Canadian Skin Management in Oncology Group (Casmo) Algorithm for the Prevention and Management of Acute Radiation Dermatitis

Tarek Hijal, MD, FRCPC¹, Maxwell B Sauder, MD, FRCPC², Anneke Andriessen, PhD³, Joel Claveau, MD, FRCPC⁴, Charles W Lynde, MD, FRCPC⁵

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Acknowledgments and Disclosure: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada.

All authors contributed to the development of this work and its review and agreed with its content.

Introduction

Up to one out of two Canadians will develop cancer in their lifetime.¹ It has been estimated that 225,800 Canadians were diagnosed with cancer in 2021.¹

Approximately 30-40% of cancer patients receive radiotherapy.² A study in Ontario on breast, colorectal, lung, and prostate cancer showed that in the year following the cancer diagnosis, 96,003 patients received radiation therapy.²

Radiotherapy damages cancerous cells’ by directly or indirectly damaging their DNA via ionization and free-radical formation.^3-5 Radiation-induced cutaneous AEs occur in up to 95% of cancer patients who will develop some form of radiodermatitis (RD).^3-5 Of those with breast cancer, 87% develop RD, and concurrent anti-cancer therapies may aggravate RD in 90% of head and neck patients.^4,5

RD affects the area that received irradiation, and the severity depends on the area treated, beam energy, total dose, dose per fraction, treatment schedule, and use of concomitant systemic agents. RD varies considerably in severity, course, and prognosis and can have severe sequelae that impact the quality of life (QoL) and potentially alter cancer treatment course and outcomes.^3-7

Radiation treatment’s impact on QoL may be profound. A prospective study conducted from July 2017 to June 2018 using the Skindex-16 pre-and post-treatment included eighty-three cancer patients [breast cancer (49%), head and neck cancer (45%), and anal canal cancer (6%)] receiving radiation treatment.⁷ All patients developed RD [Grade 1 – 59%, Grade 2 – 33%, and Grade 3 – 8%].⁷ The median composite Skindex-16 pre-treatment was 0, and post-treatment 34, demonstrating a marked negative impact on QoL.⁷

RD is categorized as acute, occurring within 1 to 4 weeks of treatment, or chronic, manifesting beyond four weeks to years after treatment.⁴

Strategies to prevent or mitigate RD are aimed at ensuring an optimal skin condition starting before the treatment. Skincare aims to improve comfort during radiotherapy, reducing inflammation and promoting healing of skin areas affected by RD.^8-12 Patients should be educated on a daily skincare regime focusing on: hygiene, moisturization, and sun avoidance and protection measures.^8-13

The Canadian Skin Management in Oncology Group (CaSMO) developed an algorithm for the reduction of severity and management of acute RD, which follows previous publications from this group that addressed general oncology-treatment related cutaneous adverse events [AEs], prevention, and skin management.^8,13

Scope

The CaSMO project initiated by La-Roche Posay Canada aims to improve cancer patients’ and survivors’ quality of life by offering tools for preventing and managing cancer-treatment-related cutaneous AEs.

The CaSMO panel of clinicians who treat cancer patients with radiation treatment-related cutaneous AEs developed, discussed, and reached a consensus on an evidence-based algorithm supporting prevention, treatment, and maintenance using OTC skin care measures for acute RD. The algorithm focuses on skincare measures to prevent and treat RD using prevention measures and a skincare regime involving hygiene, moisturization, and sun protection measures and products. The algorithm aims to improve patient outcomes and determine the best approach for oncology skin care programs for all stakeholders in the Canadian health care setting. These include oncologists, family practice/internal medicine physicians, dermatologists, oncology nurses, advanced practice providers (APPs), nurse practitioners (NP), physician assistants and pharmacists.

Methods

In the algorithm’s development, the panel used a modified Delphi approach following the AGREE II instrument.^14,15 The modified Delphi method is a communication technique for interactive decision-making for medical projects.¹⁵ The used process was adapted from face-to-face meetings to a virtual meeting to discuss the outcome of literature searches and reach a consensus on the algorithm based on the selected literature.^15,16 The virtual discussion was followed by online follow-up replacing the use of a questionnaire.¹⁵ The process entailed preparing the project, selecting the panel, and conducting systematic literature searches followed by summarizing the literature search results, grading the literature, and drafting the algorithm. On January 23, 2021, a virtual panel meeting reviewed the systematic literature review results, discussed and adopted the algorithm using evidence coupled with the expert opinion and experience of the panel. The online process was to fine-tune the algorithm and to prepare and review the publication. (Figure 1)

The CaSMO working group’s consensus on the algorithm was established as a hundred percent agreement was obtained.

Literature Review

A literature review included guidelines, consensus papers, and publications describing current best-practice in radiation-treatment related to cutaneous AEs that benefit from topical treatment using OTC skincare, clinical, and other research studies in the English language from January 2010 to December 2020. Excluded were articles with no original data (unless a review was deemed relevant), articles not dealing with skincare for prevention and treatment of RD, and publication language other than English. A dermatologist and a physician/scientist conducted the searches on January 3 and 4, 2021, on PubMed and Google Scholar as a secondary source of the English-language literature, using the terms:

RD; skincare and topical regimes for prevention, treatment, and maintenance of RD; QoL of patients with RD; adjunctive skincare use; education of staff and patients; communication strategies; adherence; concordance; efficacy; safety; tolerability; skin irritation.

The results of the searches were evaluated independently by two reviewers, resolving discrepancies by discussion. The searches yielded one hundred and twenty-two publications. After excluding duplicates and articles deemed not relevant for the algorithm ([n = 52] other subjects, low quality, a small number, case studies), seventy papers remained. Twenty-five review articles (including one guideline, one algorithm and, eighteen systemic literature reviews), and forty-five were clinical studies (including eighteen randomized controlled trials, eighteen clinical evaluations, and cohort studies, four randomized trials, and five other).

Radiation Dermatitis, Prevention, and Treatment

The goal of radiation therapy is either curative or palliative.^3,4 It can be delivered in the neoadjuvant or adjuvant setting, or can be the main treatment, with or without combined systemic treatment.^3,4 The multidisciplinary team guiding the patient through the radiation treatment process comprises the radiation oncologist, the radiation oncology nurse, the radiation therapist, medical physicist, and dosimetrist.^3,4

Radiation therapy can be external [i.e. 3-D conformal radiation therapy, intensity-modulated radiation treatment, image-guided, Thomotherapy, and stereotactic radiosurgery] or internal, such as brachytherapy, radioisotope therapy, radioimmunotherapy, and radioembolization (Table 1).¹⁷ RD is defined as a cutaneous inflammatory reaction induced by exposure to biologically effective levels of ionizing radiation.¹⁷ The mechanisms associated with a radiation induced AE include an inflammatory response and oxidative stress, which interact and promote each other.¹⁸ Inflammatory markers involved in acute inflammation secondary to ionizing radiation including IL-1, IL-6, TNF-alpha and TGF-Beta, can be expressed within hours after receiving the first radiation treatment.¹⁸ Radiation treatment exhibits biological effects within hours to weeks of exposure, through irreversible breaks of the nuclear DNA strands that cause extensive genetic damage and inhibit cells’ ability to divide and replicate.^3,18 Further damage comprises structural tissue destruction, generation of reactive oxygen species, a decrease in functional stem cells, initiation of epidermal and dermal inflammation, and skin cell necrosis.^3,18 Radiation damage is complex, and a variety of factors influence its severity.

Table 1: External beam radiation therapy

RD is generally limited to the irradiated area and depends on several factors, including the target area, dose and fractionation schedule, patient’s condition, and the use of other concomitant cancer treatments (e.g. platinum-based regimens, cetuximab, 5-fluorouracil).^3,4-6,18-22

Intrinsic factors that influence the occurrence and severity of RD include demographic or patient-related characteristics.⁶ These include age, ethnic origin, skin type, smoking, obesity, breast size, hormonal status, presence of infection, and co-existing diseases, such as diabetes or cardiovascular disease.^6,17-22

Extrinsic factors include treatment-related characteristics such as technique, dose, volume, fractionation, beam energy, use of bolus, immobilization devices, and the use of combined systemic anti-cancer therapies. Further factors comprise the clinical site of treatment, e.g., areas with skin folds [head and neck, breast and axilla].^17-22

Certain drugs (e.g. platinum-based regimens, cetuximab, 5-fluorouracil) increase sensitivity to radiation treatment, causing increased cellular damage and delayed tissue repair.²² Conventional chemotherapy agents and cancer treatment with EGFR inhibitors increase the risk for severe RD (Box 1).^22,23

RD is categorized as acute, occurring within 1 to 4 weeks of radiation treatment, or chronic, manifesting beyond four weeks to years after treatment (Table 2).^3,4,6,18-23

Box 1: Contributing factors to radiodermatitis (RD)

Table 2: Acute and chronic radiation dermatitis²⁰

*Grades of Acute Dermatitis (CTCAE V5– common terminology criteria for adverse events (National Cancer Institute)¹⁹

Cutaneous effects of radiotherapy vary considerably in severity, course, and prognosis and can have severe sequelae that impact the quality of life and disrupt cancer treatment.^7,8 The two most prevalent grading systems of RD are the RTOG (Radiation Therapy Oncology Group) and CTCAE v5 (Common Terminology Criteria for Adverse Events) systems. The RTOG assessment tool classifies RD from 0 [no visible signs of RD] to 4 [ulceration, bleeding, necrosis].^20,21 For the present algorithm, the CTCAE v5 grading system for acute RD from the National Cancer Institute (NCI) is used. This tool has five classes from 1 [faint erythema and dry desquamation] to 5 [death] (Table 3).^19,22

Table 3: CTCAE and RTOG grading for acute RD

Division of Cancer Treatment & Diagnosis Dermatitis Radiation Grading (DCTD); Radiation Therapy Oncology Group (RTOG)
Grades of Acute Dermatitis (CTCAE – common terminology criteria for adverse events (National Cancer Institute)¹⁹
A-B – Grade 1 – faint erythema and dry desquamation
C-D – Grade 2 – moderate erythema and/or edema; patchy desquamation confined to folds
E-F – Grade 3 – moist desquamation in areas other than folds and bleeding from minor trauma
Grade 4 – Life-threatening consequences; full-thickness necrosis, spontaneous bleeding; skin graft indicated

Algorithm for the Prevention and Management of Acute Rd

The CaSMO algorithm for acute RD used the mnemonic RECUR (Reliable, Efficient, Clear instructions, Understandable, Remember easily).²⁴

A clinical algorithm’s function is to standardize and support medical decision-making, such as regulating the selection and use of treatment regimens, thereby improving adherence to evidence-based guidelines.¹⁴ The algorithms have inputs and outputs, precisely defined specific steps, and uniquely defined results that depend on the preceding steps.²⁴ The current algorithm for the prevention and management of acute RD focused on preventing or reducing and managing RD using OTC skincare and topical treatment (Figure 2). Detailed information on the various grades of RD is given in Figure 3.

The algorithm details measures to be taken before radiation treatment which include education, avoidance of skin irritants, preventative skincare, and sun avoidance and sunscreen use; it also describes prophylactic measures to be taken when radiation starts. Finally, it describes how treatment assessment of skin condition and grading of RD should take place during treatment while the preventative measures continue.

Each section is discussed in the order as they appear in the algorithm.

Grading	Prevention, skincare and treatment
Grade 1: Faint erythema or dry desquamation, possible pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and use sunscreen. For dry desquamation start or continue with low to mid potency TCS to decrease progression and severity of itching, burning and irritation.3
Grade 2: Moderate to brisk erythema; Patchy moist desquamation mostly confined to skin folds and creases; Moderate edema, pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and use sunscreen. Use saline compresses for cooling. Continue TCS in the surrounding area of moist desquamation
Grade 3: Moist desquamation in areas other than skin folds and creases; Bleeding induced by minor trauma or abrasion, severe pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and discontinue sunscreen on irradiated area until the reaction is over. Use saline compresses on the areas with moist desquamation. Continue TCS in the surrounding area of moist desquamation Use a wound dressing for bullae and erosions, and select the type of dressing according to the wound bed condition and the exudate production. Consider putting radiation treatment on hold.

Figure 3: RD Treatment according to presentation

Grading according to CTCAE v5¹⁹

Education on Prevention and Treatment of RD

Education on the type of radiation treatment, on preventive and on treatment measures for RD is essential for both clinicians and patients.^13,25 Before starting the treatment, a therapeutic relationship with the patient should be built, supporting the patients’ active participation in their cancer treatment.¹³ As outlined in two previous publications by the CaSMO group, a detailed discussion between the patient, treating physician, and nurse or other team members includes explaining the radiation treatment protocol, potential side effects, hospital visits, diagnostic tests, management of AEs, and prophylactic and preventative measures.^8,13 It is recommended to provide the patients with details on who to contact in the early stages of RD to enable addressing the AEs as early as possible.^8,13 It is recommended to support education given to patients verbally by printed or online information (Box 2).^8,13

Education on general measures include avoiding skin irritants, products with an elevated pH (>7), scented products and temperature extremes.^8,13 Further skin trauma should be avoided such as the use of adhesive bandages and tape, rubbing, scratching and massaging the skin within the treatment area. The patient should be recommended to wear loose fitting cotton clothing which may help avoid traumatic shearing and friction injuries.

Patients should also be recommended to use electric shavers for hair removal. Wax or other depilatory creams and pre-shave liquids and aftershave are discouraged, as they can irritate the irradiated skin.

Patients should be asked not to shave the axilla if it is within the treatment field but may continue to use antiperspirants or deodorants during radiation therapy on dry intact skin.

Box 2: Resources and information

Sun Avoidance and Sun Protection

Patients should be educated on radiation treatment-induced photosensitivity which can result in symptoms such as severe sunburn, pruritus, erythema, or edema. It should be explained that phototoxicity may occur, primarily induced by UVA exposure.^8,13

Phototoxicity symptoms may appear on the exposed area within a few minutes to several hours after exposure to UV light.^3-5,8,13

Patients should be educated on sun avoidance as part of a healthy lifestyle, and the use of sun-protective clothing [e.g., brim hats and sunglasses].^8,13 During the course of radiation and while skin is healing the patient should keep the treatment field out of direct sunlight. ^3-5,8,13 After the skin has healed, it may be more sun sensitive and therefore requires diligent protection from sunlight and tanning beds should be avoided.^8,13

Most dermatologists recommend daily sunscreen of SPF 30 or higher, especially for sun-exposed areas. Special populations that are at higher risk for sun-induced toxicities and neoplasms are advised to avoid sun exposure by using para-aminobenzoic acid (PABA) free UVA and UVB protection as well as sun-protective clothing.^8,13 Sunscreen should be reapplied as needed (e.g. after swimming or heavy perspiration) (Box 3).

Patients may continue to swim in chlorinated pools but should rinse afterwards with a gentle cleanser followed by immediately applying a moisturizer. If RD has progressed beyond dry desquamation (CTCAE grade 1) swimming should be avoided.

Box 3: Information on photoprotection and sunscreen application

Assessment of Skin Condition

Upon presentation of a patient with RD, it is important to check the location, size of the affected area, erythema, dry desquamation, moist desquamation, exudate, signs of infection, and discomfort (burning, pruritus, pulling, tenderness, dryness, scaling, flaking, peeling).^3-5,8,13,19 Similarly, the healthcare provider should check for the presence of fever, pain, mucosal involvement and if there are significant blood laboratory abnormalities. The clinician must establish whether the AE is possibly dangerous or life threatening such as in the case of skin necrosis, ulceration of the full thickness dermis or spontaneous bleeding,^13,19 and seek urgent care via a dermatologist, or emergency room for these patients.^13,19 The patient must be asked about the duration of the AE and what products were used for cleansing, moisturizing, or dressings for erosions or bullae.^3-5,8,13,19

Finally, the impact of RD on the patients’ daily activities, sleeping, eating or drinking must be verified. In the context of the assessment, the date of the last radiation or chemotherapy treatment, as well as concurrent medication use (analgesic, antibiotic, antifungal) and efficacy must be verified.^3-5,13,19

Skincare Using Cleansers and Moisturizers

Skincare using OTC products comprises cleansers and moisturizers (Box 4).^8,13 Although evidence is lacking on the best choice of product, basic recommendations on supportive measures using OTC skincare are given in various cancer treatment guidelines and consensus papers (Table 4).^{3,9-13,22,23,25-33}

Box 4: Criteria and application of cleansers and moisturizers

Table 4: Systematic literature reviews, consensus papers, guidelines and algorithms

Rosenthal and colleagues recommended a treatment algorithm for RD that included basic hygiene measures using mild soap and lukewarm water.³ A consensus paper and skincare algorithm by the CaSMO group recommended a daily skincare regime focusing on: hygiene, moisturization, sun protection, and, if applicable, camouflage products.^8,13 They recommended to encourage patients to keep their skin moisturized using gentle products to prevent pruritus and xerosis.^8,13

The skincare formulations used for patients with RD should be safe, effective, free of additives, fragrances, perfumes, sensitizing agents, and should have a near physiologic stratum corneum (SC) pH.^8,13 To support adherence to the skincare regime, products should be cosmetically pleasant and easy to use.^8,13

Evidence levels of components of topical treatments is shown in Table 5.^{3,8,13,26-28,34-59} A systematic review³ of topical agents for the treatment of RD reported no benefits from formulations containing aloe vera²⁶, chamomile^3,37, ascorbic acid, pantothenic acid, and trolamine.⁴⁹ However, benefits or potential benefits were shown when using formulations containing hyaluronic acid (HA)^{27,28, 34,54} epidermal growth factor EGF3,^39,51 granulocyte-macrophage colony stimulating factor (GM-CSF), topical corticosteroids (TCS) 40-45 or statins.⁵⁸

Table 5: Evidence levels of components of topical treatments

Topical agents that have common ingredients known as soothing may be beneficial for the reduction of symptoms such as niacinamide, panthenol, squalene, glycerin, and allantoin.^8,13 A skincare kit including all the products needed may be easy to use for the patients supporting adherence to the regimen.^8,13 A thermal water containing skincare regime (La Roche-Posay) comprising two types of cleansers, a moisturizer, a healing baume, and an SPF50+ sunscreen was shown to be beneficial for RD prevention and treatment.⁸ The regimen was evaluated in two-hundred-fifty-three women with mostly stage I (International Union Against Cancer (UICC) /American Joint Committee on Cancer (AJCC)) breast cancer undergoing radiotherapy. The frequent users who daily used the total skincare regime showed significantly (p ≤ 0.0001) less severe RD than those who used parts of the skincare regimen infrequently.⁸

Contrary to the advice some cancer patients may receive when undergoing radiation treatment, skincare does not interfere with or increase the radiation dose to the skin and can be used in moderation before daily radiation treatments.⁶⁰ Even if applied shortly before radiation treatment, thin or moderately applied skincare may have minimal influence on skin radiation dose regardless of beam energy or beam incidence.⁶⁰ Patients are frequently concerned about toxic effects on the skin.^60,61 Allowing patients to apply skincare throughout their radiation treatment period will simplify patient instructions and reduce patient confusion and anxiety.^60,61 Allowing patients to apply skincare daily and liberally without restrictions on application timing is likely to improve patient quality of life and adherence to the prevention and management of cutaneous AEs using skincare.^60-62

Topical Pharmaceuticals

Topical corticosteroids (TCS) have anti-inflammatory effects and may be used for the prevention and treatment of RD.^{3,4,25,28,40-45,59} A meta-analysis confirmed that TCS, ranging from mild to potent, significantly prevented the incidence of wet desquamation and reduced the mean RD score.²⁸ Various studies confirmed the efficacy of mild TCS decreasing moist desquamation, lowering the incidence of severe RD and delaying time to development of grade three RD.^41-44 Extensive and inappropriate use especially of high potency TCS on the face, neck or genitalia can cause AEs including skin atrophy, permanent striae, hematomas and tearing of the skin, telangiectasia, hypertrichosis, local and systemic infections, and rarely adrenal suppression.^8,13

Although the efficacy of TCS is established in RD such as in breast cancer²⁸, it is currently under evaluation in head and neck cancer where the use of TCS is frequently associated with the onset of clinically relevant adverse events.^22,42,59 In particular, the prolonged use of TCS leads to skin atrophy, which may be particularly contraindicated in this condition.⁵⁹

Topical use of statins may be beneficial for RD as the product may display some anti-inflammatory, immunomodulatory, antioxidant, metabolic, and antibacterial properties.⁴⁸

Although topical trolamine (doxepin) is extensively used for the management of RD, its efficacy for RD has not been established.⁴⁹

Wound Healing Products

Wound healing products and barrier films are widely used, as well, in oncology for cracked skin, erosion, bullae and more severe RD healing by secondary intention. Depending on the wound bed condition and exudate levels, various dressings may be used, such as a foam dressing or a non-adherent wound contact layer, including silicone-coated dressings. The frequency of dressing changes depends on exudate level and are typically twice weekly. The evidence supporting the efficacy of various dressings is scarce. Silicone based agents may have anti-inflammatory properties and are available as a gel or as coated wound dressings.^35,36,46-48

Prophylactic topical antibiotics should be avoided to comply with antimicrobial stewardship preventing antibiotic resistance.

The Multidisciplinary Team

Prevention and treatment of RD is a multidisciplinary effort involving radiation oncologists, dermatologists, nurses, and advanced practitioners (APPs). Collaboration and an interprofessional approach between oncology and dermatology is effective in connecting cancer patients with dermatological care from the start of their radiation treatment through to completion.^8,13,63-68

Timely intervention by a radiation-oncologist or dermatologist trained in supportive dermatology for oncology patients is critical to preventing avoidable treatment interruptions.^8,13,63-68 Moreover, almost equally important is an oncology specialists’ ability to improve quality of life-related to RD and may be able to preserve cancer treatment through managing RD early.^8,13

Limitations

Statements used and recommendations given in the algorithm were based on a mix of data and expert opinion. While it is possible that alternatives for RD could exist, the recommendations are suggestions for best practice developed from a panel of expert clinicians that are supported by peer-reviewed literature.

A small panel of physicians developed the algorithm, representing a few centers, and did not include patients in the development. Although limited evidence was available to guide the development, the project will hopefully encourage more skincare studies to prevent, treat and maintain RD.

Conclusions

A multidisciplinary team treating and guiding the cancer patient who receives radiation treatment may improve cancer treatment tolerance. The CaSMO algorithm on acute radiation dermatitis and general preventive measures, including cleansers and moisturizers to prevent or reduce the severity of acute radiation dermatitis, may increase awareness and help improve cancer patient outcomes.