Int J Clin Exp Med 2016;9(6):9642-9650www.ijcem.com /ISSN:1940-5901/IJCEM0023233

Review ArticleMeta-analysis of Aloe vera for the prevention and treatment of chemotherapy-induced phlebitis

Yulu Gao1*, Ting Jiang4*, Shencong Mei2*, Shaoli Zhang2, Changtai Zhu2, Yongning Sun3

1Department of Laboratory Medicine, Kunshan Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Kunshan, China; 2Department of Outpatient, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; 3Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; 4Department of Orthopedics, The Third Affiliated Hospital, Anhui Medi-cal University, Hefei, China. *Equal contributors.

Received January 4, 2016; Accepted April 1, 2016; Epub June 15, 2016; Published June 30, 2016

Abstract: As a common side effect among cancer patients, chemotherapy-induced phlebitis (CIP) not only causes new health hazards to the patients, but also affects the smooth implementation of chemotherapy. In recent years, Aloe vera has been frequently used for the prevention and treatment of CIP in clinical practice. In this study, our aim was to evaluate the clinical value of Aloe vera for the prevention and treatment of CIP. The databases: MEDLINE, EMBASE, the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journals Full-text Database (VIP), and the Wanfang database were searched. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), a systematic review and meta-anal-ysis was performed using Review Management 5.0 software. Ten clinical trials related to the prevention of CIP and six trials about the treatment of CIP, involving a total of 4530 patients, were included in this study. Meta-analysis showed that Aloe vera was effective for the prevention of chemotherapy-induced phlebitis. The pooled OR in the Aloe vera external application treatment group was 0.13 (95% CI: 0.08-0.20, P < 0.001). Further subgroup analysis showed that the OR values in the Aloe vera treatment group for 1st, 2nd, and 3rd degree phlebitis were 0.53 (95% CI: 0.21-1.33, P > 0.05), 0.10 (95% CI: 0.07-0.14, P < 0.001) and 0.10 (95% CI: 0.03-0.34, P < 0.001), respectively. Aloe vera significantly reduced the occurrence of second and third-degree phlebitis. Compared with the control group (50% magnesium sulfate), the total efficacy rate and the cure rate (RR) of Aloe vera group for CIP were 1.29 (95% CI: 1.19-1.39, P < 0.001) and 2.38 (95% CI: 1.27-4.47, P < 0.001), respectively. These results suggested that Aloe vera could be used for the treatment of CIP. In conclusion, Aloe vera has some potential clinical value in the prevention and treatment of CIP, but it still needs further study.

Keywords: Meta-analysis, Aloe vera, chemotherapy-induced phlebitis, tumor

Introduction

Intravenous chemotherapy is the most com-mon cancer treatment in clinical practice. However, most chemotherapy drugs can cause phlebitis during the drug infusion. Previous studies reported that the incidence of chemo-therapy-induced phlebitis (CIP) in cancer pa- tients ranged from 35% to 56% [1, 2]. CIP not only causes new health hazards for the pa- tients, but also increases the difficulty of veni-puncture for nurses, which affects the smooth implementation of chemotherapy. Therefore, clinicians should pay more attention to the issue.

In recent years, Aloe vera, a plant, has been fre-quently used for the prevention and treatment of CIP in clinical practice. Aloe vera is a stem-less or very short-stemmed succulent plant. The leaves are thick and fleshy, green to grey-green. In Chinese traditional medicine, Aloe vera has been used to treat infectious diseas-es. Nowadays, extracts from Aloe vera are widely used in the cosmetics and alternative medicine industries and marketed as having various rejuvenating, healing, or soothing prop-erties. Some clinical trials have suggested that Aloe vera might be beneficial for the prevention and treatment of CIP. In this study, we per-formed a meta-analysis, following the preferred

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reporting items for systematic reviews and meta-analyses (PRISMA) [3], to determine the clinical value of Aloe vera for the prevention and treatment of CIP.

Materials and methods

Objectives

The objectives of this meta-analysis were to: i) determine the overall effect of Aloe vera for the prevention of CIP compared with no interven-tion; and ii) determine the overall effect (the pooled cure rate and effective rate) for the treatment of CIP compared with 50% magne-sium sulfate treatment.

Literature retrieval

Searches of the English and Chinese language databases including MEDLINE, EMBASE, the Chinese Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), and the Wanfang database were conducted. Search terms included “che-motherapy”, “phlebitis”, “Aloe” and “Aloe vera”. The retrieval deadline was July 31, 2015. After study selection, assessment and data extrac-tion were performed by two reviewers indepen-dently, and any disputes were resolved by discussion.

Inclusion and exclusion criteria

Clinical trials about intravenous chemotherapy for tumor patients were included in this study;

emicals; and the study used clear criteria for phlebitis. In this systematic review, the grade of phlebitis ranged from 1 to 3 degrees [4].

Studies involving cases of other infusion phlebi-tis (non CIP), duplicated documents, studies with statistical errors, non-controlled studies, case reports, and case series were excluded from the study.

Quality assessment

The quality assessment was based on the Jadad scale [5]. Randomization, concealment of allocation, blinding of investigators and out-come assessors, and completeness of follow-up were used to determine the quality of the included studies.

Data synthesis and statistical analysis

The Review Manager 5.0 downloaded from the Cochrane Collaboration Web was used for the present meta-analysis. The pooled odds ratio (OR) and relative risk (RR) with the 95% confi-dence interval (95% CI), heterogeneity (I2), and p-values were calculated across all studies and for each comparison. Simultaneously, tests for heterogeneity were carried out. If significant heterogeneity occurred (P < 0.05), a random effects model was used to calculate a pooled effect size. If the heterogeneity across the stud-ies was not significant (P > 0.05), a fixed-effect model was selected. Publication bias was assessed by funnel plot analysis generated automatically by Review Manager 5.0 software.

Figure 1. The flow chart of literature retrieval in this study.

the intervention group co- mpared Aloe vera for the prevention of CIP to con-ventional management or to 50% magnesium sulfate (50% MgSO4) treatment. The outcomes included the incidence of phlebitis and treatment efficiency. The study used Aloe vera or its fresh ingredients such as leaves, juice, and gel; the Aloe vera had not been chemically treated; the method of use was external application (app- lied to the skin surface over the vein). There was no concomitant applica-tion of other drugs or ch-

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A sensitivity analysis was conducted after excluding non-randomized controlled studies.

Results

Overview of included studies

After a preliminary screen, we selected 218 documents. Some irrelevant studies were excluded after reading the title and summary and 61 studies were initially included in this

review. After reading the full text and excluding the studies that did not meet the study criteria, a total of 16 clinical studies [6-21] were includ-ed in the present study. The flow chart of study selection is shown in Figure 1. The publication time span of the literature included in this study was 14 years (2001 to 2015), involving a total of 4530 patients (for the preventive manage-ment of CIP, experimental group: 2493 cases, control group: 1490 cases; for the treatment of

Table 1. Characteristics of the controlled trials included in this study

Author [Reference] Publication year Design Intervention

objective Participants Age (years) Range, mean

Gender Male/female

Jadad score

CX Zhou [6] 2001 Unclear Prevention 30/36 E: 45-73, 61.7 E: 36/0 0C: 40-74, 60.2 C: 30/0

X Pan [7] 2008 RCT Prevention 66/66 26-88 72/60 1CL Xiao [8] 2008 QRCT Prevention 80/80 19-73, 41.3 Unclear 1YL Dong [9] 2008 Unclear Prevention 29/28 57.8 2/55 0HL Hu [10] 2009 QRCT Prevention 2000/1000 10-84, 55 2044/956 1ZY Yang [11] 2010 Unclear Prevention 96/90 E: 36-79, 62.8 E: 56/40 0

C: 44-80, 64.4 C: 36/54XJ Chen [12] 2010 RCT Prevention 40/38 E: 11-60, 40.87 E: 23/17 1

C: 10-65, 41.13 C: 20/18YF Wan [13] 2011 QRCT Prevention 53/53 42 E: 31/22 1

C: 35/18X Chen [14] 2012 RCT Prevention 50/50 34-56, 42.26 E: 50/0 1

C: 50/0L Lei [15] 2012 RCT Prevention 49/49 24-76 53/45 1W Dong [16] 2001 RCT Treatment 80/74 23-76, 49.8 91/63 1CJ Gao [17] 2006 RCT Treatment 50/50 13-69, 58 66/34 1YM Yang [18] 2008 RCT Treatment 52/48 18-69, 46 46/54 1JM Deng [19] 2010 QRCT Treatment 43/42 21-75, 42.9 46/39 1H Tang [20] 2011 RCT Treatment 36/30 E: 3-12, 6.03 E: 23/13 2

C: 3-12, 6.11 C: 18/12DY Zhang [21] 2015 Unclear Treatment 21/21 32-76, 54 24/18 0RCT: randomised controlled trials; QRCT: quasi-randomised controlled trials; E: experimental group; C: control group.

Figure 2. The overall incidence of natural Aloe vera for the prevention of chemotherapy-induced phlebitis.

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CIP, experimental group: 282 cases, control group: 265 cases). According to the Jadad scale, the quality scores of the studies ranged from 0 to 2, suggesting that the overall quality of the included studies was relatively low. The general characteristics of the included studies are presented in Table 1.

Evaluation of the efficacy of Aloe vera for the prevention of CIP

Compared with the conventional method, the overall incidence of CIP in the Aloe vera preven-tive treatment group was lower. The OR value was 0.13 (95% CI: 0.08-0.20, P < 0.001) (Figure

2). Further subgroup analysis showed that the OR values in 1st, 2nd, and 3rd degree CIP were 0.53 (95% CI: 0.21-1.33, P > 0.05), 0.10 (95% CI: 0.07-0.14, P < 0.001) and 0.10 (95% CI: 0.03-0.34, P < 0.001), respectively (Figure 3), indicating that Aloe vera for the prevention of 2nd and 3rd degree CIP was statistically sig- nificant.

Evaluation of the efficacy of Aloe vera for the treatment of CIP

Compared with 50% MgSO4 treatment (control group), the RR values for the total efficiency rate and the cure rate were 1.29 (95% CI: 1.19-

Figure 3. The pooled incidences of natural Aloe vera for the prevention of 1, 2 and 3 degree chemotherapy-induced phlebitis.

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1.39, P < 0.001), (Figure 4) and 2.38 (95% CI: 1.27-4.47, P = 0.007), (Figure 5), respectively.

Sensitivity analysis and publication bias

After excluding non-randomized studies, a sen-sitivity analysis was carried out. According to the meta-analysis results, the pooled OR of Aloe vera for the prevention of CIP was 0.13 (95% CI: 0.07-0.26, P < 0.001), (Figure 6), and the pooled RR values (the overall efficacy rate and cure rate) of Aloe vera for the treatment of CIP were 1.27 (95% CI: 1.17-1.38, P < 0.001), (Figure 7) and 2.71 (95% CI: 1.18-6.19, P = 0.02), (Figure 8), respectively. Therefore, thro- ughout the sensitivity analysis, the interpreta-

tions of the meta-analysis results were consis-tent. Hence, the stability of this study was acceptable. Based on the evaluation data of the efficacy of Aloe vera for the prevention of CIP, the funnel plot exhibited asymmetry (Figures 9, 10) suggesting this study may be affected by publication bias.

Adverse reactions

No studies reported any adverse reactions, but some studies suggested that allergies might occur among patients susceptible to allergies [7, 10-12], so an allergy test should be carried out before treatment in order to prevent allergic reactions.

Figure 4. The overall efficacy rate of natural Aloe vera for the treatment of chemotherapy-induced phlebitis.

Figure 5. The overall cure rate of natural Aloe vera for the treatment of chemotherapy-induced phlebitis.

Figure 6. The pooled incidences of natural Aloe vera for the treatment of chemotherapy-induced phlebitis excluding non-randomized studies.

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Discussion

Most chemotherapy drugs are alkaloid agents, which can cause non-specific damage to nor-mal cells and tissues while killing tumor cells. The extent of the damage is associated with the cytotoxicity, pH, osmotic pressure, and con-centration of the drug [22]. Commonly, cancer patients need to undergo multiple chemothera-pies via vein puncture over a short period of

prostacyclin, enhance anticoagulant activity and inhibit platelet aggregation, improve local circulation and protect the integrity of the blood vessels [25]. However, many studies have shown that using 50% MgSO4 treatment for CIP has some limitations [26-28]. In recent years, some new methods have been reported to be used for the management of CIP in clinical practice in China [26-31], especially Aloe vera for the prevention and treatment of CIP.

Figure 7. The pooled efficacy rate of natural Aloe vera for the treatment of chemotherapy-induced phlebitis excluding non-randomized studies.

Figure 8. The pooled cure rate of natural Aloe vera for the treatment of chemotherapy-induced phlebitis excluding non-randomized studies.

Figure 9. The funnel plots based on the data of natural Aloe vera for the preven-tion of the overall effectiveness.

time, which can easily ca- use injury to veins and in- crease the risk of CIP. In addition, both the tissue repair ability and immune function is significantly de- creased in cancer patients, and therefore the patients are prone to developing phlebitis [23, 24].

Conventional treatment for CIP is external applications of 50% MgSO4. The mecha-nism is thought to be as fol-lows: i) 50% MgSO4 has a hypertonic convergence ef- fect; ii) magnesium ions can protect endothelial ce- lls, increase the synthesis and release of endothelial

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Aloe vera is a succulent plant species. A fresh leaf of Aloe vera contains a lot of water, aloin, emodin glycosides, isocitrate, plant thrombin, active enzymes, and essential amino acids. These components have the following pharma-cological effects [32]: i) soften blood vessels and restore blood vessel elasticity; ii) improve lymphocyte activity and human immunity; iii) dilate blood vessels and promote blood circula-tion; iv) have antibacterial functions and help to repair damaged tissue; and v) promotes wound healing and cell regeneration. Therefore, theo-retically, fresh Aloe vera has a therapeutic effect on CIP.

Sixteen clinical trials involving a total of 4530 patients (for the preventive management of CIP, experimental group: 2493 cases, control group: 1490 cases; for the treatment of CIP, experimental group: 282 cases, the control group: 265 cases) were included in this present study. The total sample size is large for the pre-vention usage, but small for treatment usage. Meta-analysis showed that compared with the conventional method, the overall incidence of CIP in the Aloe vera preventive treatment group was low, with the OR value of 0.13 (95% CI: 0.08-0.20). Further subgroup analysis showed that Aloe vera for the prevention of 2nd and 3rd degree CIP was statistically significant, indicat-ing that Aloe vera can be used to prevent se-

sistent throughout the sensitivity analysis. Hence, the stability of this study is high.

No studies reported adverse reactions, but some studies suggested that [7, 10-12] aller-gies might occur among patients susceptible to allergies, so allergy tests should be carried out in order to prevent allergic reactions. Allergy test methods were reported in the literature as follows: take a small piece of Aloe vera leaf and spread it on the inside skin of the forearm or behind the ear. If the skin turns red, or other symptoms such as itching occur, the treatment should be skipped.

The funnel plot exhibited asymmetry, suggest-ing this study may be affected by publication bias. In addition, neither the concealment of allocation nor withdrawn nor patients lost fol-low-up were reported in the included trials. Meanwhile, due to objective conditions, the tri-als could not implement blinding. According to the Jadad scale, the scores of the studies ranged from 0 to 2, suggesting that the overall quality of the included studies was relatively low. All of these factors limit the validity of the evidence in this study.

In conclusion, we believed that Aloe vera has some potential value in the prevention and treatment of CIP, but it still needs further study.

Figure 10. The funnel plots based on the data of natural Aloe vera for the pre-vention of 1, 2 and 3 degree chemotherapy-induced phlebitis.

vere and moderate CIP. Compared with 50% Mg- SO4 treatment (control gr- oup), the RR values for the total efficiency rate and the cure rate were 1.29 (95% CI: 1.19-1.39) and 2.38 (95% CI: 1.27-4.47), respe- ctively. The large effect val-ues suggested that using Aloe vera for the treatment of CIP instead of 50% MgSO4 can achieve better efficacy and a higher cure rate.

To determine the stability of the meta-analysis, we performed a sensitivity an- alysis after excluding non-randomized studies. The interpretations of the meta-analysis results were con-

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In future, well-designed clinical controlled trials based on the Consolidated Standards Of Reporting Trials (CONSORT) [33, 34] should be conducted in order to scientifically validate the clinical value of Aloe vera for the prevention and treatment of CIP.

Acknowledgements

This work was partially supported by Research Grant from Shanghai Hospital Development Center (No. SHDC12015910).

Disclosure of conflict of interest

None.

Address correspondence to: Changtai Zhu, Depart- ment of Outpatient, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China. E-mail: zct101@ 163.com; Yongning Sun, Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China. E-mail: yns2002 @126.com

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