https://orcid.org/0009-0002-6587-6049
Figures
Abstract
Background
Radiation dermatitis (RD) is a prevalent and difficult-to-manage consequence of radiation therapy (RT). A variety of interventions have been proven effective in preventing and treating RD. However, the optimal approach remains unclear. This network meta-analysis (NMA) conducted a comparison and ranking of the effectiveness and patient-reported outcomes (PROs) of the interventions currently utilized in RD.
Methods
PubMed, Web of Science, Embase, and Cochrane Library were searched to identify pertinent randomized controlled trials (RCTs) focused on the prevention and treatment of RD. The primary outcome measures included the incidence of grade≥2 RD (i.e., percentage of moist desquamation) and RD score. The secondary outcome measures encompassed patients’ subjective assessment scores of pains, itching and burning sensations.
Results
Our meta-analysis encompassed 42 studies and 4884 participants. Regarding the primary outcomes, photobiomodulation treatment (PBMT) ranked first in surface under curve cumulative ranking area (SUCRA:0.92) for reducing the incidence of grade≥2 RD. It demonstrated a significant difference when compared to Trolamine (OR 0.18,95%CrI 0.09–0.33) and Xonrid® (OR 0.28,95%CrI 0.12–0.66). Mepitelfilm (SUCRA: 0.98) achieved the highest rank in reducing the RD score, demonstrating superiority over StrataXRT® (MD -0.89, 95% CrI -1.49, -0.29). Henna (SUCRA: 0.89) demonstrated the highest effectiveness in providing pain relief, with a significant difference compared to Hydrofilm (MD -0.44, 95% CrI -0.84, -0.04) and Mepitelfilm (MD -0.55, 95% CrI -0.91, -0.19). Hydrofilm (SUCRA: 0.84) exhibited the fewest itching sensations, demonstrating superiority over Mepitelfilm (MD -0.50, 95% CrI -0.84, -0.17). No statistically significant difference was observed among various interventions in the assessment of burning sensations.
Conclusion
PBMT and Mepitelfilm demonstrated better efficacy in reducing the incidence of grade≥2 RD and RD score, respectively. In terms of PROs, Henna and Hydrofilm had fewer complaints in pain and itching sensations, respectively. However, studies with larger sample size on different interventions are warranted in the future.
Citation: Guan Y, Liu S, Li A, Cheng W (2024) Comparison of the efficacy among different interventions for radiodermatitis: A Bayesian network meta‑analysis of randomized controlled trials. PLoS ONE 19(4): e0298209. https://doi.org/10.1371/journal.pone.0298209
Editor: Huijuan Cao, Beijing University of Chinese Medicine, CHINA
Received: August 15, 2023; Accepted: January 20, 2024; Published: April 10, 2024
Copyright: © 2024 Guan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This research was supported by the Youth Science Foundation of Guangxi Medical University (No. GXMUYSF201516). The funders of this work had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Radiation therapy (RT) is the third most frequently used cancer treatment modality. Among the side effects of RT, radiation dermatitis (RD) is a common occurrence, affecting up to 95% of patients either during or after undergoing RT [1–3]. It is characterized by varying degrees of skin inflammation and damage, ranging from mild erythema to severe ulceration and necrosis. Patients undergoing RT commonly experience grade 2 or higher RD, which manifests as notable erythema, moist desquamation, edema, and is associated with significant discomfort, pain, itching, burning, and morbidity [4]. Additionally, RD can hinder the effectiveness of RT by imposing limitations on the prescribed dose and duration of treatment. Therefore, the prevention and management of RD represent essential and significant clinical challenges in the field of radiation oncology [1, 4].
The underlying mechanisms of RD are well comprehended. Ionizing radiation induces damage to the dermis, resulting in vasodilation and the release of histamine-like substances and activating inflammatory pathways and causing cytokines overproduction; which contribute to the onset of erythema [5]. The DNA damage caused by radiation leads to a depletion of dividing basal stem cells in the epidermis. Consequently, the skin experiences thinning as the superficial layers, which are normally shed, are inadequately replaced by the deeper basal cell layer [6]. This process ultimately leads to both dry and moist desquamation. The emergence of late skin effects can be attributed to imbalances between profibrotic and proinflammatory cytokines [7].
The development of RD is influenced by various risk factors, including patient characteristics and radiation treatment-related factors. Treatment-related factors encompass parameters such as total dose, fractionation schedule, use of bolus or boost, treatment surface area or volume, radiation technique, and concurrent chemotherapy or targeted agents. Intrinsic factors like chronic sun exposure, breast size, smoking status, diabetes, and obesity may also impact the severity of RD [4, 8–11].
Multiple interventions have been proposed and demonstrated to be effective in the prevention and management of RD across various categories. These interventions include topical corticosteroids (e.g., hydrocortisone) [6], barrier films and dressings (e.g., water-based, silicone-based, and silver-based) [7,12], oral supplements (e.g., glutamine) [13], photobiomodulation treatment (PBMT) in the form of laser therapies, light emitting diode photomodulation, and red light phototherapy [14–16], standard care measures (e.g., hygiene practices, moisturizers, and topical sprays) [17], natural agents like Chamomile, Calendula, Curcumin, and Henna [18–23], as well as miscellaneous agents such as trolamine and hyaluronic acid [24–26]. All these interventions share similar clinical actions aimed at promoting the wound healing process by restoring the physiological hydration levels of the affected skin areas and enhancing their biological activity. They possess antioxidant, anti-inflammatory, and antimicrobial properties without exerting any tumor protection effects.
However, the efficacy of these interventions for RD and their impact on patient-reported outcomes (PROs) are still subjects of debate. There is currently a lack of consensus regarding the optimal approach to RD management. Previous traditional meta-analyses have focused on evaluating the clinical effectiveness of interventions in comparison to standard care. However, these approaches have limitations as they provide only partial insights into the overall hierarchy of interventions. This is due to the fact that intervention effects are estimated and presented for only a subset of relevant intervention comparisons. Furthermore, they have reported conflicting results and limitations, such as heterogeneity, bias, and small sample sizes [7, 27–30]. Last but not least, most studies have focused on the individual categories of interventions rather than comparing them directly, which makes it difficult to determine the relative efficacy of different interventions for clinician decision-makers.
To tackle these challenges, a network meta-analysis (NMA) offers a solution by enabling a thorough and quantitative comparison of the efficacy of various interventions for RD [31–33]. As of now, no NMA has been conducted to assess the effectiveness of various interventions in the prevention and treatment of RD. Hence, the objective of this study was to employ a Bayesian framework to compare the clinical effectiveness of various interventions in the prevention and treatment of RD. The study aimed to estimate the relative efficacy of these interventions and rank them based on their probabilities of being the best, second-best, and so on [34]. The findings of this study hold significant implications for clinical practitioners in terms of the prevention and management of RD. By identifying superior interventions for RD, the study has the potential to enhance the quality of life (QOL) and treatment outcomes of patients undergoing RT. Moreover, the study may contribute to the development of evidence-based guidelines and recommendations for the prevention and management of RT.
Methods
Selection criteria and study design
The inclusion criteria for this study were as follows: (1) the investigation of an intervention with at least two RCTs evaluating its efficacy in the prevention and treatment of RD, and (2) the assessment of the intervention compared to a standard of care (SOC). The SOC, serving as the reference group in this context, encompasses several aspects of the following treatments: (a) Shame treatment, placebo, routine nursing methods, usual care, standard skin care, usual supportive care, normal care, or no treatment. (b) Institutional nursing staff utilized the currently recommended standard skin care treatment and standard products as per hospital protocols or institutional standards for the trials. These products include hydrocortisone, urea cream, HPRPlusTM, Biafine® cream, white Vaseline (PROPETO), Sorbolene® cream, as well as moisturizer/moisturizing base cream, aqueous creams, and other conventional products.
We excluded studies that met any of the following criteria: (1) Study design type is non-randomized controlled trial (non-RCT), including conference papers, summaries, abstracts, letters, protocols, editorials, guidelines, review articles, comments, clinical observations, case studies, cohort studies, non-randomized trials, case-control studies, non-comparative studies, and any non-experimental investigations such as cross-sectional and retrospective surveys; (2) studies investigating an intervention with only a single RCT; (3) studies where the reference group did not correspond to the SOC; (4) duplicate studies; (5) studies for which the full text was not available; (6) studies with incomplete or unreported data; (7) studies not written in English.
The prespecified primary outcomes of the study included the incidence of grade≥2 RD (i.e., percentage of moist desquamation) and RD score. The secondary outcomes comprised subjective assessment scores of PROs such as pains, itching, and burning sensations. The outcomes of interest encompassed the RD score and patients’ subjective assessment scores for overall treatment. Higher scores on the designated rating scale indicated increased skin toxicity.
All scores were defined as the highest intensity changes recorded on the rating scales presented in Table 1, at the conclusion of radiation treatments, typically occurring between five to seven weeks. The maximum level indicated the most severe skin reaction associated with a specific intervention or no intervention. These widely reported outcome measures at these particular time points hold clinical significance as the radiation dose reaches its peak cumulative level upon completion of radiation treatment. The results were recorded as closely as possible to the end of radiation therapy for all analyses. In cases where data were unavailable at the end of radiation therapy, data from time points near the conclusion of treatment were prioritized for primary outcomes, as well as secondary outcomes.
Search strategy
A comprehensive literature search was conducted using electronic databases including PubMed, Web of Science, and Embase (the period from 1964 to May 2023). Additionally, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue 5 of 12 in May 2023), was searched. The medical subject headings (Mesh), Emtree and entry terms were used as search strategies. The complete search strategy and the results can be found in S1 Appendix.
Study selection and data collection
Two researchers, YG and SL independently screened the titles and abstracts of the potentially eligible studies for initial retrieval. Subsequently, both researchers thoroughly read the full texts, extracted relevant data, and engaged in discussions to reach a consensus on inclusion validity. Any disagreements were resolved through team discussions (YG, SL, ACL, and WQC). A formal extraction record form was developed to ensure systematic data extraction. The following patient and study characteristics were extracted: cancer site, average age, gender, author, year of publication, country, sample size, study design, RD grading scales, treatment arms, frequency and duration of interventions, and outcomes. A summary of the baseline characteristics of the included RCTs is provided in Table 1 [18, 35–75].
Three-arm trials that involved two different interventions were divided into the corresponding number of pairwise comparisons, comparing each intervention against the reference group (SOC).
Quality assessment and risk of bias
Two reviewers, YG and SL, assessed the risk of bias in the selected RCTs using the Cochrane Collaboration tool within Review Manager 5.4.1. The criteria for evaluating bias included random sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessors, the integrity of outcome indicators, selective reporting, and other potential sources of bias. Each criterion was classified as having a low, unclear, or high risk of bias. A funnel plot was generated using STATA 15.1 to examine the possibility of publication bias [76]. The funnel plot revealed an asymmetric distribution, indicating the presence of publication bias. Additionally, we categorized studies with more than 100 patients per study group as large studies [77].
Statistical analysis
Initially, the collected data were consolidated before being incorporated into the analysis. For continuous outcomes indicated by mean differences (MDs), and dichotomous outcomes indicated by odds ratios (ORs), we utilized both pairwise and network meta-analysis techniques to estimate the effect sizes. The corresponding 95% credible intervals (CrI) were also calculated. In instances where the extracted data from the studies provided information on continuous variables in the form of medians, interquartile ranges, or ranges instead of means and standard deviations, we employed the method outlined by Hozo et al. [78] to transform the data appropriately.
We performed NMA using a Bayesian framework with random effects. This analysis was conducted in the R software environment version 4.2.1, utilizing the "gemtc" package [79]. Additionally, we utilized Stata 15.1, a software package by StataCorp LLC, to generate a network plot. In the network plot, each node represents either an intervention or SOC. The size of the nodes corresponds to the number of patients, while the thickness of the lines indicates the number of trials comparing the intervention against the SOC. Moreover, we calculated the surface under the curve cumulative ranking area (SUCRA) to determine the rank probabilities of different interventions. Higher SUCRA scores indicate better efficacy for each outcome. Our protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guideline (S1 Checklist). It is important to note that the current study protocol was registered in PROSPERO with the registration number CRD42023428598.
Results
Study characteristics and quality
Out of the 1725 titles that were examined, 1077 records had their abstracts evaluated. From this group, 158 complete studies were assessed to determine their eligibility. Eventually, a total of 42 publications, which involved 4884 patients and were conducted between 2006 and 2022, met the criteria for inclusion in this analysis. We obtained the 1725 titles and abstracts from various sources such as PubMed, Web of Science, Embase, and Cochrane Library. After removing 648 articles that were duplicates, a quick review helped eliminate 919 irrelevant articles. We then proceeded to evaluate the eligibility of 158 full articles. The final selection consisted of 42 studies for qualitative synthesis, and 41 studies for quantitative synthesis (excluding Ferreira, E.B. 2020 [18], as the data provided for patients’ subjective assessment scores could not be extracted or calculated as mean or standard deviation). Fig 1 illustrates the flowchart, and Table 1 provides an overview of the basic characteristics of the forty-two RCTs included.
A total of 14 different interventions were compared to SOC, namely Corticosteroid, PBMT, Glutamine, StrataXRT®, Mepitelfilm, Hydrofilm, Xonrid®, KeraStat, Chamomile, Calendula, Curcumin, Henna, Trolamine, Hyaluronicacid. These interventions represent the following classes of therapies: topical corticosteroids, PBMT, oral agents, barrier films and dressings, natural and traditional herbs, and miscellaneous agents (S1 File).
Risk of bias in included studies and publication bias
Ninety-five percent (40 out of 42) of the trials included in the analysis were double-arm studies, while the remaining 5 percent (2 out of 42) were three-arm studies. The risk of bias for the included RCTs is depicted in Fig 2. We observed a low risk of bias in all of the included RCTs regarding random sequence generation, incomplete outcome data, selective reporting, and other bias. However, there was an unclear bias risk for allocation concealment in 31 RCTs. Regarding participant and staff blinding, as well as outcome assessment blinding, 20 RCTs exhibited a high risk of bias. The funnel plots for each outcome indicated that publication bias was under control. These funnel plots were presented in Fig 3.
(A) Risk of bias graph, presented as percentage across all included studies; (B) Risk of bias summary, each risk of bias item for each included study.
(A) Incidence of grade≥2 RD, (B) RD sores, (C) Pain sensations, (D) Itching sensations, and (E) Burning sensations.
Network evaluations
Fig 4 illustrates the evidence network plots depicting the interventions tested in RCTs for their effectiveness in managing RD, focusing on primary outcomes. Similarly, Fig 5 presents the evidence network plots for secondary outcomes. In these plots, the size of the circles corresponds to the number of studies that examined each intervention, while the thickness of the lines represents the number of studies that compared the two connected interventions.
(A) Incidence of grade≥2 RD, (B) RD sores. Line width is proportional to the number of trials including every pair of interventions (direct comparisons). Circle size is proportional to the total number of patients for each intervention in the network.
(A) Pain sensations, (B) Itching sensations, and (C) Burning sensations. Line width is proportional to the number of trials including every pair of interventions (direct comparisons). Circle size is proportional to the total number of patients for each intervention in the network.
Primary outcomes.
The incidence of grade≥2 RD was assessed using 13 pairwise comparisons, which involved 37 studies and 13 interventions compared to SOC. The interventions included in this analysis were StrataXRT®, Mepitelfilm, Trolamine, Hyaluronicacid, PBMT, Chamomile, Hydrofilm, Calendula, Curcumin, Glutamine, Xonrid®, Corticosteroid, and KeraStat (Fig 4A). The RD score was determined through 8 pairwise comparisons, which encompassed 11 studies and 8 interventions compared to SOC. The interventions included in this analysis were StrataXRT®, Mepitelfilm, Trolamine, Hydrofilm, Curcumin, Glutamine, Corticosteroid, and KeraStat.
Secondary outcomes.
For pain sensations, there were 7 pairwise comparisons contributing to NMA, which involved 11 studies and 7 interventions compared to SOC. The interventions included in this analysis were StrataXRT®, Mepitelfilm, Hydrofilm, Curcumin, Glutamine, Corticosteroid, and Henna.
Regarding itching sensations, there were 5 pairwise comparisons that contributed to the NMA, involving 6 studies and 5 interventions compared to SOC. The interventions included in this analysis were StrataXRT®, Mepitelfilm, Hydrofilm, Corticosteroid, and Henna.
For burning sensations, there were 4 pairwise comparisons contributing to the NMA, involving 5 studies and 4 interventions compared to SOC. The interventions included in this analysis were Mepitelfilm, Hydrofilm, Corticosteroid, and Henna.
Forest plots
Figs 6 and 7 display the findings of the direct pairwise meta-analyses comparing various interventions with SOC for both primary and secondary outcomes.
(A) measured as odds ratio in incidence of grade≥2 RD, and (B) measured as mean difference for RD score. Interventions compared with SOC, which was the reference intervention. CrI = credible interval, T = number of trials, P = total number of patients. OR = odds ratio, SOC = standard of care.
(A) measured as mean difference in pain sensations, (B) measured as mean difference for itching sensations, and (C) measured as mean difference for burning sensations. Interventions compared with SOC, which was the reference intervention. CrI = credible interval, T = number of trials, P = total number of patients, OR = odds ratio, SOC = standard of care.
Primary outcomes.
Fig 6 shows the full findings of forest plots of network meta-analysis of all trials for primary outcomes.
ORs for the incidence of grade≥2 RD demonstrated a significant difference when compared to SOC. Specifically, Mepitelfilm (OR 0.21 [0.14–0.31]), PBMT (OR 0.16 [0.097–0.27]), Hydrofilm (OR 0.19 [0.09–0.35]), Curcumin (OR 0.57 [0.38–0.85]), Glutamine (OR 0.25 [0.07–0.85]), and Corticosteroid (OR 0.54 [0.38–0.77]) showed a more favorable outcome compared to SOC.
In terms of the RD score, Hydrofilm (MD-0.80 [-0.99– -0.61]), KeraStat (MD-0.36 [-0.61– -0.11]), and Mepitelfilm (MD-0.19 [-1.69– -0.68]) exhibited superior performance compared to SOC.
Secondary outcomes.
Fig 7 shows the full findings of forest plots of network meta-analysis of all trials for secondary outcomes.
For pain sensations, Hydrofilm (MD-0.49 [-0.73– -0.25]), Henna (MD-0.93 [-1.25– -0.61]), and Mepitelfilm (MD-0.38 [-0.55– -0.22]) exhibited an advantage over SOC in terms of providing relief from pain.
Regarding itching sensations, Corticosteroid (MD-0.70 [-1.2– -0.25]), Hydrofilm (MD-0.70 [-0.99– -0.41]), Henna (MD-0.44 [-0.77– -0.11]), and Mepitelfilm (MD-0.20 [-0.37– -0.03]) demonstrated greater effectiveness compared to SOC in alleviating itching.
In relation to burning sensations, Corticosteroid (MD-0.60 [-1.1– -0.12]), Hydrofilm (MD-0.50 [-0.77– -0.23]), Henna (MD-0.46 [-0.78– -0.14]), and Mepitelfilm (MD-0.20 [-0.37– -0.03]) were found to be more helpful than SOC in reducing burning sensations.
League tables
We conducted direct and indirect comparisons to assess the comparative effectiveness of different interventions using league tables (Tables 2–6). The direct comparisons align with the findings presented in the forest plots (Figs 6 and 7). Additionally, significant differences were observed among the interventions when considering mixed comparisons.
Primary outcomes.
In terms of the incidence of grade≥2 RD (Table 2), Corticosteroid, Curcumin, and Glutamine demonstrated greater effectiveness compared to Hyaluronicacid, with ORs of (OR 0.37 [0.18, 0.74]), (OR 0.39 [0.18, 0.8]), and (OR 0.17 [0.04, 0.67]), respectively. Additionally, Corticosteroid, Hydrofilm, Mepitelfilm, and PBMT were found to be superior to Trolamine, with ORs of (OR 0.6 [0.36, 0.99]), (OR 0.21 [0.09, 0.43]), (OR 0.23 [0.13, 0.39]), and (OR 0.18 [0.09, 0.33]), respectively. Furthermore, Hydrofilm, Mepitelfilm, and PBMT exhibited better performance than Xonrid®, with ORs of (OR 0.32 [0.12, 0.83]), (OR 0.35 [0.16, 0.79]), and (OR 0.28 [0.12, 0.66]), respectively. For RD score (Table 3), Hydrofilm was identified as the superior intervention for reducing the RD score. MDs for Hydrofilm compared to other interventions (StrataXRT® and KeraStat) ranged from −0.50 to −0.44. Additionally, Mepitelfilm showed notable effectiveness with an MD of -0.89 when compared to StrataXRT®.
Secondary outcomes.
For pain sensations (Table 4), Henna was ranked as the most effective intervention for pain relief. MDs for Henna compared to Mepitelfilm and Hydrofilm ranged from −0.55 to −0.44.
In terms of itching sensations (Table 5), Corticosteroid and Hydrofilm exhibited similar efficacy to Mepitelfilm, with MDs of -0.50 (-0.98, -0.01) and -0.50 (-0.84, -0.17), respectively.
However, for burning sensations (Table 6), Corticosteroid, Hydrofilm, Mepitelfilm, and Henna did not yield significantly different outcomes when compared to each other.
Ranking of interventions by efficacy
The ranking probability of different interventions in managing RD is presented in Table 7 and Figs 8–12. Based on the SUCRA plot and values, PBMT (SUCRA, 0.92) achieved the highest ranking in terms of the lowest incidence of grade≥2 RD, while Hyaluronicacid (SUCRA, 0.10) obtained the lowest ranking (Fig 8). In terms of decreasing RD scores, Mepitelfilm (SUCRA, 0.98) ranked the highest, while Curcumin (SUCRA, 0.03) ranked the lowest (Fig 9). Henna (SUCRA, 0.89) was ranked the highest for pain sensations relief, whereas SOC (SUCRA, 0.17) received the lowest ranking (Fig 10). Regarding the relief of itching sensations, Hydrofilm (SUCRA, 0.84) demonstrated the greatest efficacy in reducing itching sensations, while SOC (SUCRA, 0.09) had the highest incidence of itching sensations (Fig 11). For alleviating burning sensations, Corticosteroid (SUCRA, 0.81) exhibited the most effective results, while SOC (SUCRA, 0.01) was the least effective intervention (Fig 12).
The SUCRA value would be 0 when an intervention is certain to be the worst and 1 when it is certain to be the best.
The SUCRA value would be 0 when an intervention is certain to be the worst and 1 when it is certain to be the best.
The SUCRA value would be 0 when an intervention is certain to be the worst and 1 when it is certain to be the best.
The SUCRA value would be 0 when an intervention is certain to be the worst and 1 when it is certain to be the best.
The SUCRA value would be 0 when an intervention is certain to be the worst and 1 when it is certain to be the best.
Discussion
In this study, we conducted a Bayesian NMA to evaluate the efficacy of different interventions used for the prevention and treatment of RD. Consistent use of assessment tools is important to document the severity of RD and respond with appropriate therapeutic interventions. Clinicians often rely on clinician-reported outcomes (CROs) to assess the incidence of grade≥2 RD, specifically the percentage of moist desquamation, and RD score. These measures are commonly utilized as primary outcome measures in RD-related systematic reviews and clinical trials. They offer quantitative and standardized assessments of RD severity, allowing for meaningful comparisons across different studies. By considering both the analysis of the incidence of grade≥2 RD and RD score, the impact of a particular intervention in reducing the severity of RD among patients is evaluated comprehensively.
Based on our cumulative probability ranking, PBMT demonstrated significantly better outcomes compared to Trolamine and Xonrid® in reducing the incidence of grade≥2 RD. PBMT is a non-invasive and a-thermal treatment approach that utilizes light to activate epithelial healing through various metabolic processes involving photochemical reactions [52]. PBMT offers advantages such as enhanced light penetration and propagation within tissues, leading to greater anti-inflammatory, bio-stimulating, and analgesic effects. Several open-label studies have provided evidence of PBMT’s effectiveness in preventing the development of grade 2 or higher acute RD [48, 50–52]. Despite this evidence, PBMT is not currently recommended for clinical use by the Society and College of Radiographers (SCoR) due to uncertainty regarding the replicability of study results. In 2010, Fife, D. presented an opposing viewpoint suggesting that PBMT may not effectively reduce the severity of skin reactions, indicating that the effectiveness of PBMT may be influenced by various patient and treatment-related factors [49].
Many scoring systems used to assess RD share several similarities. Two similarities are as follows: (1) These scoring systems assess the severity of radiation dermatitis based on specific criteria, including erythema, edema, desquamation, and pain; and (2) these scoring systems utilize a grading system to categorize the severity of radiation dermatitis, typically ranging from grade 1 (mild) to grade 4 (severe). In terms of RD score, Mepitelfilm was more effective than other interventions in our findings, which was in agreement with several own-control studies [38, 40–42]. Mepitelfilm is a sterile, transparent, breathable, and adhesive soft silicone film. The utilization of barrier protectants is grounded in a fundamental concept and a potential mechanism that assumes safeguarding the keratinized surface and shielding the radiotherapy-affected basal stem-cell layer from surface abrasion and friction can significantly prevent skin damage. Additionally, a systematic review and meta-analysis conducted by Robijns et al. [7] provided evidence showing that Mepitelfilm had a positive impact on the severity of radiation dermatitis. Their subgroup analysis revealed that Mepitelfilm significantly reduced grade 2 radiation dermatitis in head and neck cancer patients, but did not affect the incidence of moist desquamation in these patients. Mepitelfilm was found to be more effective for radiation dermatitis of grade 2 or higher in breast cancer patients. Meanwhile, the use of barrier films and dressings lacks widespread consensus or strong recommendations among guidelines due to the challenges associated with the difficulty of designing unbiased studies on this topic. Until now, most studies on RD have relied on CROs as the primary measure for guiding clinical practice and symptom management, considering them the "gold standard." However, there has been a growing focus on incorporating the patient perspective in recent RD studies [80]. Based on the SUCRA outcome, Henna demonstrated the highest ranking in terms of improving pain relief, showing significant differences. Henna is derived from natural compounds found in Lawsonia inermis, and some researchers have presented evidence supporting its antimicrobial and antioxidant properties in the context of wound healing [75]. So far, no recommendation was made for any natural agent by practice guidelines. Our research provided valuable insights into the potential of novel herbal interventions that specifically target pain relief. In terms of PROs, Hydrofilm emerged as the intervention with the lowest incidence of itching sensations reported by patients. Hydrofilm is a transparent, waterproof polyurethane film that is coated with a hypoallergenic polyacrylate adhesive. Our findings corroborate the results of previous meta-analyses conducted by Robijns et al. [7]. Analyzing the pooled data, we found that Hydrofilm significantly reduced the average itching score and had a positive impact on limiting day-to-day activities. However, our analysis did not find a significant effect of Hydrofilm on the mean pain and burning sensation scores.
Regarding the evaluation of burning sensations, Corticosteroid proved to be the most beneficial treatment, although its effectiveness did not show statistical significance when compared to other interventions. RD is linked to an inflammatory process believed to be mediated by cytokines. Corticosteroids function as anti-inflammatory substances by controlling the attachment of white blood cells to endothelial cells, causing blood vessel constriction, reducing the permeability of capillaries, and inhibiting the multiplication and movement of white blood cells. In laboratory studies, they have been demonstrated to decrease the production of interleukin 6 [6]. Currently, most guidelines recommend the use of hydrocortisone, a moderately potent corticosteroid, in the usual institutional care to reduce the occurrence of grade≥2 RD. This recommendation is based on the lack of clear evidence supporting the superiority of other potent corticosteroids over hydrocortisone in the literature. However, it is important to note a caveat regarding its use. Prolonged use of hydrocortisone carries a significant risk of skin atrophy, telangiectasia, infection, and impaired wound healing. These factors limit its acceptance as a prescribed treatment during radiation therapy. In the current study, several newly developed high to medium potency corticosteroids, such as difluprednate, mometasone furoate, and betamethasone, were tested. In an RCT conducted by Miller RC et al. [71], utilizing three tools to measure PROs, the group receiving corticosteroids reported less itching and a lower persistence or recurrence of burning symptoms. These findings align with our own analysis. Therefore, according to the ISNCC (International Society of Nurses in Cancer Care, 2021), betamethasone valerate cream and mometasone furoate cream are recommended for managing RD during RT. However, it is emphasized that discontinuation of these creams is necessary if the skin becomes disrupted [17]. On the other hand, Ho, A. Y. et al. [69] reported no significant difference in patient-reported skin outcomes between the treatment arms (60 or 64 patients each treatment arm). Therefore, when comparing the effectiveness of different interventions, it is important to consider not only the results shown in the network plot but also the number of trials and participants involved, as well as the evidence from direct comparisons. Additionally, it is worth noting that patients may have reported more severe pain and other side effects compared to clinicians, possibly due to differences in cultural background, individual pain tolerance, and anticipation of symptom severity. These factors may partly explain the discrepancy in the reported scores.
This study has several notable strengths. Firstly, it successfully created the first network that compared 14 contemporary interventions for RD. Additionally, flexible Bayesian hierarchical modeling was employed, allowing for the integration of both direct and indirect evidence, effectively harnessing the collective strength of multiple trials and providing conservative estimations and conclusions through shrinkage estimation. The robustness of the results was further emphasized through sensitivity analyses that explored different model prior specifications and inclusion criteria.
Nonetheless, this study is also subject to several limitations. Firstly, as with any meta-analysis, there is heterogeneity in the design and reporting of the trials included in the analysis. The assessment scales for grading RD and PROs were not consistently uniform across the studies. Secondly, only RCTs were included in this network meta-analysis. While RCTs are generally well-designed and provide high-quality clinical data, the number of studies available for inclusion may have been limited. Although the intervention network was successfully established, most direct comparisons relied on data from a single RCT connection, resulting in relatively sparse direct evidence and limited assessment of incoherence. Thirdly, the outcomes would be improved if they were coupled with data from other common terms for RD such as skin reactions or skin burns in literature search. But it should be highlighted that Mesh and entry terms were used as search the most popular strategies. Fourthly, less than 30% of the trials included in the analysis were large studies. This could introduce bias due to the potential influence of small study effects. Fifthly, this meta-analysis was conducted based on aggregated study-level data. Individual patient characteristics, which can have a significant impact on treatment outcomes, were not accounted for and would require further investigation in future studies. Sixthly, while the primary focus of this study was the incidence of ≥Grade2 RD and RD scores as efficacy endpoints, adverse event (AE) data were not compared between interventions due to incomplete or unavailable data in the included studies. Due to the majority of AE reports being mild or showing no response, occasional serious AEs are typically attributed to the overall treatment for cancer, and it becomes difficult to determine if they are specifically related to the intervention being studied. Seventhly, the SUCRA curve was utilized to estimate the ranking probability of comparative effectiveness among the various therapies. However, it is important to note that the SUCRA curve has its limitations, and the results should be interpreted with caution.
Conclusion
Overall, this NMA provides a summary of the efficacy and impact on PROs for 14 different interventions used in the management of RD. Based on the findings, PBMT appears to have demonstrated better efficacy in reducing the incidence of grade≥2 RD, while Mepitelfilm showed better efficacy in reducing RD scores. When considering PROs, Henna treatment resulted in fewer complaints related to pain, while Hydrofilm showed fewer complaints related to itching sensations. When comparing different treatments, it is important to take into account the limitations of the available data, the characteristics of the patient group, and any uncertainties arising from the dosage selection or the specific context of therapy. However, since there is a lack of multi-arm RCTs that encompass all commonly used regimens, it is expected that more RCTs evaluating various interventions for RD will be conducted in the future. Despite these considerations, this NMA serves as a valuable and informative resource to guide treatment decisions in RD.
Supporting information
S1 Checklist. PRISMA-P (Preferred Reporting Items for Systematic review and Metanalysis Protocols) 2020 checklist: Recommended items to address in a systematic review protocol.
https://doi.org/10.1371/journal.pone.0298209.s001
(DOCX)
S1 File. Included interventions in the Network meta-analysis by therapeutic class.
https://doi.org/10.1371/journal.pone.0298209.s003
(DOCX)
Acknowledgments
The interpretation and reporting of these data are the authors’ sole responsibility.
References
- 1. McQuestion M. Evidence-based skin care management in radiation therapy: clinical update. Semin Oncol Nurs. 2011 May;27(2):e1–17. pmid:21514477.
- 2. Wolbarst AB, Wiley AL Jr, Nemhauser JB, Christensen DM, Hendee WR. Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Radiology. 2010 Mar;254(3):660–77. pmid:20177084.
- 3. Mendelsohn FA, Divino CM, Reis ED, Kerstein MD. Wound care after radiation therapy. Adv Skin Wound Care. 2002 Sep-Oct;15(5):216–24. pmid:12368711.
- 4. Spałek M. Chronic radiation-induced dermatitis: challenges and solutions. Clin Cosmet Investig Dermatol. 2016 Dec 9;9:473–482. pmid:28003769.
- 5. Singh M, Alavi A, Wong R, Akita S. Radiodermatitis: A Review of Our Current Understanding. Am J Clin Dermatol. 2016 Jun;17(3):277–92. pmid:27021652.
- 6. Pitzalis C, Pipitone N, Bajocchi G, Hall M, Goulding N, Lee A, et al. Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: an additional mechanism for their anti-inflammatory and immunosuppressive effect. J Immunol. 1997 May 15;158(10):5007–16. pmid:9144521.
- 7. Robijns J, Aquilano M, Banerjee S, Caini S, Wolf JR, van den Hurk C, et al. Barrier Films and Dressings for the Prevention of Acute Radiation Dermatitis: A Systematic Review and Meta-Analysis. Support Care Cancer. 2023 Mar 17;31(4):219. pmid:36929087.
- 8. Bray FN, Simmons BJ, Wolfson AH, Nouri K. Acute and Chronic Cutaneous Reactions to Ionizing Radiation Therapy. Dermatol Ther (Heidelb). 2016 Jun;6(2):185–206. Epub 2016 Jun 1. pmid:27250839.
- 9. Böhner AMC, Koch D, Schmeel FC, Röhner F, Schoroth F, Sarria GR, et al. Objective Evaluation of Risk Factors for Radiation Dermatitis in Whole-Breast Irradiation Using the Spectrophotometric L*a*b Color-Space. Cancers (Basel). 2020 Aug 28;12(9):2444. pmid:32872216.
- 10. Parker J. J., Rademaker A., Donnelly E., & Choi J. Risk Factors for the Development of Acute Radiation Dermatitis in Breast Cancer Patients. SKIN The Journal of Cutaneous Medicine, 2(1), 2–11. https://doi.org/10.25251/skin.2.1.1.
- 11. Pignol JP, Olivotto I, Rakovitch E, Gardner S, Sixel K, Beckham W, et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol. 2008 May 1;26(13):2085–92. Epub 2008 Feb 19. pmid:18285602.
- 12. Sprigle S, Caminiti R, Varenberg M. Friction characteristics of preventative wound dressings under clinically-relevant conditions. Wound Repair Regen. 2021 Mar;29(2):280–283. Epub 2020 Dec 31. Epub 2020 Dec 31. pmid:33383593.
- 13. Neu J, DeMarco V, Li N. Glutamine: clinical applications and mechanisms of action. Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):69–75. pmid:11790953.
- 14. WALT/NAALT. Photobiomodulation: mainstream medicine and beyond. WALT Biennial Congress and NAALT Annual Conference, Arlington Virginia USA2014 Sept.
- 15. Huang YY, Sharma SK, Carroll J, Hamblin MR. Biphasic dose response in low level light therapy—an update. Dose Response. 2011;9(4):602–18. Epub 2011 Sep 2. pmid:22461763.
- 16. Robijns J, Lodewijckx J, Bensadoun RJ, Mebis J. A Narrative Review on the Use of Photobiomodulation Therapy for the Prevention and Management of Acute Radiodermatitis: Proposed Mechanisms, Current Clinical Outcomes, and Preliminary Guidance for Clinical Studies. Photobiomodul Photomed Laser Surg. 2020 Jun;38(6):332–339. Epub 2020 May 27. pmid:32460613.
- 17. Finkelstein S, Kanee L, Behroozian T, Wolf JR, van den Hurk C, Chow E, et al. Comparison of clinical practice guidelines on radiation dermatitis: a narrative review. Support Care Cancer. 2022 Jun;30(6):4663–4674. Epub 2022 Jan 24. pmid:35067732.
- 18. Ferreira EB, Ciol MA, de Meneses AG, Bontempo PSM, Hoffman JM, Reis PEDD. Chamomile Gel versus Urea Cream to Prevent Acute Radiation Dermatitis in Head and Neck Cancer Patients: Results from a Preliminary Clinical Trial. Integr Cancer Ther. 2020 Jan-Dec;19:1534735420962174. pmid:32985288.
- 19. Pommier P, Gomez F, Sunyach MP, D’Hombres A, Carrie C, Montbarbon X. Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer. J Clin Oncol. 2004 Apr 15;22(8):1447–53. pmid:15084618.
- 20. Kumar S, Juresic E, Barton M, Shafiq J. Management of skin toxicity during radiation therapy: a review of the evidence. J Med Imaging Radiat Oncol. 2010 Jun;54(3):264–79. pmid:20598015.
- 21. Farhood B, Mortezaee K, Goradel NH, Khanlarkhani N, Salehi E, Nashtaei MS, et al. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J Cell Physiol. 2019 May;234(5):5728–5740.Epub 2018 Oct 14. pmid:30317564.
- 22. Tejada S, Manayi A, Daglia M, Nabavi SF, Sureda A, Hajheydari Z, et al. Wound Healing Effects of Curcumin: A Short Review. Curr Pharm Biotechnol. 2016;17(11):1002–7. pmid:27640646.
- 23. Nayak BS, Isitor G, Davis EM, Pillai GK. The evidence based wound healing activity of Lawsonia inermis Linn. Phytother Res. 2007 Sep;21(9):827–31. pmid:17533628.
- 24. Coulomb B, Friteau L, Dubertret L. Biafine applied on human epidermal wounds is chemotactic for macrophages and increases the IL-1/IL-6 ratio. Skin Pharmacol. 1997;10(5–6):281–7. pmid:9449167.
- 25. Fisher J, Scott C, Stevens R, Marconi B, Champion L, Freedman GM, et al. Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97–13. Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1307–10. pmid:11121627.
- 26. Gracy R, Lloyd KL, Phelps JL, editors. RadiaPlexRx Gel Protects Cultured Skin Cells from Oxidative Free Radical Damage Induced by Hydrogen Peroxide and by Irradiation: A Pilot Study. Radiological Society of North America 2004 Scientific Assembly and Annual Meeting; 2004.
- 27. Chan RJ, Webster J, Chung B, Marquart L, Ahmed M, Garantziotis S. Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2014 Jan 31;14:53. pmid:24484999; PMCID: PMC3909507.
- 28. Zhang Y, Zhang S, Shao X. Topical agent therapy for prevention and treatment of radiodermatitis: a meta-analysis. Support Care Cancer. 2013 Apr;21(4):1025–31. Epub 2012 Oct 12. pmid:23064885.
- 29. Haruna F, Lipsett A, Marignol L. Topical Management of Acute Radiation Dermatitis in Breast Cancer Patients: A Systematic Review and Meta-Analysis. Anticancer Res. 2017 Oct;37(10):5343–5353. pmid:28982842.
- 30. Fatima S, Hirakawa S, Marta GN, Caini S, Beveridge M, Bonomo P, et al. Topical non-steroidal agents for the prevention of radiation dermatitis: a systematic review and meta-analysis. Support Care Cancer. 2023 Mar 17;31(4):217. pmid:36928164.
- 31. Siontis GC, Mavridis D, Greenwood JP, Coles B, Nikolakopoulou A, Jüni P, et al. Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomised controlled trials. BMJ. 2018 Feb 21;360:k504. pmid:29467161.
- 32. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004 Oct 30;23(20):3105–24. pmid:15449338.
- 33. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis. Focus (Am Psychiatr Publ). 2018 Oct;16(4):420–429. Epub 2018 Oct 18. pmid:32021580.
- 34. Bafeta A, Trinquart L, Seror R, Ravaud P. Reporting of results from network meta-analyses: methodological systematic review. BMJ. 2014 Mar 11;348:g1741. pmid:24618053.
- 35. Ahn S, Sung K, Kim HJ, Choi YE, Lee YK, Kim JS, et al. Reducing Radiation Dermatitis Using a Film-forming Silicone Gel During Breast Radiotherapy: A Pilot Randomized-controlled Trial. In Vivo. 2020 Jan-Feb;34(1):413–422. pmid:31882508.
- 36. Chan RJ, Blades R, Jones L, Downer TR, Peet SC, Button E, et al. A single-blind, randomised controlled trial of StrataXRT® - A silicone-based film-forming gel dressing for prophylaxis and management of radiation dermatitis in patients with head and neck cancer. Radiother Oncol. 2019 Oct;139:72–78. Epub 2019 Aug 21. pmid:31445838.
- 37. Behroozian T, Milton L, Karam I, Zhang L, Ding K, Lou J, et al. Mepitel Film for the Prevention of Acute Radiation Dermatitis in Breast Cancer: A Randomized Multicenter Open-Label Phase III Trial. J Clin Oncol. 2023 Feb 20;41(6):1250–1264. Epub 2022 Dec 9. pmid:36493331.
- 38. Wooding H, Yan J, Yuan L, Chyou TY, Gao S, Ward I, et al. The effect of Mepitel Film on acute radiation-induced skin reactions in head and neck cancer patients: a feasibility study. Br J Radiol. 2018 Jan;91(1081):20170298. Epub 2017 Nov 8. pmid:29072852.
- 39. Zhong WH, Tang QF, Hu LY, Feng HX. Mepilex Lite dressings for managing acute radiation dermatitis in nasopharyngeal carcinoma patients: a systematic controlled clinical trial. Med Oncol. 2013 Dec;30(4):761. Epub 2013 Nov 2. pmid:24186620.
- 40. Møller PK, Olling K, Berg M, Habæk I, Haislund B, Iversen AM,et al. Breast cancer patients report reduced sensitivity and pain using a barrier film during radiotherapy—A Danish intra-patient randomized multicentre study. Tech Innov Patient Support Radiat Oncol. 2018 Jun 19;7:20–25. pmid:32095578.
- 41. Rades D, Narvaez CA, Splettstößer L, Dömer C, Setter C, Idel C, et al. A randomized trial (RAREST-01) comparing Mepitel® Film and standard care for prevention of radiation dermatitis in patients irradiated for locally advanced squamous cell carcinoma of the head-and-neck (SCCHN). Radiother Oncol. 2019 Oct;139:79–82. Epub 2019 Aug 17. pmid:31431372.
- 42. Yan J, Yuan L, Wang J, Li S, Yao M, Wang K, et al. Mepitel Film is superior to Biafine cream in managing acute radiation-induced skin reactions in head and neck cancer patients: a randomised intra-patient controlled clinical trial. J Med Radiat Sci. 2020 Sep;67(3):208–216. Epub 2020 May 31. pmid:32475079.
- 43. Abbas H, Bensadoun RJ. Trolamine emulsion for the prevention of radiation dermatitis in patients with squamous cell carcinoma of the head and neck. Support Care Cancer. 2012 Jan;20(1):185–90. Epub 2011 Feb 22. pmid:21340657.
- 44. Elliott EA, Wright JR, Swann RS, Nguyen-Tân F, Takita C, Bucci MK, et al. Radiation Therapy Oncology Group Trial 99–13. Phase III Trial of an emulsion containing trolamine for the prevention of radiation dermatitis in patients with advanced squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Trial 99–13. J Clin Oncol. 2006 May 1;24(13):2092–7. pmid:16648511.
- 45. Pinnix C, Perkins GH, Strom EA, Tereffe W, Woodward W, Oh JL, et al. Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: single-blind randomized phase III clinical trial. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1089–94. Epub 2011 Dec 14. pmid:22172912.
- 46. Rahimi A, Mohamad O, Albuquerque K, Kim DWN, Chen D, Thomas K, et al. Novel hyaluronan formulation for preventing acute skin reactions in breast during radiotherapy: a randomized clinical trial. Support Care Cancer. 2020 Mar;28(3):1481–1489. Epub 2019 Jul 4. pmid:31273506.
- 47. Censabella S, Claes S, Robijns J, Bulens P, Mebis J. Photobiomodulation for the management of radiation dermatitis: the DERMIS trial, a pilot study of MLS(®) laser therapy in breast cancer patients. Support Care Cancer. 2016 Sep;24(9):3925–33. Epub 2016 Apr 26. pmid:27116013.
- 48. Robijns J, Lodewijckx J, Puts S, Vanmechelen S, Van Bever L, Claes S, et al. Photobiomodulation therapy for the prevention of acute radiation dermatitis in breast cancer patients undergoing hypofractioned whole-breast irradiation (LABRA trial). Lasers Surg Med. 2022 Mar;54(3):374–383.Epub 2021 Sep 4. pmid:34481420.
- 49. Fife D, Rayhan DJ, Behnam S, Ortiz A, Elkeeb L, Aquino L, et al. A randomized, controlled, double-blind study of light emitting diode photomodulation for the prevention of radiation dermatitis in patients with breast cancer. Dermatol Surg. 2010 Dec;36(12):1921–7. Epub 2010 Nov 11. pmid:21070458.
- 50. Robijns J, Censabella S, Claes S, Pannekoeke L, Bussé L, Colson D, et al. Prevention of acute radiodermatitis by photobiomodulation: A randomized, placebo-controlled trial in breast cancer patients (TRANSDERMIS trial). Lasers Surg Med. 2018 Feb 10. Epub ahead of print. pmid:29427390.
- 51. Robijns J, Censabella S, Claes S, Pannekoeke L, Bussé L, Colson D, et al. Biophysical skin measurements to evaluate the effectiveness of photobiomodulation therapy in the prevention of acute radiation dermatitis in breast cancer patients. Support Care Cancer. 2019 Apr;27(4):1245–1254. Epub 2018 Oct 1. pmid:30270415.
- 52. Robijns J, Lodewijckx J, Claes S, Van Bever L, Pannekoeke L, Censabella S, et al. Photobiomodulation therapy for the prevention of acute radiation dermatitis in head and neck cancer patients (DERMISHEAD trial). Radiother Oncol. 2021 May;158:268–275. Epub 2021 Mar 10. pmid:33711412
- 53. Zhang X, Li H, Li Q, Li Y, Li C, Zhu M, et al. Application of red light phototherapy in the treatment of radioactive dermatitis in patients with head and neck cancer. World J Surg Oncol. 2018 Nov 12;16(1):222. pmid:30419911.
- 54. Garbuio DC, Ribeiro VDS, Hamamura AC, Faustino A, Freitas LAP, Viani G, et al. A Chitosan-Coated Chamomile Microparticles Formulation to Prevent Radiodermatitis in Breast: A Double-blinded, Controlled, Randomized, Phase II Clinical Trial. Am J Clin Oncol. 2022 May 1;45(5):183–189. Epub 2022 Apr 8. pmid:35393979.
- 55. Schmeel LC, Koch D, Schmeel FC, Bücheler B, Leitzen C, Mahlmann B, et al. Hydrofilm Polyurethane Films Reduce Radiation Dermatitis Severity in Hypofractionated Whole-Breast Irradiation: An Objective, Intra-Patient Randomized Dual-Center Assessment. Polymers (Basel). 2019 Dec 16;11(12):2112. pmid:31888185.
- 56. Schmeel LC, Koch D, Stumpf S, Leitzen C, Simon B, Schüller H, et al. Prophylactically applied Hydrofilm polyurethane film dressings reduce radiation dermatitis in adjuvant radiation therapy of breast cancer patients. Acta Oncol. 2018 Jul;57(7):908–915. Epub 2018 Feb 20. pmid:29463159.
- 57. Sharp L, Finnilä K, Johansson H, Abrahamsson M, Hatschek T, Bergenmar M. No differences between Calendula cream and aqueous cream in the prevention of acute radiation skin reactions—results from a randomised blinded trial. Eur J Oncol Nurs. 2013 Aug;17(4):429–35. Epub 2012 Dec 13. pmid:23245940.
- 58. Schneider F, Danski MT, Vayego SA. Usage of Calendula officinalis in the prevention and treatment of radiodermatitis: a randomized double-blind controlled clinical trial. Rev Esc Enferm USP. 2015 Apr;49(2):221–8. pmid:25992820.
- 59. Talakesh T, Tabatabaee N, Atoof F, Aliasgharzadeh A, Sarvizade M, Farhood B, et al. Effect of Nano-Curcumin on Radiotherapy-Induced Skin Reaction in Breast Cancer Patients: A Randomized, Triple-Blind, Placebo-Controlled Trial. Curr Radiopharm. 2022;15(4):332–340. pmid:35747962.
- 60. NCT01042938 AN, CN-01527471. Curcumin for the Prevention of Radiation-induced Dermatitis in Breast Cancer Patients 2010 Available from: https://clinicaltrials.gov/show/NCT01042938; https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01527471/full.
- 61. NCT01246973 AN, CN-01502015. Oral Curcumin for Radiation Dermatitis 2010. Available from: https://clinicaltrials.gov/show/NCT01246973; https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01502015/full.
- 62. Palatty PL, Azmidah A, Rao S, Jayachander D, Thilakchand KR, Rai MP,et al. Topical application of a sandal wood oil and turmeric based cream prevents radiodermatitis in head and neck cancer patients undergoing external beam radiotherapy: a pilot study. Br J Radiol. 2014 Jun;87(1038):20130490. Epub 2014 Apr 2. pmid:24694358.
- 63. Ryan Wolf J, Gewandter JS, Bautista J, Heckler CE, Strasser J, Dyk P, et al. Utility of topical agents for radiation dermatitis and pain: a randomized clinical trial. Support Care Cancer. 2020 Jul;28(7):3303–3311. Epub 2019 Nov 22. pmid:31758326.
- 64. Huang CJ, Huang MY, Fang PT, Chen F, Wang YT, Chen CH,et al. Randomized double-blind, placebo-controlled trial evaluating oral glutamine on radiation-induced oral mucositis and dermatitis in head and neck cancer patients. Am J Clin Nutr. 2019 Mar 1;109(3):606–614. pmid:30753262.
- 65. Lopez-Vaquero D, Gutierrez-Bayard L, Rodriguez-Ruiz JA, Saldaña-Valderas M, Infante-Cossio P. Double-blind randomized study of oral glutamine on the management of radio/chemotherapy-induced mucositis and dermatitis in head and neck cancer. Mol Clin Oncol. 2017 Jun;6(6):931–936. Epub 2017 May 5. pmid:28588793.
- 66. Ingargiola R, De Santis MC, Iacovelli NA, Facchinetti N, Cavallo A, Ivaldi E,et al. A monocentric, open-label randomized standard-of-care controlled study of XONRID®, a medical device for the prevention and treatment of radiation-induced dermatitis in breast and head and neck cancer patients. Radiat Oncol. 2020 Aug 13;15(1):193. pmid:32791985.
- 67. NCT03255980 AN, CN-01586347. Monocenter, Open Label Clinical Investigation on the Treatment of Radiation Induced Dermatitis With Xonrid® 2017. Available from: https://clinicaltrials.gov/show/NCT03255980; https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01586347/full.
- 68. Yokota T, Zenda S, Ota I, Yamazaki T, Yamaguchi T, Ogawa T, et al. Phase 3 Randomized Trial of Topical Steroid Versus Placebo for Prevention of Radiation Dermatitis in Patients With Head and Neck Cancer Receiving Chemoradiation. Int J Radiat Oncol Biol Phys. 2021 Nov 1;111(3):794–803. Epub 2021 Jun 6. pmid:34102298.
- 69. Ho AY, Olm-Shipman M, Zhang Z, Siu CT, Wilgucki M, Phung A, et al. A Randomized Trial of Mometasone Furoate 0.1% to Reduce High-Grade Acute Radiation Dermatitis in Breast Cancer Patients Receiving Postmastectomy Radiation. Int J Radiat Oncol Biol Phys. 2018 Jun 1;101(2):325–333. Epub 2018 Feb 14. pmid:29726361.
- 70. Kianinia Mahsa,Roayaei Mahnaz,Mahdavi Hoda,Hemati Simin. A Double-Blind Randomized Trial on the Effectiveness of Mometasone 0.1% Cream and Hydrocortisone 1% Cream on the Prevention of Acute Radiation Dermatitis in Breast Cancer Patients following Breast Conserving Surgery. Middle East Journal of Cancer, 12, 3, 2021, 406–414.
- 71. Miller RC, Schwartz DJ, Sloan JA, Griffin PC, Deming RL, Anders JC, et al. Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase III double-blind, randomized trial from the North Central Cancer Treatment Group N06C4. Int J Radiat Oncol Biol Phys. 2011 Apr 1;79(5):1460–6. Epub 2010 Aug 26. pmid:20800381.
- 72. Sunku R, Kalita AK, Bhattacharyya M, Medhi PP, Bansal S, Borah L,et al. Effect of corticosteroid ointment on radiation induced dermatitis in head and neck cancer patients: A prospective study. Indian J Cancer. 2021 Jan-Mar;58(1):69–75. pmid:33402575.
- 73. NCT03374995 AN, CN-01586677. Topical Keratin in Treating Radiation Dermatitis in Patients with Breast Cancer 2017. Available from: https://clinicaltrials.gov/show/NCT03374995; https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01586677/full.
- 74. NCT03559218 AN, CN-01660396. KeraStat(R) Cream for Radiation Dermatitis 2018. Available from: https://clinicaltrials.gov/show/NCT03559218; https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01660396/full.
- 75. Ansari M, Farzin D, Mosalaei A, Omidvari S, Ahmadloo N, Mohammadianpanah M. Efficacy of topical alpha ointment (containing natural henna) compared to topical hydrocortisone (1%) in the healing of radiation-induced dermatitis in patients with breast cancer: a randomized controlled clinical trial. Iran J Med Sci. 2013 Dec;38(4):293–300. pmid:24293782.
- 76. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013 Oct 3;8(10):e76654. pmid:24098547.
- 77. Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, et al. Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. BMJ. 2010 Jul 16;341:c3515. pmid:20639294.
- 78. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005 Apr 20;5:13. pmid:15840177.
- 79. van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012 Dec;3(4):285–99. Epub 2012 Aug 23. pmid:26053422.
- 80. Lam E, Yee C, Wong G, Popovic M, Drost L, Pon K, et al. A systematic review and meta-analysis of clinician-reported versus patient-reported outcomes of radiation dermatitis. Breast. 2020 Apr;50:125–134. Epub 2019 Sep 19. pmid:31563429.