Research ArticleClinical Studies
Open Access

Topical Prevention of Radiation Dermatitis in Breast Cancer Patients: A Network Meta-analysis of Randomized Controlled Trials

YUNG-SHUO KAO, YAO-CHENG WU, MIN-YOU WU, PEI-LIN WU, LI-YU LU and CHENG-HSIEN HUNG
In Vivo May 2023, 37 (3) 1346-1357; DOI: https://doi.org/10.21873/invivo.13216

Abstract

Background/Aim: Radiation dermatitis is a common complication of radiation therapy in breast cancer patients. Severe dermatitis may alter treatment schedules and clinical outcomes. The topical prevention strategy is the widely used option to prevent radiation dermatitis. However, the comparison between the current topical prevention strategies is insufficient. Therefore, this study aimed to investigate the topical prevention efficacy of radiation dermatitis in patients with breast cancer through a network meta-analysis. Patients and Methods: This study followed The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses guidelines. A random effects model was used to compare different treatments. The treatment modality ranking was evaluated using the P-score. I2 and Cochran’s Q test were used to evaluate the heterogeneity among studies. Results: Forty-five studies were analyzed in this systematic review. A total of 19 studies were finally included in this meta-analysis for grade 3 or higher radiation dermatitis, which included 18 treatment arms and 2,288 patients. The forest plot showed that none of the identified regimens were superior to standard care. Conclusion: A more effective regimen than standard care for the prevention of grade 3 or higher radiation dermatitis in breast cancer patients was not identified. Our network meta-analysis showed that current topical prevention strategies are similarly efficacious. However, since preventing severe radiation dermatitis is an important clinical challenge, further trials should be conducted to address this issue.

Key Words:

Breast cancer is the most common type of cancer worldwide. It is also the main cause of cancer-related deaths in women (1). Radiation therapy (RT) is a common treatment for breast cancer (2, 3), which has been shown to reduce the rate of local recurrence and improve the overall survival of breast cancer patients (4). Radiation dermatitis (RD) is a common complication of radiation therapy in breast cancer patients. Severe dermatitis may alter treatment schedules and clinical outcomes.

RD usually occurs about 2-3 weeks after the RT begins and affects about 95% of patients (5). The incidence of RD may be related to the dose and duration of radiation exposure (6). Possible risk factors are known to include body mass index (BMI), smoking habits, breast size, and diabetes mellitus (7). Improvements in RT technology have reduced the incidence of RD with time (8, 9). However, severe RD still affects the course and dose of treatment, and has a persistent negative impact on the quality of life of cancer patients (10).

RD is usually assessed using the Common Terminology Criteria for Adverse Events (CTCAE) (11) and Radiation Therapy Oncology Group (RTOG) scales (12), or considering the severity of erythema, desquamation, edema, and other skin features.

Wong et al. has published guidelines for skincare in patients undergoing RT (13). Prophylactic measures include general skincare measures and topical preventive strategies. However, there is still controversy regarding the appropriate topical medication to be used for the prevention of RD in breast cancer patients.

There have been several systematic reviews on this topic (14-16). A network meta- analysis of prevention strategies for patients with head and neck cancer has previously been conducted (17), but a comparison between different topical preventive strategies in breast cancer patients is still lacking. Radiation dermatitis for breast cancer is distinct from that for head and neck cancer due to differences in radiation dosage and treatment location. It is important to decide which prevention strategies are the most appropriate. To assess the most effective regimen to prevent RD in breast cancer patients, we conducted this network meta-analysis.

Patients and Methods

Study protocol. This study follows The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA) guidelines (18). We registered this meta-analysis at PROSPERO(CRD:CRD42022298643).

Literature search. PubMed, Cochrane, and Embase were queried by five authors (YCW, MYW, PLW, LYL, CHH), from inception to January 2022. The terms “Breast cancer” AND “Radiotherapy” AND “Radiodermatitis” AND “Prevention” were used as free-text and MeSH terms search. We also checked the references to identify possible relevant literature. When there were conflicts among the search results, the discrepancy was resolved through consensus.

Study selection.

Inclusion criteria: 1. Prospective studies exploring the topical prevention of RD, 2. Breast cancer patients, 3. Randomized control trials (RCT), 4. Considering adult populations, 5. Published in English.

Exclusion criteria: 1. Self-control studies, crossover trials, non-RCT, observational studies, case series, and case reports, 2. Conference posters, letters, and comments.

Data extraction. Five authors (YCW, MYW, PLW, LYL, CHH) independently collected and organized data from the included literature. The main outcome was grade 3 or higher RD, because a high grade may affect the course of treatment according to the RTOG and CTCAE classification. The grade of RD was considered the maximum after the patient received the first fraction of radiotherapy. We also extracted other information, including the name of the first author, nation where the trial was conducted, number of patients, treatment regimen, and other characteristics of the included studies.

Statistical analysis. The models used in this meta-analysis were generalized linear mixed models (GLMMs). The estimation of variance was carried out using the restricted maximum likelihood method. We excluded studies which we could not connect with the main network. When there was a closed loop in the network, we checked whether there was an inconsistency between the direct and indirect evidence. Ranking of the treatment modality was evaluated using the P-score, while the Cochran’s Q test and the I2 statistic were used to evaluate the heterogeneity among studies.

A p-value <0.05 was considered to denote statistical significance. All of the statistical analyses were carried out using the R language (version 3.6.1) and the RStudio software (Version 1.2.5019).

Quality assessment. We evaluate the quality of included RCTs using the risk of bias tools described in the Cochrane Handbook (19). Three authors (YCW, MYW, CHH) independently scored the studies, and the final decision was made by consensus. The risk of bias figure was generated using the Revman 5.4 software.

Publication bias. We evaluated the publication bias using a funnel plot and Egger’s test. A p-value <0.05 indicates publication bias in a meta-analysis.

Results

Search results. We initially collected 705 studies. After screening, a total of 45 studies were included in this systematic review, and a total of 19 articles were included in the final meta-analysis. The PRISMA flow diagram is shown in Figure 1. We included 2,228 patients in the NMA. The characteristics of included studies are listed in Table I.

Figure 1.
Figure 1.

Prisma 2020 flowchart.

View this table:
Table I.

Characteristics of included studies in the systematic review.

Statistical analysis. The main endpoint was grade 3 or higher RD. A total of 19 studies were investigated with respect to this endpoint, including 18 treatment arms and 2,288 patients. The network plot is shown in Figure 2 and the forest plot is shown in Figure 3. The P-scores of the included regimens are provided in Table II. From the forest plot, we did not find any included treatment to be more effective than standard care.

Figure 2.
Figure 2.

Grade 3 or higher radiation dermatitis network diagram.

Figure 3.
Figure 3.

Forest plot for network meta-analysis of grade 3 or higher radiation dermatitis.

View this table:
Table II.

P-scores for the included regimens.

Methodological quality. The study quality in the included RCTs is summarized in Figure 4 and Figure 5. In total, forty-five RCTs were evaluated. Out of these, sixteen RCTs were rated to be at high risk of bias. Twenty-nine RCTs were rated to be at unclear risk of bias, because one or more criteria were considered unclear. The overall quality of the RCTs was moderate.

Figure 4.
Figure 4.

Risk of bias presented as percentages.

Figure 5.
Figure 5.

Risk of bias items.

Publication bias. The publication bias was assessed using a funnel plot. The result is provided in Figure 6. The Egger’s test p-value was 0.4963, which indicated that there is no publication bias in this analysis.

Figure 6.
Figure 6.

Funnel plot.

Discussion

This NMA study evaluated the effectiveness of different topical strategies for the prevention of RD in breast cancer patients. After screening the available clinical trials, we analyzed data from 45 randomized trials and performed an NMA to compare the effects of different preventive measures. Although many treatments were included in our study, there was no statistical significance, when compared to standard care, for the prevention of grade 3 or higher RD. The results of the studies included in our NMA were not statistically significant, compared to standard care. The current topical prevention strategies are similar in efficacy.

The P-scores gave the following ranking: Nigella sativa L., Silver sulfadiazine, Recombinant human epidermal growth factor (EGF)-based cream, Silymarin, Mebo Ointment, Mometasone cream, Aloe vera gel, Biafine cream, Hydrocortisone cream, Lipiderm, HPR Plus, standard of care (SOC), Calendula, Curcumin, Betamethasone cream, Clobetasone.

RD is a common complication of RT. Over 85% of patients treated with RT experience more than moderate skin reactions (20). The toxicity of RT is complicated by many possible factors, such as the total radiation dose, radiation machine, volume of tissues or organs treated, and concurrent chemotherapy and comorbidities (7). Although the incidence of skin toxicity has decreased with the improvement of RT technology, severe RD still affects the quality of life of patients and the course of RT.

Topical corticosteroids have anti-inflammatory effects, and are commonly used clinically for the treatment or prevention of RD. A previous systematic review showed that topical corticosteroids improved wet desquamation and RD scores (16). In our NMA, topical steroids were not statistically significant for the prevention of moderate to severe RD in breast cancer patients, probably due to the insufficient sample sizes. The current evidence does not support the efficacy of other topical agents, such as Trolamine, Aloe vera, and silver sulfadiazine cream, for the prevention of moderate to severe RD (14, 21-24). More large-scale studies are needed, to investigate and determine possible prevention strategies.

Our study had several strengths. First, we focused specifically on RD in breast cancer, which allowed for more targeted and focused analysis. Second, we limited our investigation to RCTs, excluding patient self-control studies and crossover trials, which helped to ensure the validity of our results. Additionally, we conducted a comprehensive search and assessment process, which was carried out by independent authors to minimize potential bias.

This NMA has several limitations. First, although the quality of all RCTs was considered reasonable, the sample sizes in some of the studies were small. Second, there were inconsistencies in study design between these studies, such as patient concurrent chemotherapy or individual differences, which may further limit their comparability. Third, the p-score is used to estimate ranking probability of comparative effectiveness, however, the results should be interpreted with caution.

Conclusion

In our meta-analysis, we did not identify a more effective regimen than standard care for the prevention of grade 3 or higher RD. The current topical prevention strategies are similar in efficacy. Therefore, further trials should be initiated to address this important clinical problem. Our results could provide a reference to prevent RD in breast cancer patients.

Footnotes

  • Authors’ Contributions

    YSK and CHH conceived and designed the research; YCW, MYW, PLW, LYL, and CHH contributed to the data acquisition; YSK and CHH analyzed the data and interpreted the results; YSK and CHH drafted, edited, and revised the manuscript; All Authors reviewed the manuscript.

  • Conflicts of Interest

    The Authors declare no competing interests in relation to this study.

  • Received February 25, 2023.
  • Revision received March 9, 2023.
  • Accepted March 10, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Topical Prevention of Radiation Dermatitis in Breast Cancer Patients: A Network Meta-analysis of Randomized Controlled Trials
YUNG-SHUO KAO, YAO-CHENG WU, MIN-YOU WU, PEI-LIN WU, LI-YU LU, CHENG-HSIEN HUNG
In Vivo May 2023, 37 (3) 1346-1357; DOI: 10.21873/invivo.13216
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