Preliminary Experience with a Cleansing Mousse and a Non-Steroidal Emulsion for the Prevention and Treatment of Acute Radiation Dermatitis in Breast Cancer Patients Undergoing Adjuvant Radiotherapy

: Background: Radiation dermatitis (RD) is the most frequent side effect in patients undergoing adjuvant radiotherapy (RT) for breast cancer. Despite the skin-sparing benefits of new RT techniques, most patients develop RD. There is currently no standard treatment to prevent and soothe RD, which is generally managed with emollients, moisturizers, or corticosteroids. We conducted a prospective observational study to evaluate the rate and grade of RD with the application of a cleansing mousse and a non-steroidal emulsion during the adjuvant RT program in patients with breast cancer submitted to surgery. Materials and Methods: A cleansing mousse containing vegetable glycerin (12%), phytoextract of chamomile (0.5%), yarrow phytoextract (0.5%), sweet almond (0.1%), Oenothera oil (0.1%), and rice protein hydrolyzate (0.1%), and an emulsion containing micronized zinc oxide (3.7%), rapeseed phytosterols (1.7%), aloe (0.5%), 18-beta glycyrrhetinic acid (0.5%), alpha bisabolol (0.5%), and zanthalene (0.5%) were offered to breast cancer patients undergoing adjuvant RT to prevent the onset of RD and mitigate its severity. These specific ingredients were selected for their well-known anti-inflammatory, antioxidant, and moisturizing properties. Skin toxicities were recorded photographically and graded according to the RTOG scoring system. Results: From March 2023 to July 2023, a total of 24 patients with a median age of 59 years (range 42–75) were enrolled.


Introduction
Adjuvant radiotherapy (RT) represents a cornerstone in the treatment path of women undergoing conservative surgery for early breast cancer (BC), having definitively supplanted demolitive mastectomy procedures in the management of small tumors [1].RT could be omitted only under particular conditions carrying a very low risk of ipsilateral recurrence and cancer-specific death [2].On the other hand, its administration is warranted even in some post-mastectomy cases depending on unfavorable tumor characteristics [3].
RT to the breast or chest wall is generally well-tolerated, with the risk for late cardiac events being the most feared and attempted to be reduced when treating left-sided BC patients [4,5].Indeed, radiation dermatitis (RD) is the most common side effect of breast RT.The underlying mechanisms likely responsible for the onset of acute damage are not entirely known.Several hypotheses have been proposed, with the most relevant suggesting that ionizing radiation stimulates cells such as fibroblasts, endothelial cells, and circulating immune cells.In response, these cells release cytokines and chemokines, including IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) [6].This release occurs within a few hours of radiation exposure.In the following weeks, the hallmark of radiation-induced damage will be represented by the leukocyte infiltration in the irradiated skin [7].
Despite the skin-sparing effect related to the build-up depth of high-energy photon beams, approximately 50-60% of the prescribed dose is still deposited in the skin [8].As such, approximately 90% of irradiated patients with breast cancer develop moderate to severe RD [9].
Clinically, the first reactive changes, mainly dryness, warmth, and mild erythema, may appear towards the middle of the treatment schedule and progress to moist desquamation and oedema in the following weeks.Additionally, patients may complain of burning, itching, and pain.These events are generally self-limiting and skin integrity is restored within a few weeks after the end of RT.If not, a few patients may develop serious toxicities, such as ulcers or skin necrosis.Most cases recover completely from the acute phase with no or negligible alterations.When this does not happen, a condition of chronic dermatitis can persist indefinitely, even for months or years, showing more fibrotic, drier skin, with telangiectasias and hypo-or hyperpigmentation [10].
From this perspective, although non-life-threatening unlike radiation pneumonitis and ischemic cardiac events, RD emerges, at least, as an injury that can alter women's quality of life and treatment compliance [14].Regarding the latter, in case of severe toxicity, it may even be necessary to discontinue the treatment to manage the toxicity and allow for recovery [15].It is noteworthy to underline that any prolongation of overall treatment time due to unplanned interruptions following difficult-to-manage acute toxicity during RT may have a negative impact on prognosis [16].
Hence the need to effectively prevent and treat such a side effect.To this purpose, a wide variety of topical products exists, including emollients, moisturizers, and corticosteroids.Although several systematic reviews of the literature have attempted to clarify the benefits of one product over another [17,18], none of these preparations has proven to prevail over the others in terms of effectiveness and their choice is mainly based on patient preference and physician experience [19].Nonetheless, RD is still an active field of research due to its frequency and impact on patients' lives and natural products are gaining more and more attention, being perceived as better tolerated than drugs [20].
Here we present a single-center prospective observational study on the use of a gentle cleansing soap and an emulsion for the prevention and alleviation of acute RD among BC patients undergoing adjuvant RT, with the aim of serving as a pilot experience eventually stimulating a comparison with other available topical agents.

Materials and Methods
From March 2023 to July 2023 women who underwent breast-conserving surgery or mastectomy for non-metastatic breast cancer and required adjuvant RT were offered enrollment in a prospective, observational, single-arm study testing the combination of two non-corticosteroid topicals for the prevention and alleviation of acute RD.Inclusion criteria were: age between 18 and 80 years old, Karnofsky performance status (KPS) ≥80, histopathological diagnosis of breast cancer, need for RT following conservative surgery or mastectomy.Exclusion criteria were: state of pregnancy, suffering from psychiatric disorders or cognitive deficits, or skin diseases (e.g., psoriasis, pemphigus, current sunburn, etc.), skin involvement by cancer (pT4), known hypersensitivity to one of the components of the medications tested, history of RT for previous thoracic malignancies (e.g., lymphoma, etc.).Patients with relapsed BC were eligible for inclusion provided they did not receive any RT at first diagnosis.

Radiotherapy
A free-breathing computed tomography (CT) simulation with 3 mm thick slices was performed for each patient to plan RT delivery.An additional deep-inspiration breathhold CT scan was acquired only for left-sided breast cancer patients to identify those benefitting most from respiratory gating for cardiac radiation dose reduction, as per our center's policy [21].The target volume delineation on the CT simulation was conducted according to the ESTRO consensus guideline, i.e., cropping the clinical target volume for the residual breast tissue or chest wall (CTV_T) by 5 mm from the body surface.The CTV could also be extended to regional nodal basins (CTV_N) based on the cancer staging and risk of their involvement [22].Forward treatment planning based on two opposite tangential fields (3D conformal radiation therapy, 3D-CRT) and field-in-field technique (where necessary to improve dose coverage) was used.Two dose prescriptions were allowed: normofractionation (NF) using 50 Gy in 25 fractions over 5 weeks (NF schedule) or hypofractionation (HF) delivering 40.05 Gy in 15 fractions over 3 weeks (HF schedule).A boost to the tumor bed could be planned in three (9 Gy in 3 days) or five fractions (10 Gy in 5 days).
The photon beam energy was 6 MV for the CTV_T and, alternatively, 10 or 15 MV for the CTV_N and boost.No bolus was applied.To verify patient setup, the electronic portal imaging device (EPID) was used once a week for right CTVs and daily for left ones.

Skin Care
The recruited patients were supported by a gentle cleansing mousse and a noncorticosteroid emulsion for the prevention of acute RD.
Neither cosmetic contained alcohol or perfume.Patients were given instructions on how to apply the cleansing mousse and emulsion both orally and in writing.The emulsion was applied by the patients themselves on the irradiated skin area twice a day, 4 h before or immediately after RT and in the evening.Patients were required to use the cleansing mousse for daily personal cleansing of the irradiated skin area.The application of the emulsion and cleansing with mousse were started at the beginning of the RT schedule.Patients used the emulsion and cleansing mousse seven days a week during RT and continued the application for another 15 days after its completion or until the resolution of any skin manifestations.Patients were interviewed regularly during the observation period to ensure continued adherence to skin care instructions.They were also asked not to apply other topicals.

Aim of the Study and Toxicity Assessment
The study aimed to record the rate and grade of RD with the application of the two cosmetics described above among BC women treated with adjuvant RT.Skin toxicity was graded according to the radiation therapy oncology group (RTOG) scale [37] (Table 1) and photographically recorded at the first, mid-treatment, last day of RT program, and 15 and 30 days after its end.We investigated whether the grade of RD correlated with CTV size, type of surgery (conservative vs. mastectomy), boost delivery (yes vs. no), and dose fractionation (NF vs. HF).The flow-chart for the investigation methods is provided in Figure 1.

Statistical Analysis
Correlation analysis between the five longitudinal toxicity assessments and CTV_T, RT target, dose fractionation, and boost delivery, as well as the longitudinal skin toxicity plot, were conducted using R [38] and RStudio [39].Additional packages used for the

Statistical Analysis
Correlation analysis between the five longitudinal toxicity assessments and CTV_T, RT target, dose fractionation, and boost delivery, as well as the longitudinal skin toxicity plot, were conducted using R [38] and RStudio [39].Additional packages used for the analysis were heatmaply [40] and ggplot2 [41].Evaluation of the relationship between continuous and categorical variables was performed using Kendall's rank correlation, whereas the categorical variables were evaluated using Fisher's Exact Test.The significance level to reject the null hypothesis was set at 5%.

Results
Twenty-four patients, aged between 42 and 75 years (median age 59 years), who underwent adjuvant radiotherapy (RT) at REM Radioterapia srl in Viagrande (Catania) participated in the study.Twenty-one and three patients had undergone breast-conserving surgery and mastectomy, respectively.Twelve patients were irradiated to the right side and 12 to the left side.The NF scheme was used for 18 patients, while six were treated with the HF scheme.Boost was delivered in 18 patients (10 Gy/5 fractions in 15 patients and 9 Gy/3 fractions in the remaining three).Six women were also irradiated to the CTV_N, including four on the left side.Median CTV_T size was 541 cc (IQR 406.1-763.5).Patient and treatment characteristics are summarized in Table 2.All treatment plans met the prespecified dosimetric requirements.Halfway through the radiotherapy program, 20 patients (83.3%) had G0 skin toxicity, three (12.5%)G1, one (4.2%)G2.None of the patients had G3-G4 toxicity.
All toxicities resolved at the last assessment 30 days after the end of RT.The evolution of skin toxicities over time in all patients is represented in Figure 2. Figures 3 and 4 represent, respectively, a G1 RD and the only G3 toxicity reported by us.
No patient discontinued either the skin care program due to dissatisfaction with the tested products or RT due to skin toxicity.
The correlation analysis in Table 3 shows a small and statistically significant correlation between CTV_T and skin toxicity at timepoint T3 (after 15 days from the end of RT), T = 0.36, p-value = 0.03.All other toxicity assessments at different timepoints are not correlated with CTV_T.Furthermore, no relationships were found between the toxicity grade observed at each of the five timepoints and RT target (residual breast tissue versus chest wall), dose fractionation (NF versus HF), and boost delivery (yes or no), as shown in Table 3. Halfway through the radiotherapy program, 20 patients (83.3%) had G0 skin toxicity, three (12.5%)G1, one (4.2%)G2.None of the patients had G3-G4 toxicity.
All toxicities resolved at the last assessment 30 days after the end of RT.The evolution of skin toxicities over time in all patients is represented in Figure 2. Figures 3 and 4    Halfway through the radiotherapy program, 20 patients (83.3%) had G0 skin toxicity, three (12.5%)G1, one (4.2%)G2.None of the patients had G3-G4 toxicity.
All toxicities resolved at the last assessment 30 days after the end of RT.The evolution of skin toxicities over time in all patients is represented in Figure 2. Figures 3 and 4      No patient discontinued either the skin care program due to dissatisfaction with the tested products or RT due to skin toxicity.
The correlation analysis in Table 3 shows a small and statistically significant correlation between CTV_T and skin toxicity at timepoint T3 (after 15 days from the end of RT), T = 0.36, p-value = 0.03.All other toxicity assessments at different timepoints are not correlated with CTV_T.Furthermore, no relationships were found between the toxicity grade observed at each of the five timepoints and RT target (residual breast tissue versus chest wall), dose fractionation (NF versus HF), and boost delivery (yes or no), as shown in Table 3.
No unexpected events were recorded.

Discussion
The cosmetics tested in our study were found to be safe and satisfactory in the prevention and treatment of RD among women undergoing adjuvant RT for BC.Nearly 30% of patients did not develop signs of RD and only 12.5% had a G2-G3 exudative dermatitis with moderate oedema at the end of treatment, with no G4 toxicity recorded.Moreover, no toxicity during treatment was severe enough to threaten patient compliance with the RT program.Once RT was completed, skin integrity was rapidly restored over the following 15 days, still supported by the two cosmetics, scoring G0-G1 toxicity in 95.3% of patients.No patient showed unexpected skin reactions or complained about any aspect of the suggested topical treatment (e.g., frequency of administration, smell, consistency, stickiness, and greasiness of the two cosmetics, etc.).Overall, these findings promote our preliminary experience as worthy of further research.Indeed, RD is still an extremely common side effect of adjuvant RT among patients with BC, although several therapeutic options are available for its prevention [42].The natural compounds we tested have the advantage over topical corticosteroids of generating fewer concerns regarding possible late cutaneous effects, such as skin atrophy, telan-  No unexpected events were recorded.

Discussion
The cosmetics tested in our study were found to be safe and satisfactory in the prevention and treatment of RD among women undergoing adjuvant RT for BC.Nearly 30% of patients did not develop signs of RD and only 12.5% had a G2-G3 exudative dermatitis with moderate oedema at the end of treatment, with no G4 toxicity recorded.Moreover, no toxicity during treatment was severe enough to threaten patient compliance with the RT program.Once RT was completed, skin integrity was rapidly restored over the following 15 days, still supported by the two cosmetics, scoring G0-G1 toxicity in 95.3% of patients.No patient showed unexpected skin reactions or complained about any aspect of the suggested topical treatment (e.g., frequency of administration, smell, consistency, stickiness, and greasiness of the two cosmetics, etc.).Overall, these findings promote our preliminary experience as worthy of further research.Indeed, RD is still an extremely common side effect of adjuvant RT among patients with BC, although several therapeutic options are available for its prevention [42].The natural compounds we tested have the advantage over topical corticosteroids of generating fewer concerns regarding possible late cutaneous effects, such as skin atrophy, telangiectasias, or striae [43].Few studies are specifically dedicated to investigating this possible causeand-effect relationship and are unable to produce conclusive evidence on the safety of corticosteroids due to small sample sizes [44].
Both the mousse and the emulsion contain a mix of molecules with a soothing, hydrating, anti-inflammatory, and anti-itch action, which replaced the need for real drugs.Our results join those obtained with other non-steroidal topical medications, among which hyaluronic acid stands out for its effectiveness also in other tissues damaged by radiation [45][46][47][48].
There is more and more attention towards the local side effects caused by breast RT due to the growing request from patients to preserve their physical appearance as much as possible [49].
In our study we noticed how good hydration and gentle cleansing of the irradiated area before, during, and after RT had a positive effect on the skin's tolerability to radiation.
In our clinical practice, we usually prescribe moisturizing creams to all patients with an indication for breast RT based on the experience that preventive therapy for skin side effects is more effective than treating them once they have occurred.This approach shows significant efficacy in reducing the onset of acute skin toxicity [50].
Acute RD can also affect both the quality of life and normal daily activities of patients [51], and, in some cases, can lead to unplanned treatment interruptions, thereby reducing the overall effectiveness of the therapy [16].
Apart from thorough cleansing of the skin and prevention of local trauma, there is no well-defined protocol to prevent radiation toxicity of the [52].
From the literature data, we know that there are some risk factors including the use of the bolus, smoking, and previous chemotherapy causing alteration of the small blood vessels [53].
The first pathophysiological stage of RD is determined by an overproduction of free radicals, responsible for damaging the stem cells in the basal layer of the epidermis, resulting in diminished turnover of epidermal cells.These cells, prompted into a state of senescence by ionizing radiation, subsequently release pro-inflammatory cytokines, responsible for initiating the inflammatory cascade.As a consequence of these effects, early RD may be observed clinically.The pathophysiology of moist desquamation involves the loss of keratinized layers and depletion of basal cell population as well.The erythema is the result of epidermal damage to basal cells and dilation of capillaries associated with increased vascular permeability [54].
These effects of radiation on the skin are influenced by several treatment factors, including, besides the total radiation dose, other dosimetric parameters (evaluable on dosevolume histograms), the dose fractionation (normofractionation vs. hypofractionation), the RT technique (3D-CRT vs. intensity-modulated RT, IMRT), and the use of an imageguided protocol for daily setup verification (IGRT).Keenan et al. provided some dosevolume constraints significantly associated with the onset of acute RD, suggesting in particular to minimize the skin volume exceeding 105% of the prescribed dose [24].The rate of grade 2 or higher acute RD is also reduced by using hypofractionation rather than normofractionation [55].Compared with 3D-CRT, IMRT decreases the risk of RD by improving dose homogeneity [56].Furthermore, this reduction is greater the more complex the inverse treatment planning technique is [57].Lastly, just as with other body targets [58], a daily setup verification by cone beam CT (CBCT) is more accurate than that by EPID and results in a significantly lower rate of acute RD, likely thanks to the more precise radiation delivery that avoids the generation of unplanned hotspots [59].Large breast size is another known risk factor for skin toxicity [56].However, our cohort showed no or mild skin toxicity in most cases, regardless of breast size, type of surgery (conservative vs. mastectomy), boost delivery (yes vs. no), and dose fractionation (normofractionation vs. hypofractionation).Although the level of toxicity achieved was mild for most patients, this was sufficient to draw a positive correlation (Table 3) between breast size and skin toxicity 15 days after the end of RT (T = 0.36, p-value = 0.03) highlighting a higher risk of toxicity resulting from increased breast size, according to what Freedman et al. observed [56].Noteworthy for the same skin toxicity timepoint (T3) is the relationship with the RT target (p-value = 0.06) which is not statistically significant, probably due to the smaller size of the patients undergoing mastectomy, but which sheds light on a possible greater risk of skin toxicity for patients treated with mastectomy.No other relationship was found between the variables of interest in the study cohort; a larger and more diverse sample is mandatory to draw strong conclusions.
As regards our choice of using 3D-CRT, it should be noted that, compared to conventional tangential field irradiation, IMRT increases the integral dose to normal tissues and its potential advantage in reducing skin toxicity should be weighed against a possibly increased risk of more dreaded consequences, such as pneumonitis and secondary malig-nancies due to a worse exposure of OARs to low radiation doses [60][61][62].Accordingly, the American Society for Radiation Oncology (ASTRO) does not recommend routine use of IMRT to deliver breast RT [63].
Finally, CBCT-guided IGRT protocols, although effective in reducing skin toxicity, are time-consuming and may hinder the demands of managing high patient loads in RT departments [64].
Radiation dermatitis is still a dynamic area of research, where also the achievements from nanotechnology warrant attention.Indeed, nanocarrier-based dermopharmaceutical formulations penetrate deeper than traditional topicals, potentially resulting in improved efficacy.However, further studies are needed to establish safety and evaluate cost-benefit ratios [65].
This preliminary experience has several limitations.First, the heterogeneity (i.e., for dose fractionation, type of surgery, etc.) and small size of the cohort are underpowered to find any varying effectiveness across different subgroups.Second, the lack of a placebo control group, omitted for ethical reasons in a clinical context of exceptionally frequent skin side effects, prevents quantifying the extent of the benefit deriving from the use of the two cosmetics being tested.In this regard, our pilot study should be understood as a phase I/II trial that can transition to more mature research, hopefully involving the other topical medications available for comparison.
represent, respectively, a G1 RD and the only G3 toxicity reported by us.

Figure 2 .
Figure 2. Evolution of skin toxicities over time in all patients.Here T0, T1, T2, T3, and T4 represent, respectively, the toxicity levels at RT start, half RT completed, end of RT, 15 and 30 days after RT completion.

Figure 2 .
Figure 2. Evolution of skin toxicities over time in all patients.Here T0, T1, T2, T3, and T4 represent, respectively, the toxicity levels at RT start, half RT completed, end of RT, 15 and 30 days after RT completion.
represent, respectively, a G1 RD and the only G3 toxicity reported by us.

Figure 2 .
Figure 2. Evolution of skin toxicities over time in all patients.Here T0, T1, T2, T3, and T4 represent, respectively, the toxicity levels at RT start, half RT completed, end of RT, 15 and 30 days after RT completion.

Figure 3 .
Figure 3. Appearance of the skin breast before (A), on the last day of RT (B), and 15 days after its completion (C) in a patient who experienced G1 RD.

Figure 3 .
Figure 3. Appearance of the skin breast before (A), on the last day of RT (B), and 15 days after its completion (C) in a patient who experienced G1 RD.

Figure 4 .
Figure 4. Appearance of the skin breast before (A), on the last day of RT (B), and 15 days after its completion (C) in the patient who experienced G3 RD.

Figure 4 .
Figure 4. Appearance of the skin breast before (A), on the last day of RT (B), and 15 days after its completion (C) in the patient who experienced G3 RD.

Table 1 .
RTOG score and corresponding skin changes.

Table 2 .
Patient and treatment characteristics.