Efficacy of traditional chinese medicine in the treatment of rash caused by epidermal growth factor receptor inhibitors: A frequency statistics and meta-analysis

Shu-Yue Zheng; Hui-Juan Cui; Yan-Mei Peng; Qiang Li; Wen Shen; Jing-Yi Zhang; Chen-Yao Sun; Xu Zhang; Ke-Xin Tan; Xue-Jiao Jiang

doi:10.4103/wjtcm.wjtcm_32_19

ORIGINAL ARTICLE

Year : 2019 | Volume : 5 | Issue : 4 | Page : 269-275

Efficacy of traditional chinese medicine in the treatment of rash caused by epidermal growth factor receptor inhibitors: A frequency statistics and meta-analysis

Shu-Yue Zheng¹, Hui-Juan Cui², Yan-Mei Peng¹, Qiang Li¹, Wen Shen¹, Jing-Yi Zhang¹, Chen-Yao Sun¹, Xu Zhang¹, Ke-Xin Tan¹, Xue-Jiao Jiang¹
¹ Beijing University of Chinese Medicine, Beijing, China
² Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China

Date of Submission	16-Jul-2019
Date of Decision	28-Aug-2019
Date of Acceptance	28-Aug-2019
Date of Web Publication	03-Dec-2019

Correspondence Address:
Prof. Hui-Juan Cui
Department of Integrative Oncology, China-Japan Friendship Hospital, Yinghua Dongjie, Hepingli, Beijing 100029
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_32_19

Abstract

Objective: The aim of this study is to evaluate the efficacy of Traditional Chinese Medicine (TCM) in the treatment of rash caused by epidermal growth factor receptor inhibitors (EGFRIs). Materials and Methods: Foreign language database (such as PubMed, Web of Science, Cochrane Library, EMBASE) and Chinese language database (such as China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals [VIP], Wangfang, CBM disc) were searched for all trials of TCM in the treatment of rash caused by EGFRIs until January of 2019. We also looked through the references of relevant studies to supplement additional trials. The SPSS 25.0 was used for statistics of TCM with high frequency, and Review Manager 5.3 was used for meta-analysis. Results: A total of 22 studies were included in the study. We selected TCM whose frequency were >3.0%. They were Lonicera japonica(金银花), Licorice Roots Northwest Origin(生甘草), Cortex Dictamni(白鲜皮), Radix Sophorae Flavescentis(苦参), Schizonepeta(荆芥), Saposhnikovia Divaricate(防风). The meta-analysis revealed that the efficacy of TCM in treating EGFRIs-related rash was better than that of Western medicine or none. Conclusions: TCM could significantly relieve rash caused by EGFRIs, which is worth popularizing. Moreover, the mechanism deserves to be further explored.

Keywords: Epidermal growth factor receptor inhibitors, meta-analysis, rash, Traditional Chinese Medicine

How to cite this article:
Zheng SY, Cui HJ, Peng YM, Li Q, Shen W, Zhang JY, Sun CY, Zhang X, Tan KX, Jiang XJ. Efficacy of traditional chinese medicine in the treatment of rash caused by epidermal growth factor receptor inhibitors: A frequency statistics and meta-analysis. World J Tradit Chin Med 2019;5:269-75

How to cite this URL:
Zheng SY, Cui HJ, Peng YM, Li Q, Shen W, Zhang JY, Sun CY, Zhang X, Tan KX, Jiang XJ. Efficacy of traditional chinese medicine in the treatment of rash caused by epidermal growth factor receptor inhibitors: A frequency statistics and meta-analysis. World J Tradit Chin Med [serial online] 2019 [cited 2023 Dec 1];5:269-75. Available from: https://www.wjtcm.net/text.asp?2019/5/4/269/271967

Introduction

Molecularly targeted therapies prolonged the overall survival (OS) of advanced-stage cancer patients from 14.1 to 33.5 months.^[1] At present, epidermal growth factor receptor inhibitors (EGFRIs) are the most widely and further used in clinical application, the main side effect of which is skin toxicity. TRUST^[2] reported that the total rate of cutaneous adverse effects caused by EGFRIs was 70%, of which 44% for gefitinib of 250 mg each day, 61% for 500 mg each day. Moreover, the rate for erlotinib was 75%, of which the grade 3–4 skin toxicity was 4.8%.^[3] Besides, the rate for cetuximab was 90%, of which the grade 3–4 skin toxicity was 4.8%.^[4] However, the severe skin toxicity is more likely to reduce even terminate the application of targeted drugs in patients, which indirectly affects the final therapeutic effects for cancer patients. It has been proved by systematic review that skin rash could predict the response to EGFR tyrosine kinase inhibitors, and the patients with skin toxicity were more likely to have better OS than those without rash.^[5] It has become a significant problem of how to treat EGFRIs-related rash effectively. A combination of antibiotics and hormones is the standard therapy in Western medicine, but they do not work well.^[6] Recently, substantial success has been achieved in treating EGFRIs-related rash with Traditional Chinese Medicine (TCM). Hence, we conducted a frequency statistics and meta-analysis to assess the efficacy of treating EGFRIs-related rash with TCM.

Materials And Methods

Literature search

This systematic review and meta-analysis were reported in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement.^[7] Foreign language database (such as PubMed、 Web of Science、 Cochrane Library、 EMBASE) and Chinese language database (such as China National Knowledge Infrastructure、 VIP Database for Chinese Technical Periodicals (VIP)、 Wangfang、 CBM disc) were searched for all trials of TCM in the treatment of rash caused by EGFRIs until January of 2019. The search strategy included these terms in both Chinese and English: “gefitinib,” “erlotinib,” “icotinib,” “EFGRIs,” “skin toxicity,” “rash,” “TCM,” and variations on clinical trials. We also looked through the references of relevant studies to supplement additional trials.

Selection criteria

The inclusion criteria were listed as follows: (1) The research type should be randomized control studies. (2) The intervention of the experimental groups should include TCM. (3) Evaluation of skin toxicity grade should be National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) 3.0,^[4] NCI-CTCAE 4.0,^[8] or Multinational Association of Supportive Care in cancer skin toxicity study group.^[9] The excluded criteria used were as follows: (1) The research data were intact or incorrect; (2) The experimental group only include acupuncture or auricular needle; (3) The control group also include TCM.

Data extraction and quality evaluation

The data were extracted by three authors (Shu-Yue Zheng, Sun Chen-Yao and Qiang Li) independently. The following information were extracted from the trials: first author, year of publication, number of patients, and evaluation criterion of skin toxicity. The third author (Yan-Mei Peng) evaluated the data and disposed of the disagreement. The Modified Jadad scale was used to assess the quality of literature, which included: random sequence generation, allocation concealment, blinding methods, incomplete outcome data, and selective outcome reporting. Discrepancies were solved by Professor Cui. The score from 1 to 3 was considered as poor quality and that of 4–7 was regarded as high quality. Three authors (Shu-Yue Zheng, Yan-Mei Peng and Qiang Li) used the Cochrane Collaboration's risk of bias tool to assess the methodological quality of the included studies.

Statistical analysis

Review Manager 5.3 (Cochrane Informatics and Knowledge Management Department, Northern Europe) was used to conduct our systematical review and make forest plots. If the value of P < 0.05, the difference between two arms had a statistical significance. The heterogeneity would be low, moderated, and high, if the I²< 25%, 25%–50%, and over 50%, respectively. In this analysis, the null hypothesis that the studies were homogeneous would be rejected if P for heterogeneity was I² > 50%. When there was significant heterogeneity among the results of included study, the random effects model was used to calculate summary estimate. Otherwise, the summary estimate was calculated based on the fixed effects model, reported using the inverse variance method, assuming that the studies included in the meta-analysis had the same effect size. Publication bias was assessed using funnel plot.

Results

Search results and patients characteristics

Of the 964 Chinese and 13 English identified trials, 22 were included. The screening flow chart is shown in [Figure 1]. A total of 1452 patients were enrolled in these studies, of which experimental groups had 806 patients and 646 in control groups. The sample size was from 40 to 185. All the outcomes of the original studies revealed that the TCM was more effective than routine nursing or Western medicine. The characteristics of the trials are summarized in [Table 1].

Figure 1: Selection process for the studies

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Table 1: The characteristics of the included trials

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Quality of the included studies

The quality of the included studies was assessed by modified Jadad scale, the scores, of which 11 studies had q point, 3 studies had 3 points, 6 studies had 4 points, 1 study had 5 points, and 1 study had 7 points. It meant that there were 14 low-quality studies and 8 high-quality studies. All the literatures mentioned randomization, of which 6 studies^{[14],[15],[17],[18],[22],[27],[28],[31]} used random number table, one study mentioned allocation concealment,^[30] 3 studies^{[11],[27],[30]} used the blind methods, and 3 studies^{[21],[27],[30],[31]} reported the loss and reasons of follow-up. The assessment of risk of bias is shown in [Figure 2].

Figure 2: The assessment of risk of bias

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Analysis of Traditional Chinese Medicine frequency

There were 71 TCM in our study for treating EGFRIs-related rash and the total frequency was 170 times. TCM of which frequency was more than 2.0% is shown in [Table 2], totally 82 times. TCM whose frequency was more than 3.0% were Lonicera japonica(金银花), Licorice Roots Northwest Origin(生甘草), Cortex Dictamni(白鲜皮), Radix Sophorae Flavescentis(苦参), Schizonepeta(荆芥), Saposhnikovia Divaricate(防风).

Table 2: Traditional Chinese Medicine which frequency was more than 2.0%

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Meta-analysis

Twenty-two studies reported the total rate of rash remission. Due to I² = 55%, P = 0.0009, there was significant heterogeneity among the results of included studies, then the random-effects model was used to calculate summary estimate (odds ratio [OR], 10.76%; 95% confidence interval [CI], 6.60–17.56), Z = 9.52, P < 0.00001 (P < 0.01). We classified the studies into three subgroups, (OR, 17.65%; 95% CI, 6.47–48.18, Z = 5.60, P < 0.00001) for the “TCM orally” subgroup, (OR, 12.25%; 95% CI, 3.60–41.64, Z = 4.01, P < 0.0001) for the “TCM externally” subgroup, (OR, 6. 94%; 95% CI, 4.21–11.45, Z = 7.59, P < 0.00001) for the “TCM orally and externally” subgroup. The meta-analysis revealed [Figure 3] that the efficacy of TCM in treating EGFRIs-related rash was better than that of Western medicine or none.

Figure 3: Meta-analysis for total rate of rash remission

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Publication bias

The funnel plot for all the studies included is shown in [Figure 4], which revealed that the included studies may have publication bias.

Figure 4: Funnel plot for all the studies included.

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Discussion

Most of the clinical manifestations for EGFRIs-related rash are acne-like rash with acne or papule, even pustule. They often appear in exposed skin, such as the face and chest. Epidermal growth factor receptor (EGFR) plays an important role in the proliferation and differentiation of epithelial cells, while they are also overexpressed in tumor cells. When EGFRIs are used for anti-tumor therapy, normal functions of epithelial cells will be destroyed. Hence, the most common side effect of EGFRIs is skin toxicity. At present, the standard therapy of Western medicine for EGFRIs-related rash is to apply antibiotics and cortical hormones.^[31],[32] However, long-term application of antibiotics will result in the loss of appetite and aggravation of diarrhea (because EGFRIs also has the side effect of diarrhea). As we all know, cortical hormones have lots of side effects, especially immunosuppression. Hence, actually, those therapy methods are not suitable for the long-term application of cancer patients.

Recently, many TCM oncologists have explored how to use TCM to treat EGFRIs-related rash based on the theory of treatment based on syndrome differentiation and treating different diseases with the same method in the basic theories of TCM. Besides, they have conducted some randomized control trials to evaluate the efficacy and safety of TCM. Most of the research^{[13],[15],[19],[20],[24],[30]} deemed that EGFRIs-related rash could be considered as “drug rash” or “acne.” TCM oncologists tended to combined internal and external therapy. Some literature also reported the changes^[18],[26] of some cytokines (such as tumor necrosis factor-α, interleukin [IL]-1-β, IL-6, and so on) and the expression of EGFR in the skin.^[19] They proved the efficacy of TCM in treating EGFRIs-related skin toxicity in the levels of molecules and cells.

The frequency statistics and meta-analysis showed that TCM could relieve EGFRIs-related rash evidently and improved the life quality of patients. The high frequency (>3.0%) of TCM are Lonicera japonica(金银花), Licorice Roots Northwest Origin(生甘草), Cortex Dictamni(白鲜皮), Radix Sophorae FlaveTscentis(苦参), Schizonepeta(荆芥), Saposhnikovia Divaricate(防风). The meta-analysis for TCM revealed that the efficacy of TCM in treating EGFRIs-related rash was better than that of Western medicine or none.

However, as to the included trials, their research design and techniques need to be improved. First, some literature reported incompletely in the aspects of generation of random sequences, allocation concealment, blind methods, and so on. By reviewing the funnel plot, we could not exclude that some negative results were not published, which would lower the strength of evidence to a certain degree. Second, there were a few high-quality, large sample and multicenter randomized controlled trials in TCM treating EGFRIs-related skin toxicity. Moreover, most of them had not conducted a larger sample further research after the good curative effect of small sample trials. Third, the control groups of some trials did not use the standard therapy^[9] for EGFRIs-related rash in the international guidelines. Some trials even used the blank control. These designs of trials could not prove the advantages of TCM in treating EGFRIs-related skin toxicity well. Finally, many trials did not report their observation of side effects and long-term curative effects of TCM. Therefore, we suggest that high-quality, large sample and multicenter randomized control trials as to efficacious TCM compound should be further conducted. Application of allocation concealment and blind methods should be stricter. The standard therapy in Western medicine ought to be considered as control group. Effectively follow-up and the observation of side effects and long term curative effect should be strictly carried out. We hope to obtain more objective and precise evidence of TCM in treating EGFRIs-related skin toxicity.

Conclusions

The frequency statistics and meta-analysis proved that the efficacy of TCM in treating EGFRIs-related skin toxicity and they were worth further clinical popularizing. It is necessary to improve the preciseness and quality of the research of TCM in treating EGFRIs-related skin toxicity. Moreover, their mechanism needs to be further explored.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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