were browsed independently by two reviewers. A consensus was reached through consultation. If there was no agreement, a third reviewer was involved in the decision. Full texts of retrieved relevant essays were read to choose trials that satisfied inclusion criteria, which were RCTs of cancer patients treated with chemotherapy with vitamin E intervention. Conversely, trials that were not RCTs or/and trials of patients without chemotherapy and/or trials without vitamin E and placebo for comparison and/or diabetes patients were excluded.

Data extraction

The two reviewers collected and organized the following data from all included trials independently. Items included were first author name, publication year, country, number of total participants, cancer type, vitamin E prevention regimen, chemotherapy regimen, number of participants in each group, and outcomes. The characteristics of the included articles were summarized in a form.

Methodological quality and risk of bias

The influence of the methodological quality of RCTs was assessed by two researchers (M.H.K. and L.R.Z.) independently to avoid the risk of overestimation of intervention effects. The specific assessment methods were based on Cochrane risk-of-bias criteria: (1) generation of the allocation sequence; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; and (6) selective reporting. Each was graded as low-risk, high-risk, or unclear risk.

Data analysis

The main outcomes were the incidence of peripheral neuropathy induced by chemotherapy and other evaluation parameters, including sural amplitude, median amplitude, neurotoxicity score and the incidence of reflexes and distal paraesthesias. Review Manager (RevMan) version 5.3 was used for statistical processing. For dichotomous variables, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. For continuous variables, mean differences (MDs) with 95% CIs were calculated. If there were no significant heterogeneities in the data of the different trials, the fixed-effects model was applied. Otherwise, we used the random-effects model [16]. Subgroup analyses by the dose of vitamin E (either 600 mg/d or 400 mg/d) and the type of chemotherapy regimen (either cisplatin or oxaliplatin) were applied to assess the efficacy of vitamin E in the prevention of peripheral neuropathy induced by chemotherapy. In addition, subgroup analysis of the number of chemotherapy cycles (either three or six cycles) was applied to assess the parameters of sural amplitude. The I² was calculated, which can be interpreted as the percentage of the variation between studies that is attributed to heterogeneity rather than chance. I²= 0% means no heterogeneity, I² > 50% indicates a high heterogeneity, and I² = 100% means that all variation derives from study heterogeneity. Sensitivity analyses were performed to exclude specific studies and to evaluate if any study could significantly influence the overall results. Publication bias was evaluated via Funnel plots made by RevMan5.3. The statistical significance was determined as P < 0.05.

Search results

A total of 508 references were identified in the initial search from the PubMed, EMBASE and Cochrane databases. No references were gained from non-English databases, according to the inclusion criteria. After getting rid of the duplicate references, 452 references remained to be browsed. Due to improper study design or intervention or disease or outcome measure, there were 40 references left to be assessed for full-text review. The final eight references were considered for inclusion after excluding the other 32 references for other reasons. The entire search progress is described in Figure 1.

Study characteristics

Among the final eight references, four studies were conducted in Europe, two in Greece [11,17] and two in Italy [9,10], and for non-European studies, two studies were conducted in Iran [12,15], one in the USA [13], and one in Brazil [14]. The major characteristics of the included studies are summarized in Table 1. In all, 555 patients were included in the meta-analysis, and the number of participants in each arm ranged from 13 to 96. The experimental intervention was vitamin E supplementation as an adjuvant to cisplatin, paclitaxel and other chemotherapies. In four trials, 210 patients received vitamin E treatment at a dose of 400 mg/d [10,12,14,15], and in three trials, 251 patients received 600 mg/d vitamin E [11,13,17]. In only one trial, 27 patients received 300 mg/d vitamin E in the experimental group [9]. The durations of treatment with vitamin E varied from initiation of chemotherapy to 3 months after the cessation of chemotherapy.

Table 1

Main characteristics of all studies included in the meta-analysis.
First Author,Year	No.	Country	Type of cancer	Intervention group	No.	Contrast group	No.	Chemotherapy	Outcomes
Pace, 2003	27	Italy	Lung, Ovarian, Rhinopharinx, Uretheral, Gastric, Testicular, Esophageal, Ethmoidal, Tongue	Vitamin E 300 mg/d	13	Placebo	14	Cisplatin	IPN, NS, SA, SSCV, MA, RDP
Argyriou, 2006	30	Greece	Lung, Cervix, Testicular, Head and Neck, Gastric	Vitamin E 600 mg/d	14	Placebo	16	Cisplatin	IPN, SA
Argyriou, 2006	32	Greece	Lung, Breast, Ovarian	Vitamin E 600 mg/d	16	Placebo	16	Paclitaxel	IPN, SA
Pace, 2010	108	Italy	Lung, Glioblastoma, Endometrial, Bladder, Surrenal gland, Carcinosarcoma	Vitamin E 400 mg/d	17	Placebo	24	Cisplatin	IPN, NS, SA, MA, RDP
Kottschade, 2011	189	America	Breast, Lung, Other	Vitamin E 400 mg/d	96	Placebo	93	Paclitaxel, cisplatin, carboplatin, oxaliplatin	IPN
Samuel, 2013	34	Brazil	Colorectal, Gastric	Vitamin E 400 mg/d	18	Placebo	16	Oxaliplatin	IPN
Zeinab, 2015	65	Iran	Colorectal	Vitamin E 400 mg/d	32	Placebo	33	Oxaliplatin	IPN, NS
Gholamreza, 2017	70	Iran	Breast	Vitamin E 400 mg/d	35	Placebo	35	Paclitaxel	SA, SSCV
No. Number, IPN Incidence of Peripheral Neuropathy, NTS Neurotoxicity score, SA Sural amplitude, SSCV Sural sensory conduction velocity, MA Median amplitude, RDP Reflexes and distal paresthesia

Methodological Quality

Overall, five trials (62.5%) had adequate sequence generation, four trials (50%) had adequate concealed allocation, and the outcomes of four trials (50%) were judged to be adequately blinded. However, most of these studies (87.5%) did not have enough information about the risk of incomplete outcome data, and none of them mentioned selective reporting bias (Figure 2).

Primary outcomes

Incidence of peripheral neuropathy

The incidence of peripheral neuropathy was the primary outcome because the incidence directly reflected the occurrence of CIPN. Seven of the eight studies were available to investigate the incidence of peripheral neuropathy, and the total number of participants was 206 and 212 for the vitamin E group and placebo group, respectively. The pooled results found a significantly lower incidence of peripheral neuropathy with vitamin E compared to placebo with high heterogeneity, which was not ignored (RR 0.82; 95% CI 0.68 to 0.98; P=0.03; I²= 88%) (Figure 3A). Considering that different doses of vitamin E and various chemotherapy regimens were used in different studies, we conducted parallel subgroup analysis of the fixed-effects model. The subgroup analysis results of vitamin E 600 mg/d revealed no significant difference in the incidence of peripheral neuropathy in patients treated with vitamin E compared with placebo, with high heterogeneity (RR 0.81; 95% CI 0.57 to 1.15; P=0.24; I²= 79%). Due to apparent heterogeneity in the group receiving vitamin E 600 mg/d, we did a sensitivity analysis by excluding the study of Kottschade [13] due to its low methodological quality. Results of the sensitivity analysis found a significantly improved effect on preventing CIPN with supplementation with vitamin E 600 mg/d as compared to placebo (RR 0.31; 95% CI 0.14 to 0.65; P = 0.002; I²= 0%) (Figure 3B). However, the vitamin E 400 mg/d group displayed no difference in the reduction of the incidence of peripheral neuropathy compared with the placebo group (RR 0.93; 95% CI 0.79 to 1.10; P = 0.39; I²= 82%). Besides, due to the single study conducted by Pace [9], the effective of vitamin E 300 mg/d on the reduction of the incidence of peripheral neuropathy might have little clinical significance.

In the same way, subgroup analysis was conducted by grouping for the type of chemotherapy in the fixed-effects model (Figure 3C). The combination of vitamin E and cisplatin group[9,10,11] displayed a significantly lower incidence of peripheral neuropathy with no heterogeneity compared to the combination of placebo and cisplatin group (RR 0.28; 95% CI 0.14 to 0.54; P = 0.0001; I² = 0%). However, for the combination of vitamin E and oxaliplatin group, the result showed that there was no difference in the incidence of peripheral neuropathy compared with the placebo group (RR 1.08; 95% CI 0.95 to 1.22; P = 0.24; I²= 34%).

Sural amplitude

Sural amplitude is the action potential amplitude of the sural muscle, which is a reliable index for evaluating the condition of peripheral neuropathy. Five studies measured changes in sural amplitude before and after supplementation with vitamin E. We used the fixed-effects model to merge MD values, and the pooled MD was 0.58 (95% CI -0.24 to 1.40; P = 0.17) with high heterogeneity (I² = 72%) (Figure 4A), which indicated that vitamin E did not improve sural amplitude compared to placebo. Thus, a subgroup analysis was conducted by the number of chemotherapy cycles. Further analysis indicated that vitamin E significantly reduced the extent of sural amplitude in patients after three rounds of chemotherapy compared with the placebo group, but high heterogeneity still existed (MD = 1.06; 95% CI 1.04 to 1.98; P = 0.02; I²= 82%). Subsequently, we performed a sensitivity analysis by excluding a study conducted by Shamsaei et al. [12], as the study’s adopted population was Asian instead of European. The sensitivity analysis found a significantly improved effect on sural amplitude with vitamin E after three rounds of chemotherapy compared with placebo (MD = -2.66; 95% CI -5.09 to -0.24; P =0.03; I²= 0%). Nonetheless, vitamin E supplementation after six rounds of chemotherapy did not show significant improvement in sural amplitude compared with placebo (MD = -1.28; 95% CI -3.11 to -0.54; P = 0.17; I² = 40%) (Figure 4B).

Median amplitude

Similar to sural amplitude, median amplitude is another indicator that reflects the severity of peripheral neuropathy. The two studies [9,10] reporting median amplitude were available to measure the change in median amplitude before and after the application of vitamin E. Compared to the participants treated with placebo, vitamin E was more effective in the reduction of median amplitude with a pooled MD of -3.00 (95% CI -5.32 to -0.68; P = 0.01) with low heterogeneity (I²= 0%) (Figure 4C).

Secondary outcomes

The secondary outcomes in the meta-analysis were the neurotoxicity score, sural sensory conduction velocity, and the incidence of reflexes and distal paraesthesias.

A composite neurotoxicity score was calculated for each patient in three included studies, according to the severity of neuropathic symptoms and electrophysiologic changes [18]. Analysis showed that vitamin E significantly decreased the neurotoxicity score and displayed moderate heterogeneity (MD = -1.47; 95% CI -2.25 to -0.49; P = 0.003; I² = 67%). Then, we carried out a sensitivity analysis by excluding the study conducted by Salehi et al. [15], as it had a different chemotherapy regimen. The results found a significantly improved effect on the neurotoxicity score with vitamin E compared to placebo (MD = -2.65; 95% CI -4.01 to -1.29; P =0.0001; I²= 0%) (Figure 5A). The sural sensory conduction velocity is the action potential conduction velocity of the sural muscle in electromyography. The pooled results showed that there was no significant difference in the vitamin E group compared with the placebo group (MD = -0.39; 95% CI -1.82 to 1.03; P = 0.59; I²= 52%) (Figure 5B). Reflexes and distal paraesthesias reflected the physiological status of limb muscles. The pooled result by analysing the two studies included revealed that vitamin E showed a significant role in the lower incidence of reflexes and distal paraesthesias compared to placebo (MD = 0.50; 95% CI 0.29 to 0.87; P < 0.01; I²= 8%) (Figure 5C).

Publication bias

The funnel plots based on the incidence of peripheral neuropathy and sural amplitude change are shown in Figures 6A and 6B, respectively. However, the shapes of funnel plots were not symmetrical, indicating the existence of reporting bias.

Peripheral neuropathy is one of the most debilitating toxicities in cancer patients receiving chemotherapy [19]. However, there are no generally accepted preventative interventions for this complication. The initial symptoms of CIPN are paraesthesias (tingling) and dysesthesias in the toes and fingers, and it spreads proximally in a “glove-and-stocking” distribution, which is similar to the symptoms of vitamin E deficiency [20]. The incidence of CIPN varies with different antineoplastic agents, namely, 28%-100% of patients who receive cisplatin [21], 57%-83% of patients who receive paclitaxel [22], and 85%-95% of patients who receive oxaliplatin [1]. In addition to antineoplastic agents, the incidence was often related to the therapeutic dose [23]. Severe acute CIPN required chemotherapy dose reduction or cessation, leading to the progression of cancer and eventually a poor prognosis in patients [24]. Additionally, chronic CIPN often protracted the completion of chemotherapy, which severely impacted the quality of life and functional status of patients [24]. All of the adverse complications of peripheral neuropathy increase the social and economic burdens of public health [2].

Successful prevention of CIPN is facilitated by full courses and adequate doses of chemotherapy for cancer patients, which provides a favourable prognosis and high quality of life for cancer survivors. Many pharmacological agents, such as glutathione [25], calcium and magnesium infusions [26], and venlafaxine [27] have been studied for the treatment of CIPN. Albers published three articles (in 2007, 2011, and 2014, respectively) that analysed the potential effectiveness of interventions for preventing neuropathy caused by cisplatin [23, 28, 29]. Quantitative sensory testing was regarded as the first outcome in their study and they demonstrated a positive outcome in terms of neuroprotection with amifostine but did not find favourable findings with vitamin E using quantitative nerve conduction studies. However, the result of the animal study proved the positive effect of vitamin E, which urged more researchers to seek its validity in clinical trials [5, 30]. After investigating 48 related clinical trials on CIPN, the American Society of Clinical Oncology (ASCO) only made a moderate recommendation of duloxetine for the treatment of CIPN [6, 31], but there was no evidence for the recommendation for the prevention of CIPN [6, 32]. Measures for the treatment of CIPN are not necessarily helpful for the prevention of CIPN.

In the above studies, some antioxidants or cytoprotective agents were considered to be effective drugs for CIPN. Vitamin E, a lipid-soluble vitamin, is a common antioxidant known to protect cells and tissues from oxidative damage, which is associated with side effects induced by cytotoxic drugs [7]. The effect of vitamin E on the improvement of CIPN is still controversial. A previous review made by Bove found that the severity of peripheral neuropathy varies inversely with the level of vitamin E and tried to evaluate the efficacy of vitamin E for preventing chemotherapy-associated neurotoxicity [33]. The vitamin E deficiency caused by chemotherapy made the nervous system more vulnerable to damage [34]. However, another review, published in 2011, included only two RCTs that contained vitamin E supplementation and lacked sufficient data to prove the preventative effect of vitamin E against CIPN [23]. In another published meta-analysis, which included 5 available RCTs, the positive neuroprotective effects of vitamin E were confirmed [35], and the study showed that vitamin E supplementation could attenuate the development of CIPN. Paradoxically, Huang’s meta-analysis in 2014, which included 6 RCTs, found that vitamin E administration did not decrease the incidence of CIPN [36].

In our study, we collected all the newest published RCTs and tried to make a higher evidence-based quality analysis. Our primary outcomes included the incidence of peripheral neuropathy, which directly reflected the occurrence of CIPN in cancer patients after chemotherapy [37]. According to our analysis, vitamin E supplementation provided a significant reduction in the incidence of peripheral neuropathy in the cisplatin group, which was consistent with the meta-analysis by Eum that showed a significant preventive effect of vitamin E on CIPN with a probability of benefit greater than 95% [35]. The exact mechanisms of neuropathy associated with various chemotherapy drugs remains to be fully elucidated. Researchers tended to assume that cisplatin-induced neuropathy was dose-related, and the symptom manifested after an accumulative cisplatin dose [23]. Bove reported that the plasma concentrations of vitamin E fluctuated over the process of cisplatin treatment and returned to a favourable level after this chemotherapy cycle [33], which suggested that vitamin E exhaustion after cisplatin treatment had a potential association with the occurrence of peripheral neuropathy. Oxidative stress-induced antioxidant consumption, instead of diminished intake of vitamin E, was regarded as the major reason for the reduction in plasma vitamin E concentration [7]. In addition, studies revealed that the depletion of vitamin E rendered neural tissues more sensitive to free radicals [34], which further induced the occurrence of peripheral neuropathy. Combined with our results and the above evidence, we inferred that vitamin E supplementation could eliminate free radicals and protect tissues from damage from oxidative stress, further alleviating the peripheral neuropathy induced by cisplatin. However, our results showed that vitamin E did not play a role in reducing the incidence of peripheral neuropathy in the paclitaxel group. Although it was reported that paclitaxel has also been confirmed to cause dose-dependent distal axonal sensorimotor polyneuropathy, both of the RCTs [12, 17] in our meta-analysis revealed that no marked difference was found between the vitamin E and placebo groups after treatment with paclitaxel. More high-quality RCTs are needed to investigate the influence of vitamin E on the peripheral neuropathy induced by paclitaxel.

Furthermore, in our study, only 600 mg/d vitamin E for three months showed significant protective effects on the prevention of CIPN. It is worth noting that the dose and regimen of vitamin E were distinguished from existing studies. A study showed that an overdose of vitamin E could be harmful and increase the risk of overall mortality [38]. Another study also reported that long-term vitamin E supplementation may increase the risk of haemorrhagic stroke [39]. However, other studies have argued that vitamin E supplementation did not have an effect on all-cause mortality, regardless of the dosage [40]. Currently, the European Food Safety Authority has set the recommended dose for adults at 300 mg per day [41]. However, no adverse effects from vitamin E supplementation were reported by any of the reviewed studies. In our study, although there is lack of long-term observation of high-dose vitamin E, the use of vitamin E 600 mg/d for three months did not cause any adverse effects. Generally, the regimen of vitamin E 600 mg/d for three months might be preferred for the prevention of CIPN.

The evaluation methodology of CIPN not only involves symptoms of pain and paralysis but also changes in electromyography [42]. In the meta-analysis, other outcomes measured by electromyography were also analysed. We found that vitamin E provided improvement of sural amplitude for patients who finished three cycles of chemotherapy, while there was no significant effect on sural amplitude for patients who finished the six entire cycles of chemotherapy. The original target of medical treatment is to cure cancer or delay progression of the disease, but current attention is focused more on the long-term influence for patients. Our study showed that vitamin E supplementation was not enough to improve the sural amplitude of patients who finished the six entire cycles of chemotherapy. To thoroughly evaluate the effect of vitamin E on the improvement of CIPN, we also conducted a meta-analysis to assess other indicators reflecting the severity of peripheral neuropathy, including median amplitude, neurotoxicity score, sural sensory conduction velocity, reflexes and distal paraesthesias. Vitamin E played a key role in the improvement of median amplitude, neurotoxicity score, reflexes and distal paraesthesias, and all this evidence gave us more confidence on the recommendation of vitamin E in the prevention of CIPN.

However, there are some limitations in our analysis. First, only eight small sample RCTs were involved in the analysis. The methodological quality of the RCTs involved were not satisfactory, and only 2 RCTs were of high methodological quality. Second, varied cancer populations across studies influenced the consistency of the research. In addition, clinical outcomes, such as the disease response, adverse effects and conditions of prognosis, were not reported clearly, preventing further analyses due to insufficient data.

In this meta-analysis, the available data indicated that vitamin E supplementation conferred moderate prevention of CIPN, and large and well-designed RCTs are needed in the future to achieve a clear conclusion whether vitamin E is useful for the prevention of CIPN.

Vitamin E might prevent CIPN in patients undergoing neurotoxic chemotherapy. The use of vitamin E as the standard of care for prevention of CIPN is moderately recommended in our study. More high-quality trials with standardized reporting of clinical outcomes about peripheral neuropathy are needed to explore the exact role of vitamin E in the prevention of CIPN.

CIPN: Chemotherapy-induced peripheral neuropathy; RCT: Randomized controlled trials; RR: Risk ratios; CI: Confidence intervals; SD: Standard deviation; MD: Mean differences; ROS: Reactive oxygen species; ASCO: the American Society of Clinical Oncology

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All data and material are searched from public database, including PubMed, EMBASE and the Cochrane databases.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation (81871986).

Zhesheng Wen, who is the funder of National Natural Science Foundation (81871986), was involved in critically revising the manuscript and providing suggestions when submitting.

Authors’ contributions

MHK and LRZ conceived and designed the study. CDN and HJ performed the analysis, prepared the figures and tables and wrote the main manuscript. CYF and WZS were involved in critically revising the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank AJE Company (www.aje.com/services/) for polishing this manuscript.

Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155(12):2461-2470.
Pike, C.T., Birnbaum, H.G, Muehlenbein C.E, et al. Healthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer. Chemotherapy research and practice, 2012, 2012.
Starobova H. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. Frontiers in molecular neuroscience. 2017;10:174.
Ladas, E.J., Jacobson, J.S., Kennedy, D.D. et al. Antioxidants and cancer therapy: a systematic review. J. Clin. Oncol. 2004;22(3):517-528.
Appenroth, D., Frob, S., Kersten, L. et al. Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats. Arch. Toxicol. 1997;71(11):677-683.
Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:1941-1967.
Granados-Principal, S., Quiles, J.L., Ramirez-Tortosa, C.L. et al. New advances in molecular mechanisms and the prevention of adriamycin toxicity by antioxidant nutrients. Food Chem. Toxicol. 2010;48(6):1425-1438.
Kalkanis JG, Whitworth C. Vitamin E reduces cisplatin ototoxicity. Laryngoscope. 2004;114:538-542.
Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003;21:927-931.
Pace A, Giannarelli D, Galiè E, et al. Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology. 2010;74:762-766.
Argyriou AA, Chroni E, Koutras A, et al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results. Support Care Cancer. 2006;14:1134-1140.
Shamsaei G, Ahmadzadeh A, Mehraban N. The Vitamin E Preventive Effect on Taxol-Induced Neuropathy Among Patients With Breast Cancer: A Randomized Clinical Trial. Jundishapur J Nat Pharm Prod. 2017;12(4):e65027.
Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Care Cancer. 2011;19:1769-1777.
Afonseca SO, Cruz FM, Cubero Dde I, et al. Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: a pilot randomized clinical trial. Sao Paulo Med J. 2013;131:35-38.
Salehi Z. Effect of Vitamin E on Oxaliplatin-induced Peripheral Neuropathy Prevention: A Randomized Controlled Trial. Int J Prev Med. 2015;6:104.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88.
Argyriou, A.A., Chroni, E., Koutras, A. et al. Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation. J. Pain Symptom Manage. 2006;32 (3):237-244.
Chaudry V, Rowinsky EK, Sartorius et al. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: Clinical and electrophysiological studies. Ann Neurol. 1994;35:304-311.
Cioroiu C, Weimer LH. Update on chemotherapy-induced peripheral neuropathy. Curr Neurol Neurosci Rep. 2017;17:47.
Muller, D.P.R., Lloyd, J. and Wolff, O.H. Vitamin E and Neurological Function. Lancet. 1983;321 (8318), 225-8.
Kannarkat G, Lasher EE. Neurologic complications of chemotherapy agents. Curr Opin Neurol. 2007;20:719-725.
Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst. 2008;13(1):27-46.
Albers, J.W., Chaudhry, V., Cavaletti, G. et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst. 2011;Rev.(2) CD005228.
Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer. 2014;22(8):2261-2269.
Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20:3478-83.
Gamelin L, Boisdron-Celle M, Delva R, Guérin-Meyer V, Ifrah N, Morel A, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: A retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004;10:4055-61.
Durand JP, Alexandre J, Guillevin L, Goldwasser F. Clinical activity of venlafaxine and topiramate against oxaliplatin induced disabling permanent neuropathy. Anticancer Drugs. 2005;16:587-91.
Albers J, Chaudhry V, Cavaletti G. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2007;CD005228.
Albers JW, Chaudhry V, Cavaletti G. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;CD005228.
Leonetti C, Biroccio A, Gabellini C, et al. Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer. 2003;104:243-250.
Smith EM, Pang H, Cirrincione C, et al. Efect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-1367.
Ewertz M, Qvortrup C, Eckhof L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol. 2015;54:587-591.
Bove L, Picardo M, Maresca V, et al. A pilot study on the relation between cisplatin neuropathy and vitamin E. J Exp Clin Cancer Res. 2001;20:277-280.
Traber, M.G., Sokol, R.J., Ringel, S.P. et al. Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy. N. Engl. J. Med. 1987;317 (5):262-265.
Eum S, Choi HD, Chang MJ, et al. Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials. Int J Vitam Nutr Res. 2013;83:101-111.
Huang H, He M, Liu L, Huang L. Vitamin E does not decrease the incidence of chemotherapy-induced peripheral neuropathy: a meta-analysis. Contemp Oncol (Pozn). 2016;20(3):237-241.
Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011;12:1151-61.
Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142: 37-46.
Schürks, M., Glynn, R.J., Rist, P.M., Tzourio, C. and Kurth, T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010; 4,341:c5702.
Abner, E.L., Schmitt, F.A., Mendiondo, M.S., Marcum, J.L., Kryscio, R.J. Vitamin E and all cause mortality: a meta-analysis. Curr. Aging Sci. 2011;4 (2);158-170.
European Food Safety Authority. Tolerable upper intake levels for vitamins and minerals. 2006;European Food Safety Authority, Parma, Italy.
Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: a comprehensive survey. Cancer Treat Rev. 2014;40:872-82.

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Protective Effects of Vitamin E on Chemotherapy-Induced Peripheral Neuropathy: A Meta-Analysis of Randomized Controlled Trials

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