CSMed® wound dressing for prophylaxis and management of radiation dermatitis in breast and head–neck cancer patients: a single hospital prospective clinical trial

Purpose CSMed® wound dressing, a dressing with various herb extracts, was tested for its therapeutic effect in radiation dermatitis of breast and head-and-neck cancer patients. Methods This study included 20 breast cancer patients and 10 head-and-neck cancer patients. Half of the irradiated area was covered with CSMed® and the other half was under routine treatment. The severity of radiation dermatitis was evaluated with radiation therapy oncology group (RTOG) grade throughout the treatment and the follow-up period. The RTOG grade between the dressed and undressed area were compared to illustrate the therapeutic effect of CSMed® dressing. Results The results showed that CSMed® dressed area had significant lower RTOG score at 3–7 weeks and final record during the treatment, and 1–3 weeks during follow-up than undressed area. Conclusions This indicated that CSMed® can delay the onset, reduce the severity, and enhance healing of radiation dermatitis. CSMed® can be used for prophylaxis and management of radiation dermatitis. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-024-05624-6.


Introduction
Radiation dermatitis is the most common side effect after radiotherapy.Patients with radiation therapy usually receive multiple small doses of radiation to kill cancer cell while minimizing damage to surrounding healthy cells.Depending on the radiation dosage and the tissue sensitivity of patients, radiation dermatitis manifests within days or weeks after radiation exposure.Radiation dermatitis is restricted to the exposure area and the skin changes at the boundary are demarcated sharply (Leventhal and Young 2017).Although there is still no standard procedure in preventing and treating radiation dermatitis, patients are advised to avoid cosmetic products, sun exposure, wearing tight-fitting clothing, and extreme heat or cold (Hegedus et al. 2017).These advices do prevent the condition of radiation dermatitis from deterioration clinically, but the damaged tissues still need to recover without any support.
Various methods can be used for prevention and management of radiation dermatitis.Among these methods, using dressing on irradiated skin can maintain a moist environment and promote healing and re-epithelialization of the wound (McQuestion 2011).In addition, different therapeutic ingredients can be added onto the dressing, which can further promote wound healing and ease the uncomfortability.
Addressing the challenges in treating radiation dermatitis, our team has developed CSMed ® wound dressing.This innovative dressing, composed of bio-cellulose, herbal extracts, and γ-PGA, offers notable anti-inflammatory and wound healing properties.In this study, we evaluate its efficacy in treating patients with breast or head-and-neck cancer, aiming to provide clinical evidence for its effectiveness and insights for potential future improvements.

Methods
Patients arranged to receive radiation therapy between August 2020 and December 2020 were recruited for this study.The inclusion criteria were (1) patient were diagnosed with breast cancer or head-and-neck cancer; (2) patients aged between 20 and 70; and (3) patients underwent radiation therapy.The exclusion criteria were (1) patients had dermatitis or burns which is not induced by radiation therapy; (2) patients whom did not apply CSMed ® dressing for 2 consecutive days, necessary to ensure consistent treatment efficacy; (3) patients whom cannot complete the whole treatment and follow-up procedures; and (4) patient who are allergic to the ingratiation of the CSMed ® dressing.A written informed consent with respect to the use of topical agents and clinical data management for research purposes was obtained from all participants.This trial was designed and conducted in accordance with the principles outlined in the Declaration of Helsinki and within the guidelines of Good Clinical Practices (trial registration numbers: NCT06001463, August 23, 2023).This trial was approved by the Institutional Review Board of the Chung Shan Medical University Hospital (212250-017-F-001).

Study design
The size and position of breast or head-and-neck cancer were stimulated and target contoured via computed tomography.The physicians determined the dosage and treatment time in intervals rather than a single generic dose based on the results.Radiologists conducted the radiation therapy followed a fractionation regimen and patients received weekly irradiation for 4-8 weeks in treatment and were followed-up for another 4 weeks.The radiation dosage was recorded and the irradiated area was labeled.An irradiated area of 11 cm*14 cm with best fit or easy accessibility was chosen for CSMed ® wound dressing application, suited to typical radiation areas in head and neck and breast cancer treatments.The area without dressing was treated with routine skin care in each patient.This routine care involved daily cleansing of the skin with warm water, along with instructions for patients to avoid other dressings, cosmetic products, direct sun exposure, tightfitting clothing, and exposure to extreme temperatures.The CSMed ® dressing application started from the first day of treatment and till the day of the first follow-up.The dressing was renewed daily.The patients were also asked to avoid other dressing, cosmetic products, sun exposure, wearing tight-fitting clothing, and extreme heat or cold.The skin condition between dressed and undressed area were compared for each patient.

Composition and properties of CSMed®
CSMed ® wound dressing is made from bio-cellulose membrane and herbal extracts of Aloe vera, Centella asiatica, and Abelmoschus esculentus.Purified γ-PGA is also included in the ingredients.Thus, CSMed ® wound dressing has the ability of anti-inflammation, antioxidation, angiogenesis, and wound healing.

Patient evaluation
The severity of acute radiation dermatitis was graded using the radiation therapy oncology group (RTOG) clinical grading standard.Grade 0 indicates no visible change to the skin.Grade 1, characterized by faint erythema or dry desquamation, was assigned a score of 1 in this study.Grade 2a includes bright erythema or dry desquamation, along with sore, itchy, and tight skin, and was assigned a score of 2. Grade 2b, featuring patchy moist desquamation, yellow/pale green exudate, soreness, and oedema, was assigned a score of 3. Grade 3, which involves moist desquamation other than in skin folds and creases, was assigned a score of 4. Finally, Grade 4, characterized by skin necrosis or ulceration of full thickness dermis, was assigned a score of 5.The RTOG scores were assessed weekly by radiation oncologists.For a detailed view of this scoring system, please refer to Supplemental Table 1.

Statistical analysis
Categorical data are presented as n (%) and performed Fisher's exact test.Continuous data are presented as the median (range) and analyzed by the Wilcoxon signed rank test.Furthermore, we assessed the association of patients' characteristics with RTOG level using generalized estimating equations (GEE) with a first-order auto-regression covariance matrix.Data management and statistical analyses were conducted using SAS version 9.4 software (SAS Institute, Inc.).

Results
A total of 30 patients were included in this study, and 20 patients were diagnosed with breast cancer and the other 10 patients were diagnosed with head-and-neck cancer.Table 1 shows the demographic characteristics of the patients.All of the breast cancer patients were women (n = 20), and all but one head-and-neck cancer patients were male (n = 9).Most of the patients with head-and-neck cancer live with their spouses.
The comparison of the score converted from RTOG grade in skin with dressed and undressed area during the treatment period and the follow-up period are shown in Table 2.At the beginning of the treatment period, there was no difference in RTOG grade due to all patients have a zero score.The score converted from RTOG grade in skin with dressing was significantly lower than undressed skin at 3-7 weeks and the final record (all p < 0.05) during the treatment periods.During the follow-up periods, similar results were found at 1-3 weeks (all p < 0.001).For all patients, the median cumulative RT dose was 60.4 Gy (range 55-70.4Gy) and the median cumulative RT frequency was 28.5 times (range 25-35 times) during the treatment periods.
The subgroup analyses by cancer types are shown in Table 3.For breast cancer patients, the score converted from RTOG grade in skin with dressing was significantly lower than undressed area at 3-6 weeks and the final record (all p < 0.05) during the treatment periods.For head-and-neck cancer patients, the score converted from RTOG grade in skin with dressing was significantly lower than undressing at 4-7 weeks (all p < 0.05).For the two types of cancer patients, similar results were found at 1-3 weeks (all p < 0.05) during the following periods.
We further analyzed the relationship between patients' characteristics and the risk of RTOG level (Table 4).The score greater than 0 was defined as a worst event.GEE analysis revealed that patients in week 4 and week 5 had significantly higher odds ratio (OR) (6.12-or 29.47-fold, respectively) for worse events than in week 3. Compared with undressing, skin with dressing significantly reduced the OR for the worse event (OR = 0.20, 95% CI 0.15-0.27).
Further multivariate analysis revealed that the skin with dressing still significantly reduced the OR for the worse event (OR = 0.07, 95% CI 0.03-0.18).

Discussion
In this prospective study, CSMed ® wound dressing had proved to be an excellent dressing for radiation dermatitis treatment.Our results indicated that CSMed ® delayed the onset of radiation dermatitis for more than 1 week and area covered with CSMed ® showed significant lower score than undressed area during weeks 3-7 of treatment.During the follow-up period, CSMed ® also led to significant lower RTOG grade and shorter healing time.In short, irradiated area covered with CSMed ® developed milder syndrome of radiation dermatitis and healed quicker than untreated area.
Compared with other studies which used double-blind or compared the effectiveness among different subject groups, this study was conducted and compared on the same patient.Since half of the radiated area was covered with CSMed ® dressing, and the other half was not dressed and treated with routine procedure, the difference of personal sensitivity and response against radiation or treatment were eliminated by this procedure.The therapeutic results can then be compared directly between dressed and undressed area.
The radiation dosage in the conventional breast cancer therapy is 45-50 Gy (Kim and Algan 2021) and the dosage can be increased to 60 Gy in standard dose fractionation regimen (Chakraborty and Chatterjee 2021).The dosage for intensity modulated radiation therapy of head-and-neck cancer is between 50 and 60 Gy (Murthy et al. 2017).In this study, the average radiation dosage for breast cancer and head-and-neck cancer were 54 Gy (ranged between 46.8 and 60) and 66 Gy (ranged between 60 and 70.4), respectively.Comparing these data, the dosage in this study was higher than others.This indicates that CSMed ® can have an outstanding effect in a high dosage regimen, and CSMed ® can surely have the same effect in a routine radiation therapy.
The supportive material of a dressing can be made by wool, cotton, collagen, cellulose and its derivatives, plastics, rubber, and composite materials (Chattopadhyay and Raines 2014;Sharma et al. 2014).Among those materials, several strains of K. xylinus produce extracellular cellulous forming a biofilm of varying thickness to serves as a protective barrier against drying, natural enemies and radiation (Portela et al. 2019).This bio-cellulous has advantages in purity, biocompatibility, biodegradability, non-toxicity, higher surface area, elasticity, resistance, and flexibility (Klemm et al. 2001;Rahman and Netravali 2016).And it has the capacity to retain moisture, absorb exudates from the injured tissue and accelerate granulation (Khalid et al. 2017;Li et al. 2015).Medical plants are used for treating diseases and wounds for thousands of years.Bioactive constituents in medicinal plants are responsible for the therapeutic activities, and these phytochemicals have unlimited potential for application (Asha and Thomas 2019).They can be taken orally directly.They can also be extracted and added onto dressings for wound healing and tissue regeneration.Aloe vera is a medicinal plant traditionally used in many countries for disease and skin lesion treatment (Hekmatpou et al. 2019;Shelton 1991).Aloe vera contains chemicals which can improve wound healing and cytokine production.Aloe vera can also inhibit inflammation, itching, and irritation (Bunyapraphatsara et al. 1996;Heck et al. 1981;Somboonwong et al. 2000).Centella asiatica is known for its nutritional and therapeutic properties (Arribas-López et al. 2022).Due to having antimicrobial, antioxidant, anti-inflammatory, neuroprotective, and wound healing properties (Prakash et al. 2017;Tan et al. 2021).It is used for the treatment of dermatoses and skin lesions by improving collagen synthesis (Brinkhaus et al. 2000;Maquart et al. 1999) and microcirculatory function (Cesarone et al. 2001;Incandela et al. 2001).Abelmoschus esculentus is an herbal medicine used to treat wound healing with antioxidant, antibacterial, and anti-inflammation properties (Nesa et al. 2014).This is due to the phenolic compounds like saponin, tannin, alkaloid, and flavonoid in the fruit (Sipahi et al. 2022).
Previous studies showed that ultra-high molecular weight poly-γ-Glutamic Acid (γ-PGA) successfully stimulated corneal wound healing by inducing an inflammatory effect, enhancing cell migration and cell proliferation (Bae et al. 2010).A wound healing study in rat showed γ-PGA also promoted production of transforming growth factor-beta (TGF-β), keratinocyte growth factor (KGF), and β-catenin, collagen cross-linking, angiogenesis, and re-epithelialization, and formation of hair follicles (Choi et al. 2015).
Despite the good results, there are several limitations in this study.First of all, the sample size was small.Only 30 patients were included in this study.Second, only breast cancer and head-and-neck cancer patients were included in the study.Radiation therapy can be conducted on other cancer patients, and radiation dermatitis may occur in other part of skin.In the future, we will recruit more patients and make sure the findings in this study remain valid.In addition, different treatment strategies may be applied to check the curative effect.For example, applying the dressing in an earlier stage of treatment, such as one week before radiation therapy.It is also reasonable to examine the effectiveness of this dressing on other cancer patients.

Conclusion
The effectiveness of CSMed ® wound dressing on reducing the severity and increasing the healing of radiation dermatitis in patients with breast cancer and head and neck cancer shows its potential in prophylactic application.

Table 3
Score converted from radiation therapy oncology group (RTOG) grade between dressing and undressing by cancers Data are presented as median (range) and performed by Wilcoxon signed rank test.Significant values are showing in bold

Table 4
Relationship between Score converted from radiation therapy oncology group (RTOG) grade and patient and cancer characteristics Performed by generalized estimating equation (GEE) with a first-order auto-regression covariance matrix.Significant values are showing in bold Adjusted for gender due to the biological importance of the variables in multivariate analysis