Introduction

Radiotherapy (RT) is an essential element in the treatment of cancer. Around 50–70% of cancer patients receive RT at some point of the course of their disease. Of these, almost 95% experience some form of skin lesion induced by radiation. Radiation Dermatitis (RD) refers to a group of skin changes that result from the combination of RT characteristics and intrinsic risk factors of the patients. RD can affect the patient’s quality of life during and after treatment. Consequently, the management of radiation-induced skin lesions is an important aspect of cancer treatment.1 Internationally, there is a great variety of topical treatments that are used to prevent and treat RD, often with little or no evidence base. For this reason, there is no standardized consensus on RD management [2–5].

Our guide for the management of RD in Mexico is based on input provided by Mexican physicians with experience in radiotherapy, whose criteria were gathered using the Delphi Method and based on published national and international evidence.

Radiation dermatitis is a group of skin lesions that appear after exposure of the skin to ionizing radiation [6]. Such changes depend on intrinsic and extrinsic factors [4, 14, 15]. There is an acute and a chronic form [7]. Up to 90% of patients having undergone RT have experienced any RD grade [2, 5, 9]. It is more frequent in patients that received RT of the breast and concurrent chemotherapy for cancer of the head and neck [9]. Late damage from radiation appears in up to 15% of cases [10]. For the RD assessment the scale recommended by different guidelines is that developed by the Radiation Therapy Oncology Group (RTOG) [4, 7, 14, 15].

The cutaneous damage is observed 10 to 14 days after the first fraction [11]. The seriousness of skin reactions can increase 7 to 10 days after ending RT. This period is known as the maximum adverse “peak”. Four to six weeks after RT, the skin should begin to heal with some pigmentation changes on the radiated area (Fig. 1).

Figure 1. Cycle of clinical manifestations of radiation dermatitis along with cellular replacement

Physicians frequently explain to their patients that the radiation will produce a “burn” to convey the understanding of RT’s effects on the skin. However, it must be made clear that this is not a burn (Tab. 1). As is known, the frequency and severity of RD can be predicted considering certain predisposing factors (Tab. 2, 3) [15].

The process of evaluating the skin

Integral care of the patient should begin with a general questionnaire (Supplementary File — Annex 2).

Predicting the severity of cutaneous lesions might be difficult due to variations of radiosensitivity of the skin and to a series of contributing factors (Supplementary File — Annex 3). Both intrinsic and extrinsic factors can significantly increase the seriousness of RD and delay the healing process. The Fitzpatrick Classification of phototype of the skin is used to estimate the minimum erythema dose (MED). It has been shown that the Fitzpatrick I–III skin types have a lower MED in comparison with types IV–VI [16].

Adequate evaluation of the skin is essential to guarantee proper timely management in order not to compromise the healing process [4].

The use of a tool to quantify the intensity of RD is recommended, the scale that is most frequently used to evaluate the degree of RD is the RTOG (Radio Therapy Oncology Group). (Tab. 4).

Management of radiation dermatitis

The objectives of the prevention, treatment and general recommendations of RD [4, 5] is listed in the Card with General Recommendations (Supplementary File — Annex 1).

Radiation oncologists usually avoid the use of topical agents immediately before radiation sessions to avoid the bolus effect. However, in a dosimetry and preclinical study, there was no difference on the surface of the radiated skin with or without a 1–2 mm thick layer of topical agents metallic or non-metallic, regardless of the energy or the incidence of the beam. On the other hand, it has been shown that when thick layers are applied, the superficial dose is increased [9].

Recommendations before and after radiotherapy:

Recommendations after radiotherapy:

Additional recommendations [4]:

Guide for the treatment of RD according to severity

Most of the previously listed measures are directed toward preventing lesions, limiting their severity and lessening the symptoms. Once RD has begun, treatment is indicated according to the severity of the situation while maintaining the recommendations for prevention (Tab. 4, Fig. 2) [18].

Figure 2. Process flow diagram for management of acute radiation dermatitis

Adequate hydration improves the barrier function of the skin, reduces pruritus, burning, stinging, and prevents infection secondary to scratching. In this way, skin reactions can be prevented and controlled before, during and after RT. Different moisturizing agents are classified as dermocosmetics and medical devices.

Dermocosmetics are non-pharmacological products used in personal hygiene, and in the cleaning, hydration, and photoprotection of the skin [19]. The catalog for the dermocosmetics can be found in the listed reference (Annex 4, 6–7) [20]. The main components of the dermocosmetics used in RD are:

A multinational study [22] was carried out on women who began RT for breast cancer to evaluate the combination of hygiene products. The goal was to demonstrate the tolerance of a dermocosmetics regimen specifically on the radiated area and its efficacy for reducing or retarding the intensity of acute RD. The results were measured for erythema, edema, dryness of skin, desquamation, and evaluation of the physical condition of the patient using an “index of benefit” to the patient, carried out at the beginning and at the end of treatment (± 2 weeks). In the study group, 36% of patients were non-habitual users of dermocosmetics while 57% were habitual users. Dermocosmetic care regimes were well tolerated on radiated skin and this group presented less severe RD than those patients who did not.

Medical device with hyaluronic acid for the management of radiation dermatitis

The medical device used in RD is a topical gel composed of the following [23]: hyaluronic acid, gluconolactone, poliacrilamide and xanthan gum (Annex 4). It is indicated in the treatments of symptoms of the skin such as: erythema, burning sensation, stinging and pruritus caused by RT or other causes. It acts by forming a protective barrier shield that reduces transepidermic water loss, increases hydration and promotes the healing process of the skin, including folds and wrinkles, with or without minor abrasions.

There are two studies supporting the action of the medical device with hyaluronic acid [23, 24]. Iacovelli et al. 2017 [23], a pilot study at the Referral Center for the Treatment and Management of Cancer, Milan, Italy, evaluated patients over the age of 18 with head and neck tumors with neck nodes inclusion who received > 50 Gy RT treatment. The patients were evaluated for cutaneous toxicity during treatment and up to 2 weeks after the treatment. All radiated subjects were instructed on the application of a layer of the medical device, twice daily on the radiated area, avoiding application 1 to 4 hours before the RT session, from the first day of treatment until 2 weeks after the treatment was completed. The treatment with the medical device reduced the rate of cutaneous toxicity up to 20% in RT treated patients. 2) Ingargiola et al. 2020 [24], in a unicenter-2 branch clinical setting, open labeling, randomized study, compared the medical device associated to a previous standard of care study vs a standard care only study, to prevent and treat acute RD in cancer of the head and neck, and breast cancer patients, undergoing RT. Patients were told to apply the medical device in the radiated area 3 times a day, beginning with the first day of RT and up to 2 weeks after completing the treatment or until grade 3 RD developed. On week 5, the percentage of breast cancer patients that had received the medical device that did not present with G2 RD was greater than the control group. Quality of life index measured with Skindex-16 was always greater in the patients using the medical device which delayed the time for developing RD.

Topical corticosteroids in RD

Topical corticosteroid [25] have been used for a long time in the prevention and treatment of RD due to their underlying anti-inflammatory physiopathology [18] immunosuppressive, antiproliferative and vasoconstrictive properties. Various cytokines and proteins are the target of this pharmacological group, with reduction of the production of IL-1, IL-2, IFN-TNF and inductive lipocortins that inhibit the release of phospholipase A2. The suppression of queratinocyte mitosis and the inhibition of the migration and proliferation of fibroblasts explain the antiproliferative effects. The application of steroids of low to medium potency in the field of treatment 1 or 2 times a day after each RT session was used to reduce the severity of acute RD and decrease symptoms, such as pruritus, irritation, burning and discomfort. Topical steroids used in RD [25]: hydrocortisone, ,ometasone, betamethasone, beclomethasone, methylprednisolone (Annex 7, 10).

Appropriate dressings/bandages for RD

For RD grades 2 and 3, treatment should be directed toward prevention of secondary infections and to cover these areas. The bandages are used to maintain a moist environment on de-epithelialized skin, allowing greater healing of the wounds [18]. Characteristics of the bandages [4, 27]:

Examples of bandages used in RD treatment:

Kedge [27] in a systematic review, included an analysis of 10 studies, analyzed the effectiveness and acceptability of the interventions on moist desquamation on patients treated with RT. The use of hydrogel and hydrocolloid bandages is well established for the healing of moist wounds, and it alleviates patients’ symptoms. However, there is mixed evidence on their effectiveness and more research is needed to issue more accurate recommendations.

Analgesics

If RD is causing pain or discomfort, the use of the pain scale of the World Health Organization (WHO) is to be used as the reference for adequate pain management [4, 27].

Antibiotics

If the affected skin becomes infected, it should be treated with topical or systemic antibiotics, according to the severity of the infection [26, 28]. Topical antibiotics should be avoided unless a swab of the wound has been made and the bacterial infection is confirmed [15, 21].

Nutritional supplements and vitamins

Zinc supplements used in conjunction with RT can postpone the development of mucositis and severe dermatitis in patients with cancer of the head and neck. There is evidence that suggests the use of zinc is useful in prevention of acute RD, but more information is required to support this recommendation [7]. Ascorbic acid (vitamin C) has a powerful antioxidant and free radical elimination properties but, in studies, no benefit has been able to be demonstrated. Pantothenic acid (vitamin B5) has a central role in metabolism and is essential for the integrity of normal skin. However, when compared to placebo, it didn’t demonstrate a protective effect against RD [5].

Surgical intervention

Advanced lesions (RTOG 4) should be managed as conservatively as possible before surgical debridement and reconstruction with skin grafts and myocutaneous flaps is considered [26].

Other therapeutic interventions

Beta-sitosterol, an herb-based formula with antibacterial, analgesic, and anti-inflammatory effects, in a clinical trial vs trolamine were not associated with relevant improvement of RD, although the incidence of severe pruritus and local pain was significantly reduced [5]. Oils: In a clinical trial of 94 patients with head and neck cancer that presented acute RD, the intensity of the symptoms was reduced with the application of olive oil. In a trial of 50 patients, a cream containing curcuma (turmeric) and sandalwood oil was able to prevent the appearance of cutaneous lesions [5]. Superoxide dismutase (SOD): the topical use of SOD once a day showed promising results but greater research to support the recommendation is required [7]. Silver sulfadiazine: in a randomized controlled study, cream at 1%, 3 times/day, 3 days a week was shown, for 5 weeks during RT and one week after, to reduce the severity of RD compared to general care of the skin only. But due to potential secondary effects, it is reserved optionally for patients with high risk of acute RD [26].

Referral and counter referral

Any patient that presents with high risk for developing RD should be referred to the dermatologist. Patients with RD grade 2 or greater should also be referred [7].

Nevertheless, due to the lack of dermatologists in the institutions where patients receive RT, it is necessary for the radiation oncologist to be qualified to prevent and treat the toxicity caused by radiation to the skin.

Materials and methods

A search of national and international evidence was carried out regarding the management and guidelines of RD and a synthesis was made. A consensus of 25 radiation oncology and dermatology management experts was gathered.

A questionnaire of twenty questions with two types of answers was constructed:

A threshold of 80% or higher was used to define consensus. If at any time in the survey a management strategy was selected by fewer than 10% of panelists, it was not included as an option.

An iterative process was structured at the beginning using the Delphi method for answering questions in several rounds by experts, so that answers become more specific. This did not continue because the opinion of the experts converged by 70% or more, in 11 of the 20 questions. In the questions relating to the change from dermocosmetics to medical device (6 questions), convergence did not reach 70% because not all participants had access to the medical devices in their institutions and due to the lack of published evidence. In the remaining three questions, two of them did not reach the stipulated convergence because there was no dermatology department in their institutions to refer the patients to. The last question, regarding RD grade 4, was divided between very infrequent (55%) and never (45%).

Results

The results of the questions are summarized in Table 5. More than 80% of the panel agreed with the statement that the use of dermocosmetics or the medical device can be recommended in the prevention of RD and in the treatment of RD grades 1 and 2. As for grade 3, they recommend individualizing each case and reaching an agreement with a dermatologist. Steroids should be used when there is burning or pain of the skin, a topical steroid should be applied. Given the availability and cost of the bandages in our country (Mexico), they consider the use of soaking elements (cold chamomile or oatmeal powder) to be a possible alternative. Care of the skin must be continued to avoid or reduce the severity of late skin lesions. Management algorithm was proposed (Fig. 2).

Discussion

Faced with the inability to avoid RD, all the members agree that care of the skin should be included in the education of the RT patient and as a preventive recommendation to reduce the severity of RD. This strategy is also recommended by the Society and College of Radiographers (SCoR) [4, 14. 15].

In the SCoR, emphasis is placed on standardized dermatologic evaluation [14] before and during RT, for identifying risk factors for developing more severe RD. The panel did not reach a consensus because most of the institutions did not have a dermatology department where they could seek support. Additionally, the panelists postulate that the radiation oncologist should be prepared to treat all toxicities related to the use of RT and, in the case of RD grade 3, the panelists considered recommending evaluation by the dermatologist. Also, unfortunately in Mexico we need to empower nurses to be part of RD treatment.

Almost all the participants in the panel agreed on the topical use of moisturizing and hydrating creams and other products from the start of RT, as is mentioned in the SCoR guide14. Care should be maintained for life due to the risk of developing chronic RD, especially in patients that received systemic treatment along with RT.

In RD grade 1 and 2, the application of the indicated hydrating product with greater frequency is recommended, but not the systematic use of topical steroids, only to lessen symptoms such as itching or pain. This is in accordance with the SCoR guide, and they should not be applied on areas of moist desquamation [14].

In agreement with SCoR [14], for the management of RD grade 3, the panel recommendation is the use of pharmacological products with drying effects. The panelists did not reach consensus for recommending a change to the medical device due to the scarcity of published evidence [23, 24] on its efficacy and on its availability.

Based on the above, we consider that a single round of questions was sufficient to establish a consensus of experts for the management of RD in our country. However, we are conscious of the lack of procedural manuals and registry of the frequency, severity, and management of this adverse event in our institutions, so we propose a flow chart (Fig. 2) to standardize attention of RD on a national level.

It is needed to consider new approaches in RD treatment. The use of Photobiomodulation therapy (PBMT) is an emerging intervention to reduce RD, although further research is needed on long-term effects of the use of PBMT as a prophylactic intervention before it could be recommended [29, 30]. Different barrier films/dressings such as Mepitel film, StrataXRT, Cavilon No Sting Barrier Film [31–34] should be considered in the future, when they have approval in our country.

Also, we need to consider continuous evolution in RD management based on different radiation techniques (IMRT, APBI) and different schedules (hypofractionation or extreme hypofractionation) in breast cancer, for example, with no difference in RD incidence [35–39].

Conclusions

This consensus was developed as a supportive educational tool that can be adapted to individual clinical needs and institutional context. We hope that it will be useful for professionals involved in RT treatment of patients.

The consensus of the specialists is that dermocosmetics or the medical device can be recommended in the prevention of RD and in the treatment of RD grades 1 and 2. As for grade 3, they recommend individualizing each case and designing each treatment together with a dermatologist.

The steroids should be used taking the symptoms of the patients into account. When there is itching or pain of the skin, a topical steroid should be applied.

Given the availability and cost of bandages in our country (Mexico), the panel considers a possible alternative of using soaking elements (cold chamomile or oatmeal powder).

Care of the skin must be continued to avoid or reduce the severity of late skin lesions.

Acknowledgements

This study was presented as an poster on ASTRO 2021 SOMERA, Galapharma.

References