Disclosures: 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 study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

Introduction: Over the years, the number of surgical excisions, cryosurgery, electrodesiccation, curettage, and facial laser treatment has increased. Presently pre- and post-procedural care and minor wound management remain highly variable, and standards are lacking. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods: A panel of eight Canadian dermatologists (panel) who perform dermato-surgery convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment. The information from the literature searches, together with the panels’ expert opinions and experience, was applied in this review.

Results: Peri-procedural measures depend on individual patient factors and the type of treatment. Post-procedure moisturizer application may be beneficial for promoting wound healing. Studies have shown no differences in infection rates between post-procedural sites treated with topical antibiotics and petrolatum-based products. Moreover, topical antibiotics are among the top ten allergic contact dermatitis-causing agents.

Conclusions: Cutaneous healing should occur with minimal discomfort and an esthetic scar. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Standards for peri-procedural care and minor wound management may support healthcare providers in improving patient outcomes.

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Introduction

Over the years, the number of skin surgery procedures (surgical shave and elliptical excision, Mohs surgery, cryosurgery, electrodesiccation, curettage, electrodesiccation and curettage (ED&C), laser, and other facial rejuvenation treatments) has increased. The American Society for Dermatologic Surgery reported over 15.6 million cosmetic treatments performed in 2020 in the United States (U.S.) alone.¹ About 13.3 million of these were minimally invasive cosmetic procedures, including neuromodulator injections, soft tissue filler injections, microdermabrasion and chemical peels).¹ The top minimally invasive cosmetic procedures comprised neurotoxins 3.65 million (33%), dermal fillers 1.85 million (32%), skin treatment (chemical peels, hydro-facials) 1.39 million (6%), hair removal 0.45 million (2%), skin treatment (combination Lasers) 0.43 million (4%) and skin tightening 0.39 million (7%).²

While many guidance and consensus documents exist that describe best practices for performing skin surgery procedures, few discuss specific pre- and post-procedure measures. Surveys of aesthetic medicine providers confirmed a lack of consistency in the types and duration of peri-procedural measures for dermatosurgery, laser, and minimally invasive cosmetic procedures.^3,4 Presently, skin surgery pre and post clinical care and minor wound management remain highly variable and there are no standards,^3,4 however, cutaneous healing should occur with minimal discomfort and an esthetic scar. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods

The project aims to provide insights into skin conditions and lesions created when performing dermatosurgery, minimally invasive cosmetic procedures, and facial laser treatment, followed by developing standards for these measures.

A panel of eight Canadian dermatologists (panel) who perform skin surgery was convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment.

We searched PubMed and Google Scholar (secondary source) databases for studies published from 2010 until September 2022. We divided the search terms into four groups to allow optimal results and avoid duplications.

Group 1: Pre-/post-procedure measures AND surgical excision OR curettage OR ED & C) OR cryotherapy OR facial laser treatment; AND Guidelines OR Algorithms OR consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure; AND antimicrobial stewardship OR topical antimicrobials OR systemic antimicrobials

Group 2: Surgical excision, curettage, ED & C, cryotherapy AND healing by primary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 3: Surgical excision healing by secondary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 4: Peri-procedure measures for laser treatment; AND Guidelines OR Algorithms OR Consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure OR Skincare OR wound healing regimen

Exclusion criteria were no original data, information not specific to peri-procedure measures for skin surgery, minimally invasive procedures, and facial laser treatment, and publication in a language other than English. The results of the searches were evaluated independently by two reviewers (AA, TE) and yielded 98 papers. After reviewing abstracts and removing duplicates and papers that did not contribute to this review (n = 43), fifty-five remained. Guidance and consensus documents are available on dermatosurgery, minimally invasive procedures, and facial laser treatment; however, few discussed peri-procedural measures and wound treatment which did not allow for grading.

Results

Procedures Included in the Review

The review addresses the following procedures: surgical excision, cryotherapy, electrodesiccation, curettage, ED&C, and facial laser treatment.

Surgical Excision

A Canadian national survey amongst dermatologists showed that epileptiform excisions, shave excisions, punch biopsies, curettage, and ED&C was most frequently performed, whereas Mohs micrographic surgery (MMS) was the least frequent procedure.⁵ These procedures are used to remove benign and malignant lesions.⁵

Adverse events are usually minor and include bleeding, hematoma, wound dehiscence, infection, discoloration (post-inflammatory hyper (PIH) or hypopigmentation), and atrophic, hypertrophic, or keloid scar formation.⁵

Curettage and Electrodesiccation

Curettage or electrodesiccation can be used to remove benign (e.g. condyloma acuminatum, seborrheic keratosis, pyogenic granuloma, excess granulation tissue) and malignant lesions. With malignant lesions, curettage is often combined with electrodesiccation (ED&C) or cryotherapy. For many indications, ED&C has been replaced by curettage alone, as it yields similar cure rates and a better cosmetic outcome.^12-16 Dermatologists routinely perform these procedures in their offices.

The disadvantage of curettage with or without electrodesiccation or cryotherapy is the absence of histopathologic margin evaluation.^13-15 Studies on low-risk non-melanoma skin cancers show 5-year ED&C cure rates from 91 to 97%.^15,16

Cryosurgery

Cryosurgery has several indications for both benign and malignant lesions. Benign lesions that can be treated with cryosurgery include seborrheic keratosis, verruca, skin tags, molluscum contagiosum, solar or senile lentigo, and actinic keratosis.^16-20 In the case of exophytic lesions, curettage should be considered prior to cryotherapy. This procedure can be delivered quickly and cost-effectively in an outpatient setting.^16-20

Recurrence rates of actinic keratoses treated with cryotherapy vary significantly (1–39%) in prospective studies likely due to a lack of homogeneity in patient and tumor selection, follow-up period, and inter-operator performance approach.^19,20 Malignant lesions can be treated with this modality, but the depth and extent of freezing may not be known without the use of a cryoprobe. Light cryotherapy often leaves no mark but may not remove the desired lesions. A deeper freeze may be associated with permanent white marks due to the destruction of melanocytes, postinflammatory hyperpigmentation, pseudoepitheliomatous hyperplasia, and depressed scars, which may resolve spontaneously, alopecia which may be permanent due to the destruction of hair bulge cells, and tissue distortion (e.g. nail dystrophy or notching of cartilage) due to damage to the nail matrix/cartilage.¹⁶ Cryosurgery should not be used for conditions that can be exacerbated by cold exposure (cryoglobulinemia, multiple myeloma, Raynaud disease, cold urticaria) and a previous history of cold-induced injury or poor circulation at the site or in that body part.¹⁷ Vasoconstriction induced by cryosurgery in poorly perfused areas may lead to tissue necrosis.¹⁷

Facial Laser treatment

Many different types of lasers are available, and laser treatment has many indications.³ Pulsed dye lasers (PDL) may be used for the treatment of port wine stains in adults and children. A further indication for PDL may be the treatment of telangiectatic rosacea.³ Other indications include radiodermatitis, ulcerated hemangioma, and erythrose of the neck.

For hair removal, various types of lasers, such as pulsed diode lasers, Nd: YAG lasers, or intense pulsed light (IPL) lasers, can be used.³ With the proper preparation and an experienced provider, patients with richly pigmented skin can also safely undergo laser and light-based treatments for hair removal, pigment abnormalities, skin resurfacing, and skin tightening.²¹ Facial rejuvenation aims to correct rhytides, telangiectasias, lentigines, and skin texture.³ Laser and energy devices may be used for facial resurfacing, depending on clinical indication, individual subject characteristics, and the operator’s expertise.^3,4 Lasers, such as CO2 or erbium laser, can be used to remove tattoos, Ota’s nevus, and, to a lesser degree, liver spots and Becker’s nevus.^3,21-24 These lasers permit dermabrasion in treating verrucous hematoma, extensive benign superficial dermo-epidermal lesions, and the esthetic treatment of non-muscular wrinkles, i.e., excepting wrinkles of the forehead and nasal sulcus.^21-24 Laser-assisted administration of photodynamic therapy (PDT) photosensitizers has demonstrated efficacy for superficial BCC.^25-27 The recurrence rates of BCC were markedly reduced in two randomized controlled trials using aminolaevulinic acid PDT with erbium compared to PDT and erbium.^25-27

Cutaneous adverse events with all types of laser treatment, such as reactive hyperemia, edema, scarring, and discomfort, may occur.^3,21-24

Pre-procedural Measures

All Discussed Procedures

Skin conditions and infections can exacerbate and cause complications following skin surgery.^3,4,28,29 For all patients considering having a procedure done, medical history including current and previous treatments, including procedures for the lesion under question, what the patient and treating physician hope to accomplish with the proposed procedure, current medications, and allergies, history of systemic disease, history of abnormal wound healing such as post-inflammatory dyspigmentations, abnormal scarring.^3,4,28,29 In patients that have had previous surgical treatments anywhere on their body, it is often good to assess the resultant scars prior to agreeing to perform a procedure on the individual.

Before the procedure, patients should attend the clinic with clean skin without makeup or cosmetics in the area to be treated.^30-34 Hair should be secured away from the treatment area. Patients should not shave since shaving can cause micro-wounds and increase the risk of infection.

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

Laser devices are frequently used for facial rejuvenation. Device and treatment choice depends on individual patient characteristics, expectations, and physician expertise.^22-24 For optimal treatment outcomes, patients should be appropriately selected and screened, followed by a physical exam before treatment, depending on the type of procedure.^23,24 Outcomes of previous skin or surgical treatments are obtained, especially dermabrasion (if previously performed) responses.^28,29 People with hypertrophic scars, keloids, or changes in pigmentation will need peri-procedural cosmetic practices to reduce the risk of these complications or should be advised against the procedure.^28,29 Previously published surveys and algorithms confirmed more than 90% of clinicians recommended sun avoidance before, during, and after facial cosmetic treatments.^3,28,29

Peri-procedural measures are based on individual patient factors and the type of laser procedure.^21-24 For patients receiving ablative laser therapy, pre-treatment of underlying conditions, such as rosacea, dermatitis, and prevention of recurrences in patients with recurrent Herpes simplex, may reduce complications and enable adequate healing time to restore the skin’s barrier function.^3,28 Check patients for remote infections. Caution should be applied when considering extensive laser procedures in patients with compromised immune systems, such as HIV, cancer treatment, immunotherapy, or poorly controlled diabetes.^3-28

Measures During the Procedure

Surgical Excision

Prior to the procedure, the surgical site may be prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Povidone iodine is less commonly used since it is messy and permanently stains clothing. Chlorhexidine is an effective cleanser but may induce allergic contact dermatitis and can be toxic to the eyes and ears, whereas isopropyl alcohol is flammable and can irritate the skin.^31,32 Stabilized HOCL is highly active against bacteria, viruses, and fungal organisms without chlorhexidine’s oto or ocular toxicity; it has been proposed as a future gold standard for wound care.³³ HOCL has been shown to have dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone-iodine and media alone.^33,34 It also increases skin oxygenation at treatment sites which may aid healing. There is evidence that HOCL may reduce the risk of hypertrophic scars and keloids as it reduces inflammation and the risk of infection. ^33,34

Local anesthesia and pain management can be customized depending need based on the procedure and patient factors and added at the treating physician’s discretion.

Cryosurgery, Electrodesiccation, Curettage, ED&C

Minimal skin preparation is needed for cryosurgery, ED or curettage if the procedure does not result in bleeding. Therefore, antiseptics are not typically indicated in the majority of procedures.¹⁶ However, topical antiseptics should be applied to lesions that are to be curetted or treated with ED&C.¹⁶

Pain management can be customized depending on the procedure and added at the treating physician’s discretion. Pre-procedure anesthesia should be considered for lesions to be curetted or treated with ED&C and large or extensive lesions. Topical anesthetics applied several hours before the procedure or intralesional anesthesia can help reduce surgical pain. For small lesions, injection of local anesthetic may be more painful than the procedure itself and is therefore not indicated.

Laser Treatment

Before the procedure, makeup removal and skin cleansing using a gentle cleanser is required.^30-34 The treatment site is prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Local anesthesia and pain management can be customized depending on the procedure and added at the discretion of the treating physician.^28,29

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

A local anesthetic given before the procedure takes about 1-2 hours to wear off. For further pain management post-surgery, oral acetaminophen is preferred over aspirin, naproxen, or ibuprofen, as the latter encourages bleeding.

Topical postoperative wound care involves maintaining a protected wound and a clean, moisturized surface.^35,36 Wound care includes cleansing with either a gentle cleanser or water, applying a topical, and covering the wound with a dressing.^35,36 While previous investigators have evaluated methods for reducing risks of adverse events due to the treatment procedure, robust studies on post-procedural wound management for primarily closed wounds are lacking.^35-38

Physicians typically cover sutured wounds using either a dressing, adhesive tape strips, or both.^35-38 Wound dressings can be classified according to their function, material, and physical form of the dressing (Table 1).³⁵ Wound dressings for sutured wounds are typically left in place for 24-48 hours after surgery.^35-37 If there is a lot of tension on the wound or bleeding during the procedure, the dressing is typically left on for 2 or more days. The dressing can act as a physical barrier to protect the wound until skin continuity is restored and to absorb exudate from the wound, and prevent bacterial contamination from the external environment.^35-37 Some studies have found that the moist environment created by some dressings accelerates wound healing, although excessive exudate can cause maceration of the suture line and peri-wound skin.^35-37 A dressing should absorb wound exudate, minimize maceration and prevent bacterial contamination.³⁶

Table 1: Types of wound dressings and moisturizers

The utility of dressing surgical wounds beyond 48 hours of surgery is controversial, although^35-37 in addition to the above, dressings can prevent irritation from rubbing from clothing.

A systematic review on early versus delayed dressing removal after primary closure of clean superficial wounds found no detrimental effect on the patient when removing the dressing after 24 hours.³⁵ However, the point estimate supporting the conclusion is based on very low-quality evidence.³⁵

Cleansing the suture line after dressing removal post-procedure using an antimicrobial solution or applying an antimicrobial ointment is equally controversial.^35,36

The incidence of surgical site infections (SSI) varies between 1% and 80% depending upon the types of surgery, the hospital setting (community hospital, tertiary‐care hospital, etc.), the classification of surgical wounds, and the method of skin closure.³⁵ In addition, many skin surgeries are performed in the community in physician offices where infection rates range from 0.2% to 2.5%.⁴¹ Antimicrobial resistance is a growing concern, especially when antimicrobial products are used routinely and inappropriately.^39-44 Moisturizers are frequently used to keep the wound moist; however, evidence for beneficial effects on sutured wounds is inconclusive and mainly from small studies.^45-50

After suture removal, the topical application of a moisturizer containing madecassoside, panthenol, and copper-zinc-manganese has been shown to be beneficial.^45-48 The product is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48 Petrolatum jelly and water-free petrolatum-containing ointments or products containing HOCL may also be used postoperatively to keep the wound moist, however, since they are occlusive, they may induce maceration.^49,50

In a study on postoperative wound care after MMS procedures (N = 76) patients were randomized to wound care with an ointment containing petrolatum, humectants, and natural barrier lipids (group 1: n = 27), white petrolatum (group 2: n = 32) or no ointment (group 3: n = 17).⁵⁰ Group 1 demonstrated an incidence of swelling and erythema of 52% (14/27); in group 2 erythema occurred in 12% (4/32) and swelling and erythema in 9% (3/27); and in group 3 erythema was noted in 12% (2/17) and swelling and erythema in 6% (1/17) patients.⁵⁰ The use of antibiotic-containing ointments is best avoided as they may cause allergic reactions and contribute to antimicrobial resistance.^39-44 Moreover, the rate of surgical site infections in minor surgical wounds is low and preventive use of topical antibiotics is not indicated.^35,44-52

If a hypertrophic scar develops, treatment with a silicone gel sheet or gel may improve the scar appearance and pain. Another option is self-adhesive propylene glycol and hydroxyethyl cellulose sheeting; however, evidence of the efficacy of these products in improving scar appearance and reduction of pain is inconclusive.⁵³

Surgical Excision, Curettage, ED&C, and Cryosurgery Healing by Secondary Intent

In a simplified model, wound healing processes occur in four phases 1) vascular response, 2) coagulation, 3) inflammation, and 4) new tissue formation.^54-57 During the initial inflammatory phase, the adaptive immune system is activated to prevent infection at the wound site.^54-57 Macrophages remove neutrophils, bacteria, and debris from the wound site. They then change phenotype to M2 macrophages, starting the proliferative and epithelialization phase, producing anti-inflammatory mediators and extracellular matrices.^54-57 If this phase is hindered, wound healing may be disturbed. The proliferative or epithelialization phase overlaps with the inflammatory phase and usually takes two to three weeks post-procedure.⁵⁴ During this phase, the dermal matrix matures, and inflammatory processes continue in the reticular dermis. The reticular dermis is sensitive to wound stress and infection and is affected by patient-related conditions such as age, sun exposure, or genetic profile.^54-57 Persistent inflammation plays a role in the development of hypertrophic or keloid scars, although it may not be the entire cause.^54-57 During the remodeling phase the wound contracts, and collagen remodeling occurs, which can last for up to a year post-procedure.

Pain management is similar to that previously discussed for primary healing wounds. Patients should be instructed to avoid sun exposure to the treated area, along with sun protection measures such as sunscreen with SPF 50 plus UVA block to prevent discoloration.^3,4,28,29

When a dressing is used post-procedure, the patient should be instructed to keep it dry and leave it in place for 24-48 hours. After dressing removal, a gentle, non-irritating cleanser can be used twice daily to cleanse the treated area.^3,4,28,29 The wound site must be handled with care, particularly during the initial healing phase of 7-10 days when newly formed epithelium can be early inadvertly removed.^3,4,28,29

Moisturizers or products containing HOCL may be applied to keep the wound moist and to promote wound healing (Table 2).^49,50 Similar to what was discussed for sutured wounds, moisturizers containing antibiotics should not be used on wounds not showing signs of infection to avoid allergic reactions and antimicrobial resistance.^39-44,49-52

Table 2: Complications from laser treatment

A moisturizer containing madecassoside, panthenol, and copper-zinc-manganese may be beneficial.^45-48 It is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48,59 In an unpublished international observation study, 11,464 adults, children, and infants with a mean age of 31 years (1 week to 97 years) with superficial wounds applied the ointment for 14 days. Clinical (desquamation, cracks, erosion, erythema) and subjective symptoms (tightness, pain, burning sensation, pruritus) showed a significant improvement at 14 days, while tolerance and esthetic aspects of the ointment were rated good.

Wound Healing After Laser Procedures

For patients undergoing ablative procedures, prophylactic oral antivirals such as acyclovir (400 mg orally three times daily) or valacyclovir (500 mg orally two times daily), starting typically one day before resurfacing and continuing for 6–10 days post-procedure may be indicated.^3,28 Patients undergoing ablative laser treatment with baseline melasma or post-inflammatory hyperpigmentation may require pre-procedure lightening agents such as hydroquinone 2-4% cream twice per day in the morning and evening.^3,28

Gold and colleagues developed an algorithm for pre-/post-procedure measures for facial laser and energy device treatment and listed complications from laser treatment and actions that can be taken (Table 2).²⁸

Post-laser management is similar to that discussed for secondary healing wounds.

Limitation

Although few studies on peri-procedural measures for dermato-surgery care and minor wound management are available, the advisors recommend applying a moisturizer without antibiotics for antimicrobial stewardship and contact allergy avoidance.

Conclusion

Peri-procedural measures depend on individual patient factors and the type of dermato-surgery. Standards are required to support healthcare providers to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Studies are required to evaluate purpose-designed moisturizers for dermato-surgery post-procedural application improving patient outcomes.

¹Clinical Professor, Laval University, Quebec University Hospital Center, Hotel-Dieu of Quebec, Quebec, QC, Canada
²Dermatology resident, McGill University, Montreal, QC, Canada
³Medical Director and Principal Investigator, Dermatological Research Center of Metropolitan Quebec (CRDQ), Quebec, QC, Canada

Abstract

Drs. Joël Claveau & Julien Ringuet, two Canadian dermatologists with prominent clinical and research practices, attended the Les Journées Dermatologiques de Paris conference in Nov-Dec 2022, with a focus on presentations and posters about psoriasis. This article reviews key insights they obtained at the meeting. In brief:

• Psoriasis has a profound and multifaceted impact, but remains undertreated
• Progression to psoriatic arthritis is common; dermatologists can facilitate earlier detection
• The presence of comorbidities may inform the choice of biologic treatment
• New topical and systemic options enable treatment optimization for various subgroups
• Adverse effects of cancer immunotherapy include psoriasis, which requires treatment

PDF download available in English French

Psoriasis is a chronic inflammatory skin disease that affects an estimated 2% of people worldwide, with higher rates in Caucasian than Asian populations.¹ Plaque psoriasis is by far the most common form of the disease, accounting for about 90% of cases.¹ A relapsing condition with a wide range of severity, psoriasis often requires long-term therapy.¹

High Impact & Complex Comorbidities

The impact of psoriasis extends across all dimensions of life. The skin manifestations alone, which typically include thick, scaly and sometimes pruritic plaques, can significantly impact psychosocial well-being. Research has found that about 80% of patients feel embarrassment and shame, while 75% see themselves as unattractive and sexually undesirable.² A 2020 French study found that psoriasis also affected the quality of life and sexuality of patients’ life partners.³ In patients who develop psoriatic arthritis, inflamed joints, pain and fatigue can significantly impair mobility and occupational functioning.²

Now recognized as an immune-mediated inflammatory disorder, psoriasis extends to several other body systems.¹ Characteristic comorbidities are listed in Table 1.

Table 1: Comorbidities associated with psoriasis^4,5

Psoriatic arthritis, the most prevalent comorbidity of psoriasis, develops in about 30% of patients and appears about 10 years after the onset of psoriasis, on average.⁶ A heterogeneous disease, psoriatic arthritis may affect a few or many hand and foot joints (peripheral disease) and/or may involve the spine and sacroiliac joints (axial disease). Depending on how it is defined, axial involvement occurs in 25% to 70% of people with psoriatic arthritis.⁷

Presenters at the meeting emphasized that psoriatic arthritis develops along a “pathological continuum” that is often undetected. Indeed, about 15% of psoriasis patients followed by dermatologists have undiagnosed psoriatic arthritis.⁴ Dermatologists are in a unique position to identify early psoriatic arthritis. They should question their psoriasis patients about joint pain, stiffness, and search for signs of dactylitis and enthesitis. They could also consider referring patients for imaging and rheumatologic evaluation when deemed appropriate.^6,8

Treatment Trends & Unmet Needs

New advances in psoriasis treatment have raised the expectations and goals of treatment. Ninety-percent improvement in the Psoriasis Area Severity Index (PASI 90), or even PASI 100, has become a realistic treatment goal.⁹ The focus has also shifted toward absolute outcomes (e.g. PGA clear or almost clear).⁹ Efficacious treatments improve not only psoriasis symptoms, but also quality of life.² Treatment should be initiated early, especially when psoriatic arthritis is involved, to prevent disabling joint damage.⁸

Current medical treatment classes include topical agents (e.g. corticosteroids, vitamin A and D derivatives), traditional systemic agents (e.g. methotrexate, cyclosporine, acitretin), the oral phosphodiesterase-4 (PDE-4) inhibitor apremilast, and an expanding array of biologic agents (Table 2), sometimes recommended as first-line agents for moderate-to-severe plaque psoriasis.¹⁰ Historically, phototherapy (UVB and PUVA) was widely used to treat moderate to severe psoriasis, and narrow-band UVB phototherapy continues to be a good option for some patients.¹⁰

Table 2: Biologic agents used to treat psoriasis^11,12

Several presentations at the meeting focused on biologics that inhibit the IL-17 and IL-23 cytokine pathways. In patients with moderate-to-severe arthritis, high levels of these cytokines are associated with an increased risk of comorbidities.¹³ IL-17 and IL-23 inhibitors, which target psoriasis immunopathology and show an overall superior skin efficacy, have been gradually displacing anti-TNF agents and IL-12/23 inhibitors as first-line biologic options.^9,13 A meta-analysis of 44 studies established the overall safety and tolerability of IL-17 and IL-23 inhibitors.¹⁴ Common adverse events with these classes include infections, nasopharyngitis, and headaches,¹⁴ although the causality of these effects remains uncertain.

Despite the effectiveness of current treatments, psoriasis remains undertreated. In a 2019 online survey conducted in Germany, 59% of patients who received medical care for psoriasis were only moderately or less satisfied with their treatment.¹⁵ In the US, a study of registry patients found that, while most showed an “acceptable” treatment response after 6 and 12 months of systemic therapy, fewer than half reached their treatment targets.¹⁶ Clinicians are advised to optimize treatment in such patients. Effective strategies include increasing the dose, reducing the interval between treatments, or switching to another agent.⁹

Considerations in the Choice of Biologic Treatment

While both IL-17 and IL-23 are involved in the pathogenesis of psoriatic arthritis, IL-17-mediated inflammation may play a greater role in the development of axial disease and cardiometabolic comorbidities, while IL-23 may have greater involvement in the development of IBD.¹³ These distinctions can inform the choice between the two classes (Table 3).

Table 3: Choosing a biologic class based on comorbid PsA or IBD^8,11

Axial psoriatic arthritis: If patients require biologic therapy, anti-TNF agents are often used first-line, but IL-17 inhibitors are preferred if skin involvement is significant.⁷ In the MAXIMIZE study, over 60% of patients receiving the IL-17 inhibitor secukinumab showed an ASAS20 response at week 12, compared to 31% in the placebo group, and response was maintained through week 52.⁷ Drugs targeting the IL-12/23 pathway are not currently recommended due to a lack of studies showing clear efficacy⁷ as well as negative studies for ankylosing spondylitis.

Peripheral psoriatic arthritis: Evidence exists for all classes of biologics used to treat psoriasis, as well as for the PDE-4 inhibitor apremilast.⁸ The JAK inhibitors tofacitinib and upadacitinib have also shown efficacy and are approved for this indication.

Inflammatory bowel disease: For psoriasis with comorbid IBD, positive data exist for the use of anti-TNF inhibitors, the IL-12/23 inhibitor ustekinumab, and IL-23 inhibitors.¹¹ Of note, Health Canada approved the IL-23 inhibitor risankizumab for Crohn’s disease in late 2022. On the other hand, the IL-17 inhibitors secukinumab and brodalumab have failed studies in Crohn’s disease.¹¹ Cases of new-onset IBD have been observed in psoriasis patients treated with IL-17 inhibitors, though the signal is low and these cases may arise from the disease process itself, rather than as an outcome of IL-17 inhibition.¹¹

Speed of onset of action has become an important differentiator among systemic treatments, as patients place high value on rapid clearance.⁹ Dosing regimen also comes into play, with many patients showing a preference for less frequent administration.

Oral candidiasis, a rare side effect related to the mechanism of action of IL-17 inhibition, generally responds to treatment and is not a reason for discontinuing the biologic.¹¹ Reported cases of suicidality with brodalumab have led to further investigations; to date, a causal relationship has not been established.¹¹

New Molecules

Several new practice-changing molecules were introduced at the meeting. Topical tapinarof, a hydrocarbon receptor-modulating agent, has been investigated for both psoriasis and atopic dermatitis and is expected to enter the Canadian market soon. In two Phase 3 PSOARING trials, a Physician Global Assessment (PGA) response occurred at week 12 in 35.4% and 40.2% of patients treated with tapinarof, respectively, compared to 6.0% and 6.3% in the vehicle groups.¹⁷ Of note, 58% of the patients who did not achieve PGA-0 or PGA-1 at week 12 reached this outcome at week 52 in the open-label extension study.¹⁸ In patients who reached PGA-0, the median duration of remission after discontinuation of treatment was 130 days.¹⁸ A second new topical agent, a potent PDE-4 inhibitor called roflumilast, showed similar results in the DERMIS 1 and 2 trials: at week 8, 42.4% and 37.5% reached the Investigator Global Assessment (IGA) endpoint in the active treatment groups, respectively, versus 6.1% and 6.9% in the control arms.¹⁹ A distinctive feature of this agent is its efficacy and tolerability in special sites such as facial, genital and intertriginous areas.

Deucravacitinib is a new oral JAK inhibitor that specifically targets the TYK2 receptor, which differentiates it from less targeted JAK inhibitors. As shown in the Phase 3 POETYK-1 and -2 trials, the molecule is potent enough to treat moderate-to-severe psoriasis. In the trials, 53-58% of patients in the treatment arms reached the co-primary endpoint of PASI 75, compared to 35-40% in comparator apremalist arms and 9-12% in the control arms.²⁰ Corresponding results for the other co-primary endpoint (IGA 0-1) were 50-53% for deucravacitinib, 32-34% for apremilast, and 7-8% for placebo.²⁰ Longer-term data showed that efficacy was maintained for up to 52 weeks. These results led Health Canada to approve this agent in late 2022.

Deucravacitinib has also been investigated for psoriatic arthritis in a recently published Phase 2 study.²¹ Patients were randomized to receive placebo or one of two doses (6 mg and 12 mg daily) of deucravacitinib, with ACR-20 response at week 16 as the primary endpoint. Response was significantly higher with deucravacitinib 6 mg (52.9%) and 12 mg (62.7%) than with placebo (31.8%),²¹ suggesting this oral agent may play a role in the treatment of psoriatic arthritis. Phase 3 studies are ongoing.

A first-in-class biologic called spesolimab, which targets the IL-36 receptor, has recently been approved by the FDA for the treatment of generalized pustular psoriasis (GPP), a severe form of psoriasis that causes pustules on an erythematous base often associated with systemic symptoms. In the Phase 2 trial of patients with severe GPP, spesolimab 900mg IV demonstrated clear superiority over placebo (54% vs. 6%) for the main outcome measure of GPPGA-0.²² [GPPGA = Generalized Pustular Psoriasis Physician Global Assessment.] Serious adverse events were reported in 6% of patients on spesolimab versus 0% on placebo, and a signal of infectious risk also emerged in the spesolimab group. The ongoing Effisayil 2 trial is evaluating spesolimab as maintenance treatment for GPP.²³

Cancer Immunotherapy and Psoriasis

The meeting helped raise awareness of an increasing challenge in dermatology: the management of adverse events induced by cancer immunotherapy. Immune checkpoint inhibitors (ICIs) represent a significant leap in cancer treatment, but they come at the cost of various immune-related adverse events, including dermatologic adverse events in about 40% of cases.²⁴ In a multi-centre study of patients on ICI therapy, psoriasis accounted for 23% of skin-related side effects.²⁵ While most ICI-induced psoriasis is the plaque subtype, all other subtypes have been reported.²⁴ Other common dermatologic sequelae of ICI treatment include lichenoid and eczematous eruptions, pruritus, and vitiligo.

Figure 1: Checkpoint inhibitor-induced psoriasis

ICI treatment can induce psoriasis de novo or cause preexisting psoriasis to flare up.²⁴ This can complicate treatment decisions and underscores the need for oncologists to consult dermatologists when treating patients with a history of psoriasis or psoriatic arthritis, including during flareups.

On a positive note, the presence of skin toxicities may signal that ICI treatment is working. In a population-level cohort study that reviewed a database of over 200 European and US patients treated with ICI, the development of cutaneous adverse events was strongly associated with therapeutic response and patient survival.²⁶ If more severe ICI-induced skin toxicities are not managed, however, they may compromise the therapeutic outcome of cancer treatment.²⁵

For moderate cases of CI-induced psoriasis, acitretin, methotrexate, and/or apremilast are deemed suitable options.²⁴ For more severe presentations, the EADV task force “Dermatology for Cancer Patients” recommends reinforcing therapy for moderate disease (including dose optimization) and consideration of anti-TNF and IL-23-targeting biologics in non-responders.²⁴ The paper also advises avoiding IL-17-targeting agents due to their gastrointestinal effects,²⁴ though this is still a subject of debate. Ideally, ICI treatment should be discontinued until the psoriasis improves to grade 0 or 1.²⁴

Overall, the management of ICI-induced dermatologic adverse events requires a balance between reducing troubling skin toxicities that compromise patients’ quality of life and preserving the benefits of cancer treatment.

Conclusions

The global medical community has come to understand psoriasis as a systemic disease with a profound impact. The optimal treatment choice depends not only on the disease subtype and severity, but on a patient’s comorbidity profile. While both systemic and topical treatments continue to improve, many patients remain undertreated. Dermatologists can play a significant role in detecting emergent psoriatic arthritis and in managing psoriasis induced by cancer treatment.

Test Your Knowledge

Question 1: Which class of biologic is not suitable for psoriasis patients with comorbid inflammatory bowel disease, and why?

Question 2: If patients on cancer immunotherapy develop psoriasis, should they be switched to a different cancer treatment?

Abstract

Background: Skin barrier differences and variations in the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been reported in racial/ethnic Canadian patients. This review discusses skin barrier differences and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.
Methodology: A literature review and panel discussions followed by an online review were used to adopt five statements and recommendations to promote a healthy skin barrier in various racial/ethnic Canadian AD populations.
Results: The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Studies comparing ethnic groups have reported variations in transepidermal water loss, skin lipid levels, and stratum corneum pH. However, these studies frequently have flaws. The panel agreed that essential skincare principles apply to all AD-affected patients regardless of racial/ethnic background.
Conclusion: Robust comparative studies are needed to help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers containing lipids for AD management regardless of disease severity and prescription treatment.

Acknowledgments: All authors participated in all the steps of the project, selection of the literature, and the review of the manuscript. All authors read and approved the final version of the manuscript.

Disclosures:
The authors disclosed receipt of an unrestricted educational grant from CeraVe Canada for support with the research of this work. The authors also received consultancy fees for their work on this project.

Keywords: Racial/ethnic skin barrier variations, skincare, atopic dermatitis

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Background

Genetic and environmental factors influence the structure and function of the stratum corneum (SC) barrier.¹ Approximately 30% of Canadians are estimated to be part of a fast-growing racial/ethnic population by 2031.² However, morphology and descriptions of dermatoses are based on White patients and the historic assumption that most residents of Canada and the United States are of Northern European descent.²

Differences in the skin barrier properties and function and the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been observed in subjects with richly pigmented skin compared to White subjects.^1-6 Several studies have investigated SC differences between racial/ethnic skin, comparing SC properties of self-identified Black, White, and Asian skin.¹ In one such study, White subjects had an intermediate barrier strength as evidenced by tape strippings, and Asians have been demonstrated to require the least number of tape strippings to disrupt the SC barrier.¹ This finding indicates a weaker barrier strength and slower recovery from barrier damage in the Asian population, supporting the observation of sensitive skin seen in Asians.¹

There are significant disparities in the prevalence and treatment of skin conditions across Canadian populations.^2-6 The burden of AD is higher in racial/ethnic populations, and numerous barriers to treatment exist, including systemic and institutional racism, poverty, crowded housing conditions on reserves, access and cost of basic skincare regimens, and clean water access.^2-4 Promoting a healthy skin barrier remains a particular challenge for Indigenous groups, who lack access to appropriate treatments and skincare.^2-6

This review discusses skin barrier differences in various racial/ethnic Canadian populations and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.

Methods

A group of dermatologists assembled during the Dermatology Update conference on November 13, 2021, in Montreal, Quebec. The panel (advisors) [four Canadian dermatologists and one dermatologist from the US] reviewed skin barrier differences in various racial/ethnic Canadian groups exploring dermatology issues related to skin barrier integrity. Additionally, the advisors determined the relevance of skincare-containing ceramides comprising cleansers and moisturizers for these populations to promote a healthy skin barrier and mitigate AD. Finally, the advisors looked into patient and clinician education tools to promote a healthy skin barrier in various racial/ethnic Canadian populations.

The project used a modified Delphi process comprising face-to-face discussions followed by an online follow-up.^7-9

Literature Review

Structured literature searches on PubMed and Google Scholar as secondary source of the English-language literature (2010 – September 2021) were conducted before the meeting on September 21 and 22, 2021. We searched for guidelines, consensus papers, clinical studies, and reviews describing skin barrier properties in various racial/ethnic Canadian populations and current best-practice in promoting a healthy skin barrier and mitigation of AD using ceramides containing non-prescription skincare cleansers and moisturizers. Excluded were papers with no original data (unless a review article was deemed relevant), or not dealing with racial/ethnic Canadian or skincare, and publication language other than English.

The Nomenclature Used for the Searches

Searches were performed for the main ethnic Canadian groups [Black, White, Asian and Indigenous populations] and ethnic regions in Canada.^2-6 Indigenous is a preferred term within Canadian communities. It is an umbrella term that covers Aboriginal, Metis, and Inuit populations. The publications collected a range of demographic data, including ethnic origin. Demographic factors referred to the quantitative data relating to the study population and its composition, which allowed portions of the population to be broken down into subgroups for closer examination.^2-6 Further searches included associations between these demographic factors and the biophysical nature of racial/ethnic skin, skin care practices, and AD treatment product use.

Search Terms

The searches explored present clinical guidelines, treatment options, and therapeutic approaches addressing racial/ethnic Canadian populations using the following terms:
Racial/ethnic Canadian populations AND AD prone skin, OR Black, White, Asian and Indigenous populations in Canada AND AD, OR racial/ethnic Canadians AND skin barrier physiology OR skin barrier function/dysfunction OR racial/ethnic Canadians AND depletion of stratum corneum lipids, OR racial/ethnic Canadians AND AD prevention, OR racial/ethnic Canadians AND AD treatment, OR Black, White, Asian and Indigenous populations in Canada AND mitigation of AD, OR racial/ethnic Canadian populations with AD/AD prone skin AND skincare, OR Black, White, Asian and Indigenous people in Canada AND cleansers OR moisturizers OR emollients OR ceramides OR ce¬ramide containing skincare OR racial/ethnic Canadian AD populations AND skincare efficacy OR safety OR tolerability OR skin irritation

The searches were performed by a dermatologist and a physician/scientist (reviewers). After selection, the publicatiodns were manually reviewed for additional resources.

Priority was given to studies on SC barrier function and the benefits of skincare using cleansers and moisturizers in racial/ethnic Canadian populations with AD or AD-prone skin.

The searches yielded 248 papers, and after excluding 173 articles [duplicates, poor quality, not about Canadian racial/ethnic AD populations or skincare], 75 remained, comprising 4 epidemiology, 4 quality of life (QoL) studies, 20 guidelines, consensus papers and systematic reviews, 19 reviews, 24 clinical studies, and 4 others.

Role of the Panel

The advisors used the literature review results, clinical experience, and expertise to adopt statements and recommendations. The results were integrated into the summary statements presented and discussed during the face-to-face meeting. For example, in a workshop, advisors divided into three groups to create a final set of summary statements about Canadians’ racial/ethnic differences in SC barrier structure and function and skincare for this population, working with 12 draft messages. The final five statements integrate the combined output from the workshop groups and post-meeting online reviews from individual advisors.

Results

Statement 1: The properties and conditions of the skin vary with body site and can be influenced by factors such as skin type, ethnicity, gender, or lifestyle.
Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations.^6,10-13

A three months population survey of all children aged 2-12 years in the community in the First Nations reserve of Natuashish, Labrador, Canada, showed that of 182 examined children, 30 (16.5%) mainly (20/30) had moderate to severe AD.⁶ IgE levels in children with and without AD had average values at least ten-fold higher than other populations.⁶

A systematic review and meta-analysis extracted 21 studies [1990 to 2020] from three medical databases [Pubmed, Embase, and Web of Science] to examine the prevalence of AD, clinical manifestation, and risk factors among children and adolescents in the Arctic.¹⁰ The cumulative AD incidence was 23%, and the 1-year prevalence was 19%, with the highest incidence in Arctic Scandinavia, lower Greenland, and Russia.¹⁰ The review indicated that the risk for AD in indigenous children living in rural Arctic areas seems slightly lower.¹⁰ Although the systematic review looked at the Arctic regions and included indigenous peoples, it did not mention Canadians.

A further study [2018] showed an AD prevalence of 20.5%, with the highest prevalence recorded among grade-1 Inuit children at 25%, compared to 15.4% among mixed ethnicity and 14.3% among non-Inuit children.¹¹ The variations in prevalence and risk factors of asthma, allergic rhinitis, and AD among the different ethnicities living in the same subarctic environment may be related to genetic, gene-environment interaction, or lifestyle factors.¹¹

An international study of asthma and allergies using written questionnaires included 8334 adolescents aged 13 to 14 in Vancouver, Saskatoon, Winnipeg, Hamilton, and Halifax, Canada.¹² Although AD was significantly more prevalent in Winnipeg (1.31; 1.01-1.69) and Vancouver (1.28; 1.04-1.58), the highest prevalence rates of allergic rhinoconjunctivitis or AD were not observed in the same regions as the highest prevalence rates of wheezing, suggesting dissimilar risk factors.¹²

A cross-sectional study in Europe and Canada on AD patient-reported burden of disease showed a substantial impact (pruritus, pain, loss of sleep, higher levels of anxiety and depression) which was highest in those with severe AD.¹³

A similar high burden of AD has been shown in studies from other countries.^14-18

Statement 2: The literature suggests racial/ethnic variations in ceramide content, SC structure, and filaggrin mutations. Racial/ethnic differences in barrier structure and function have been observed between Black, White, Asian, and Indigenous populations. Differences in TEWL have also been reported, but data are conflicting, and further research is needed.

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations.¹⁹ Genetic and immunophenotypic differences between racial/ ethnic AD populations, such as lower rates of filaggrin gene mutations, have been described among Black populations.^20-33 Studies involving small groups of East Asian and African American patients have identified differences in cytokine expression compared to European-American patients.^20-33 A literature review on clinical and molecular features of AD found differences in filaggrin (FLG) loss-of-function mutations across various ethnic groups with AD.²⁹ The authors noted that studies in European American compared to Asian American AD populations have consistently shown a higher prevalence of FLG loss-of-function mutations in up to 50% of European and 27% of Asian American patients, respectively.^29,30 However, the association between FLG loss-of-function mutations and AD development in populations of African descent is unclear, and other genes may be involved in skin barrier dysfunction.³⁰

A higher prevalence and persistence of AD has been noted in African American children and racial/ethnic disparities in health care utilization and access to therapies.^22-30

However, most of the information on racial/ethnic and geographic AD population variations originates from the US and may only be partially applicable to Canadians.

Statement 3: Data on racial/ethnic differences in skin barrier structure and function are limited but suggest variations in some characteristics relevant to skincare.

A healthy skin barrier function depends on the complex interplay among SC pH, desquamation rate, and the appropriate ratio of intrinsic lipids.^37-40 The lipids comprise approximately twenty percent of the volume of the healthy stratum corneum (SC) and are composed of CERs (40–50%), cholesterols (20-33%), and free fatty acids (7–13%).^37-39 Further lipids include cholesterol-3-sulfate (0-7 %) and cholesteryl esters (0-20 %).^37-40

The slightly acidic surface of healthy skin is required to mature and maintain the SC barrier, inhibiting the growth of pathogenic microorganisms.³⁹ Skin acidification plays an important role in SC barrier maturation and the activation of enzymes involved in the extracellular processing of SC lipids.³⁹ The SC pH influences barrier homeostasis, integrity and cohesion, and antimicrobial defense mechanisms.³⁹

It is unclear why specific changes in CER composition do not seem to affect a healthy SC and why deficiency of specific CER species and alterations in fatty acid composition occur in certain skin diseases such as AD.^41-45

There is some evidence that the skin barrier in Black skin contains fewer CERs and that the skin barrier in Asian skin is most vulnerable to disruption.^1,19 A less cohesive skin barrier in Asian skin might help explain differences in trans-epidermal water loss in this population.^1,19 The advisors suggested that studies correlating skin barrier structure to dysfunction in Asian skin (perhaps involving tape stripping) could provide insights. Skin barrier differences (lipids, less cohesive skin barrier) may contribute to ethnic differences in the prevalence of xerosis, pruritus, and AD.

Some individuals with AD may produce inadequate amounts of certain CERs.^31,41-45 Many with AD or AD-prone skin exhibit baseline increases in TEWL even within their unaffected, normal-appearing skin.^31,41-45 Racial and ethnic differences have been reported in the SC barrier function, including CERs content and TEWL.⁴⁵

Conventional moisturizers contain occlusives, humectants, and emulsions.³⁹ Newer classes of moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions, such as CERs, cholesterol, and essential fatty acids.^37-40

CER-containing moisturizers were found to benefit AD patients when used as mono, adjunctive, and maintenance treatment.^{19,37-39,46-52} Guidelines, algorithms, and consensus papers agreed that the use of moisturizers that contain lipids, such as CERs (or their precursors) reduces pruritus, helps control xerosis, and improve the dysfunctional skin barrier in AD patients.^34-39,53

Other ingredients in moisturizers (i.e., virgin coconut oil, glycyrrhetinic acid, V. vinifera, shea butter, mineral water and hyaluronic acid) have also been recommended.^54-59

A Canadian study including 47 patients with inflammatory dermatosis, applied thermal water and hyaluronic acid-containing moisturizer for 4 weeks as an adjunct to treatment and found a markedly improved skin condition.⁵⁹

A systematic review of 92 randomized controlled trials on the efficacy and safety of moisturizers for AD showed that those containing a mixture of substances (urea, glycerin or glycyrrhetinic acid, ceramides) seem to have greater effectiveness than basic emollients.⁶²

Additionally, regular moisturizer use improves pruritus frequently caused by AD.⁶³
As the mainstay of treatment, moisturizers should be liberally applied both in AD-prone skin and AD.^{34-39, 53, 60-62} The moisturizer should be used at least twice daily directly after bathing and more frequently during acute flare-ups.^{34-39, 53} Further moisturizers must be suitable for the patient’s skin type, climate, humidity, and environmental conditions.^36-39,53-55

The advisors agreed that focusing too much on minor ethnic variations in the skin barrier of AD-affected patients could interfere with essential skincare principles that apply to all skin types. Instead, concentrating on similarities while acknowledging the differences may be more helpful.

A Canadian algorithm for topical treatment of mild-to-moderate AD for adults and pediatric patients and US guidelines for topical treatment of AD include education and avoiding triggers.^34,35 Routine skincare with gentle cleansers and moisturizers is considered an integral part of AD management regardless of disease severity and prescription treatment (Table 1).^34-38

Table 1: Cleanser and moisturizer use

Statement 4: Skin barrier differences between racial/ethnic populations may contribute to variations in the prevalence and severity of atopic dermatitis, xerosis, and, pruritus. Environmental issues and disparities in access to care may also play a role.

Although some authors reported a direct relationship between the severity of AD and the degree of SC lipid depletion^41-45, the evidence demonstrating an association between CER depletion and AD is inconclusive.¹⁹ Other factors may play a role in SC lipid depletion, and the reduced CER could be an epiphenomenon of AD.¹⁹

Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations; while studies do not support the assumption that skin barrier differences are a factor.^26-31 It is presumed that the impact of the cold, dry climate throughout parts of Canada may play a role in skin barrier dysfunction amongst these populations at large.

Delays in diagnosis or underestimation of severity may occur in patients with richly pigmented skin due to knowledge gaps in recognizing morphologic features of AD across the spectrum of skin complexions and racial/ethnic populations.^19,64-66 Patients with richly pigmented skin may present with variations in the appearance of erythema (Figure 1). AD lesions may appear reddish-brown, violaceous, gray, or hyperchromic rather than bright red (Figure 2). Perifollicular accentuation, papules, scaling, lichenification, and pigmentary changes may be more prominent (Figure 3 and Figure 4). As a consequence, patients with SOC may present with a more advanced stage of AD severely impacting their QoL.¹⁹

Canadian Indigenous children and young adults continue to face higher rates of health disparities than their non-Indigenous counterparts.² In dermatology, this includes a high burden of AD and secondary skin infections.^2,3 Environmental factors and disparities in access to care could be a particular challenge for Indigenous groups, who frequently lack access to appropriate treatments.^2,3 A systematic review of the pediatric dermatology literature reported on systemic [finances, wait times, geography], sociocultural [culture beliefs and communication], and individual barriers [patient beliefs and health knowledge] to diagnosis, treatment, and maintenance approaches of AD and other skin conditions.⁶⁷ The identified barriers are interesting to explore further in Canadian AD populations. However, further research is needed to obtain insight into any interventions’ impact on overcoming these barriers.

Awareness amongst AD patients and caretakers, specifically Indigenous groups, on the cause of AD, general treatment principles, available treatments and the role of moisturizers, and adherence to moisturizer regimens are inconsistent.⁶⁸

Statement 5: Cultural perceptions of healthy skin impact the choice of skincare.

First Nations people have been using medicinal plants for AD treatment. Natural Indigenous medicinal discoveries [safrole, salicylic acid, and ascorbic acid derived from Sassafras albidum, genus Salix trees, and Sassafras officinale] by the Iroquoian and Algonquian-speaking Peoples of North America for AD and other dermatologic conditions are mentioned in the European literature.⁷¹ Further examples are Western red cedar’s known principal active compound, β-thujaplicin, has shown efficacy in AD.⁷⁰ Another active principal compound (7-hydroxymatairesinol) of White spruce may offer benefits due to its anti-inflammatory activity.⁷⁰ Plants and algae such as hazel may also have benefits; however, studies need to confirm this.⁷¹

The effect of traditional treatments and natural remedies for AD may be of interest in managing racial/ethnic Canadian AD populations.^70,71 However, such AD treatments may result in adverse effects such as postinflammatory hyperpigmentation or keloid scarring at a higher rate than evidence-based treatment.¹⁹

Optimal management of AD is multipronged and includes patient education, prescription treatment, and skincare promoting a healthy skin barrier.^68,72-74

Nurse practitioner or physician assistant interventions may significantly increase correct and frequent moisturizer use, reducing AD.⁷⁶

The choice of skincare should be supported by evidence but is mainly a personal and individual choice.^{34,36-38,61,75}

It is important to note that there are variations in skincare norms across diverse populations; therefore, these cultural variations when providing skincare recommendations need to be considered.¹⁹ Integrating evidence-based recommendations for skin care in a culturally competent manner that aligns with the patient’s norms/preferences is key to successful outcomes across diverse populations.^2,19 More research is needed to guide culturally appropriate recommendations better.

Limitations

A detailed discussion on genetic factors of racial/ethnic Canadian AD populations is outside the scope of the review. There is an overall lack of robust studies focusing on the prevention, treatment, and maintenance of AD in racial/ethnic Canadian AD populations.

Conclusions

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Available data suggest that skincare strategies to improve AD patients’ outcomes should consider racial/ethnic differences, integrating recommendations for skin care in a culturally competent manner that aligns with the patient’s norms and preferences. Future robust comparative studies will help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers as an integral part of AD management.

Abstract

Introduction: Breast and prostate cancer patients frequently use hormonal therapy to improve treatment outcomes and survival. However, these medications can be associated with numerous dermatologic adverse effects. If not appropriately managed, these cutaneous reactions can reduce the quality of life and interfere with treatment adherence.
Objectives: The Canadian skin management in oncology (CaSMO) algorithm was developed to improve the quality of life for cancer patients and survivors who experience hormonal therapy-related dermatologic toxicities.
Methods: The CaSMO advisory board created a practical algorithm for preventing and treating hormonal therapy-related cutaneous adverse effects based on the results of a literature search and their clinical expertise.
Results: Skin toxicities related to hormonal therapy include symptoms of menopause/andropause, androgenic alopecia, rosacea, hirsutism, and other eruptions. The algorithm provides practical steps for preventing and treating these cutaneous conditions.
Conclusions: The CaSMO algorithm provides information for all healthcare providers who treat oncology patients receiving hormonal therapy and can be used to help prevent and manage common dermatologic toxicities, thereby improving patient adherence, quality of life, and treatment outcomes.

Acknowledgments and Disclosure: None

Keywords: Hormonal cancer therapy, cutaneous adverse events, algorithm for hormonal therapy-related cutaneous adverse events

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Introduction

An estimated 229,200 Canadians were diagnosed with cancer¹ in 2021. Excluding non-melanoma skin cancer, the most commonly diagnosed types are lung, breast, colorectal, and prostate, making up almost half of all new cancer diagnoses in Canada. Advances in treatment have contributed to a reduction in breast and prostate cancer mortality over the past couple of decades. The five-year survival rate for both cancer types is around 90%. However, with a growing number of survivors, providers should be aware of the potential health effects these patients may experience. It is imperative to be familiar with the adverse effects of hormonal therapies, typically used long-term by many breast and prostate cancer patients. These treatments have been associated with numerous skin toxicities, usually not life-threatening but can reduce the quality of life, limit treatment adherence, and potentially affect health outcomes.

Scope of the Canadian Skin Management in Oncology Project

The CaSMO project was developed to improve the quality of life for cancer patients and survivors by offering tools to prevent and manage cutaneous adverse effects (cAEs).^2-4 A general management algorithm to reduce the incidence of all cutaneous toxicities and maintain healthy skin using general measures and over-the-counter agents³ and an algorithm to reduce and treat acute radiation dermatitis⁴ were previously published. These algorithms aim to support all health care providers (HCPs) treating oncology patients, including physicians, nurses, pharmacists, and advanced providers.^3,4 The algorithms were followed by a practical primer on prevention, identification, and treatment, including skin care for cutaneous immune-related adverse effects (AEs), focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid. The next step in the project was to develop an algorithm for cAEs in oncology patients receiving hormonal therapy.

Methods

The advisors convened for a meeting to develop the CaSMO hormonal therapy-related cAEs algorithm. The advisors used a modified Delphi approach following the AGREE II instrument.^5-7

Literature Review

The literature review included guidelines, consensus papers, and publications on the prevention and management of hormonal therapy-related cAEs published in English from January 2010 to January 2022. A dermatologist and physician/scientist conducted searches on PubMed and Google Scholar for English-language literature on January 25 and 26, 2022, using the following AND OR search terms:
Hormonal therapy; Hormonal therapy-related cAEs AND oral prescription medications OR topical regimes OR skincare, for prevention OR treatment OR maintenance; Hormonal therapy-related cAEs AND adjunctive skincare use, OR education of staff and patients, OR communication strategies, OR adherence, OR concordance, OR efficacy, OR safety, OR tolerability, OR skin irritation

Two reviewers independently evaluated the results of the literature search. Of the one hundred and ninety-one papers identified in the search, sixty-six were excluded for duplication or poor quality. The remaining one hundred and twenty-five publications included ninety-nine papers on hormonal therapy, six guidelines that included hormonal therapy, and twenty papers that discussed hormonal therapy-related cAEs, treatment, and skin care.

Hormonal Therapy

Breast cancer and prostate cancer are the most diagnosed cancers in females and males. In Canada, breast cancer accounts for 25.0% of all new cancer cases in females, and prostate cancer accounts for 20.3% of all new cancer cases in males.¹ Hormonal therapy is often given as adjuvant treatment for these cancer types to reduce levels of hormones that can fuel the growth of cancer cells.^8,9 These medications are used for extended periods, and adherence is threatened by AEs and their effect on patient quality of life.¹⁰

Approximately two out of three patients with breast cancer have hormone receptor-positive disease⁸ and will receive hormonal therapy for five to ten years to decrease the risk of disease recurrence and improve survival (Table 1).¹¹ Hormonal treatment for breast cancer consists of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and high-dose hormones. Prostate cancer cells need androgens to grow, and hormonal therapies decrease androgen levels by interfering with androgen production or blocking androgen actions.⁹ Hormonal treatment for patients with prostate cancer includes luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, androgen receptor blockers, and androgen synthesis inhibitors.^9,12

Table 1. Hormonal Therapies and Associated Cutaneous Adverse Effects

Type of Skin Reactions Associated with Hormonal Therapy

Hormonal therapies for breast and prostate cancer are associated with numerous dermatologic effects involving the skin, hair, and mucosal surfaces.¹³ Due to the decrease in estrogen or androgen levels, they can induce menopause or andropause, respectively, leading to various general and skin-specific symptoms. Flushing, reversible alopecia, and vulvovaginal atrophy are experienced by many patients taking SERMs and AIs. In general, tamoxifen causes more frequent and severe hot flashes and higher alopecia rates than AIs. Conversely, vulvovaginal atrophy is more common in patients receiving AI therapy.^13,14 In addition to symptoms of menopause/andropause, these medications can also cause androgenic alopecia, exacerbation of rosacea, hirsutism, and rashes.

The most common dermatologic AEs with androgen deprivation therapy (ADT) for prostate cancer are hot flashes, pruritus, and rash.⁹ Generally, men do not typically visit their doctor concerning skin issues associated with hormonal therapy. Instead, they are more likely to present with complaints of hot flashes, sweating, and changes to libido.

Patient and Caregiver Education

Most skin reactions associated with hormonal therapy for breast and prostate cancer are not life-threatening; therefore, providers may view them as minor or cosmetic issues.¹⁵ However, cAEs associated with these medications can profoundly affect the quality of life and are often not anticipated by patients. Almost 70% of patients who experienced cAEs reported that their reactions significantly limited their daily activities.¹⁶ Additionally, most patients reported that cAEs were worse than expected before starting therapy.¹⁷ As a result, these toxicities can threaten treatment adherence. Pretherapy counseling is critical to identify risk factors for skin toxicities, educate patients about potential cAEs, and identify helpful interventions that can enhance adherence.¹⁰

All HCPs who treat oncology patients receiving hormonal therapy should be involved in managing skin toxicities. Ideally, the oncology team should provide pretherapy counseling to all patients, so they are aware of potential dermatologic toxicities, know what symptoms they should report, and are familiar with preventive strategies. In addition, they can advise patients about which products to use or avoid, provide key messages about skincare, and potentially distribute skincare starter kits. When skin concerns arise, patients are likely to contact their family doctor, and they should be prepared to discuss preventive measures, offer treatment recommendations, assess the severity of cAEs, and refer severe cases to a specialist. Finally, dermatologists will see patients with more severe reactions and should be familiar with possible skin toxicities in patients receiving hormonal therapies and recommended treatment options.

Quality-of-life studies indicate that women are affected by dermatologic toxicities more than men.¹³ Ferreira and colleagues noted the potential impact of cAEs, stating, “These toxicities can affect a woman’s self-image, cultural identity, femininity, sexuality, and mental health.”¹³ Although women are more likely than men to contact their doctor with skin complaints, educating all patients on ways to prevent and treat skin toxicities associated with hormonal therapy is important. In addition, because they have less experience with skincare and are less likely to present with skin complaints, it is imperative to develop messages and visuals targeted explicitly to men receiving hormonal therapy for prostate cancer.

Algorithm on the Management of Hormonal Therapy-Related Cutaneous Adverse Effects

The algorithm aims to improve patient comfort during and after treatment, reduce the incidence of skin toxicities, and treat cAEs using prescription medication and skin care. After a systematic search for relevant publications, a dermatologist and a physician/scientist reviewed the literature and created a draft algorithm. Next, the advisors met to workshop the draft algorithm, incorporating their collective feedback and reaching a consensus through blinded votes. The final algorithm provides a high-level overview of the management of skin reactions associated with hormonal therapy (Figure 1).

The algorithm highlights the importance of educating patients before initiating hormonal therapy on the type of medication they will receive, its mechanism of action, and potential cAEs associated with the treatment. Additionally, the algorithm emphasizes the value of preventive skin care throughout hormonal cancer treatment (Table 2). This daily skin care regimen should include the use of gentle cleansers, moisturizers, and sun protection by all patients. Practitioners should continue to educate and assess patients for skin toxicities throughout treatment to improve adherence to therapy.

Table 2. General Skin Care Recommendations

Menopause/Andropause Symptoms

Hormonal therapies can induce menopause or andropause by interfering with hormone production or blocking hormone action. Patients receiving these treatments may present with general symptoms, including hot flashes, flushing, sleep disturbances, and hyperhidrosis. Additionally, they may experience skin-specific symptoms such as vulvovaginal atrophy, facial atrophy, and xerosis (Table 3).

Table 3. Treatments for Menopause/Andropause Symptoms

General symptoms of menopause/andropause:

Hot flashes, described as brief episodes of intense and uncomfortable heat, have been reported in 46% to 73% of breast cancer survivors.¹⁸ The feeling of overheating is often accompanied by facial flushing and blotchy erythema that spreads over the face, neck, and chest. Hot flashes typically have a quick onset and resolution and may be accompanied by sweating, palpitations, and anxiety.^19,20 Occurring at night can lead to night sweats and affect sleep quality.²⁰ Breast cancer survivors report higher rates of vasomotor symptoms than women without breast cancer, possibly due to the rapid transition to menopause during breast cancer treatment and exacerbation of estrogen deficiency caused by hormonal therapy.¹⁴ A population-based survey found that breast cancer survivors were over 5.3 times more likely to experience menopausal symptoms than women in the general population.²¹

All patients who will be treated with hormonal therapy should receive pretherapy counseling on lifestyle interventions and environmental modifications to prevent hot flashes and flushing. It may be helpful to wear lightweight clothing and dress in layers, use fans and other cooling aids, and avoid triggers, such as heat, stress, hot beverages, spicy food, and alcohol.^13,21 Additional nonmedical approaches that may be beneficial for some patients include exercise, yoga, hypnosis, acupuncture, and cognitive behavioral therapy that teaches relaxation and paced breathing.¹⁴

Although hormone-replacement therapy is the most effective treatment for vasomotor symptoms, it is contraindicated in patients with breast cancer.²² Nonhormonal management of hot flashes in breast cancer patients and survivors consists of low-dose antidepressants, anticonvulsants, clonidine, and oxybutynin.¹⁸ Recommended antidepressants include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), which have shown a 20% to 65% reduction in the severity and frequency of hot flashes in randomized clinical trials.²³ Paroxetine is the only nonhormonal therapy approved for treating vasomotor symptoms.^14,23 However, because paroxetine is a potent inhibitor of CYP2D6, its use should be avoided in patients taking tamoxifen. Instead, citalopram and escitalopram are the preferred SSRIs for patients taking tamoxifen.²³ SNRI venlafaxine is widely used in clinical practice because it has been well studied and has shown effectiveness in reducing hot flashes.^11,23 Venlafaxine and desvenlafaxine, another possible SNRI option, are safe to use in tamoxifen patients.²³ For vasomotor symptoms, doses of SSRIs and SNRIs are typically lower than antidepressant doses, and effects can be seen as soon as two weeks after treatment initiation.^18,23

Other than antidepressants, the anticonvulsant gabapentin is another first-line treatment option that has been associated with reductions in hot flash frequency and severity. As an added benefit, it may also help improve sleep quality.²³ Alternatively, pregabalin may be used, although it has been studied less than gabapentin.²³

Second-line agents for hot flashes include clonidine and oxybutynin. Clonidine is somewhat effective, although its use is limited by AEs such as hypotension, dizziness, xerostomia, and constipation.^14,23 The dose of clonidine should be titrated to the desired effect on vasomotor symptoms and effect on blood pressure.¹⁴ Long-acting transdermal clonidine is preferred to avoid AEs associated with oral clonidine. The anticholinergic agent oxybutynin may also be used to help manage vasomotor symptoms.¹⁸ Data are limited on the safety and efficacy of phytoestrogens, botanicals, and dietary supplements in breast cancer patients and survivors, and their use is not recommended.^14,18

Between 50% and 80% of men treated with ADT for prostate cancer report vasomotor symptoms.¹⁸ For most patients, hot flashes increase in frequency three months after initiating ADT therapy and persist throughout treatment.²⁴ It is important for clinicians to talk to their prostate cancer patients about this potential AE, as it can be debilitating and lead to treatment discontinuation. In fact, between 15% and 27% of patients receiving ADT indicate that hot flashes are the AE with the most significant impact on their quality of life. Prevention and treatment of ADT-related hot flashes in men is similar to what is recommended for women. Venlafaxine and gabapentin have both been studied in males experiencing hot flashes; the other agents are used in clinical practice but have not been tested in this population.¹⁸ Hormonal treatment using megestrol acetate, depot medroxyprogesterone, or transdermal estrogen may also be considered in male patients, but the benefits of these agents should be weighed against the risk of weight gain, sexual dysfunction, cardiovascular complications, and potential progression of prostate cancer.²⁴ Additionally, intermittent administration of ADT may be an option for some patients dealing with vasomotor symptoms.¹²

Sleep disturbance affects nearly 60% of patients receiving hormonal therapy for breast cancer²⁵ and is also commonly associated with the use of ADT for prostate cancer.¹⁸ Effects on sleep may result from changes in hormone levels, hot flashes, or night sweats.²⁵ Treating hot flashes may improve sleep quality, and gabapentin may be particularly helpful at bedtime. For patients who experience nighttime vasomotor symptoms that disrupt sleep, it is recommended to take gabapentin as a single dose one hour before bedtime to reduce hot flashes and help with sleep initiation.¹⁴ Alternatively, patients who experience vasomotor symptoms during the day and night can take gabapentin twice daily, with one dose in the morning and the second dose is taken one hour before bedtime. Melatonin may be beneficial for patients experiencing sleep disturbances, although it has not been studied explicitly in cancer patients or survivors taking hormonal therapy.²² Additionally, mind-body interventions, such as exercise, yoga, meditation, acupuncture, and cognitive behavioral therapy, may also have benefits for sleep.^22,25

Patients receiving hormonal therapy for breast and prostate cancer may also experience hyperhidrosis due to decreasing estrogen and androgen levels. Additionally, the SERMs raloxifene and tamoxifen are known to cause secondary hyperhidrosis.²⁶ Treatment recommendations depend on the severity and location of hyperhidrosis. Topical 20% aluminum chloride is recommended as first-line therapy for patients with hyperhidrosis. Intradermal administration of onabotulinumtoxinA can be used for patients who fail treatment with aluminum chloride or as first-line treatment for patients with severe symptoms; these treatments can be used in combination when patients fail monotherapy with the individual agents. Additional first-line options include iontophoresis for plantar or palmar hyperhidrosis and compounded topical 2% glycopyrrolate for craniofacial hyperhidrosis. When hyperhidrosis does not resolve using the above approaches, oral anticholinergic agents, such as oxybutynin and glycopyrrolate, may decrease sweating and disease severity.

Skin-specific symptoms of menopause/andropause:

Vulvovaginal atrophy is a common AE associated with hormonal therapy for breast cancer, with symptoms reported in up to 40% of patients taking tamoxifen and 74% of patients taking an AI.¹³ Hypoestrogenism results in thinner vulvar and vaginal epithelium, loss of glycogen, and increased vaginal pH.²⁷ As a result, patients may experience dryness, burning, irritation, and itching that can lead to dyspareunia. Vulvovaginal atrophy is also associated with urinary incontinence and urinary tract infections. These changes can significantly impact patient relationships and quality of life.^11,27

Mild symptoms of vulvovaginal atrophy can be treated with vaginal moisturizers and lubricants.^13,22 It is important to inform patients of the difference between moisturizers used continuously to increase vaginal moisture and improve pH and lubricants used as needed before intercourse.¹⁴ Vaginal dilators and pelvic floor physical therapy may also be helpful for some patients.¹³ When moisturizers and lubricants are not effective, low-dose vaginal estrogen therapy may be considered after consultation with the oncologist to discuss the benefits and risks of treatment.^13,14

Estrogen deficiency also affects facial skin by causing a decrease in sebum production, collagen content, dermal thickness, and elastin fibers.²⁸ When estrogen levels decrease, women may notice dryness, decreased firmness, thinning of the skin, fine wrinkling, and poor wound healing. For skin-specific symptoms of menopause, it is important to use a broad-spectrum sunscreen with SPF 30 or higher to protect the skin and prevent new wrinkles.²⁹ A mild cleanser and a moisturizer with hyaluronic acid or glycerin can help manage dryness. Retinoids may be recommended to increase collagen and improve wrinkles.

Androgenic Alopecia:

A meta-analysis¹⁰ including data from over 13,000 patients treated with hormonal therapy indicated that tamoxifen was the single-agent treatment associated with the highest incidence of all-grade alopecia (9.3%) and grade 2 alopecia (6.4%). Hair loss was observed in 2.2% to 2.5% of patients receiving single-agent AI therapy. The incidence of alopecia was highest for patients who received a combination of hormonal treatments. With hormonal therapies that lower estrogen levels, alopecia is thought to be caused by decreased estrogen stimulation and increased androgen stimulation of the hair follicles,¹⁵ which leads to an increase in hair loss during the telogen phase and a decrease in hair shaft diameter that leads to fragility, breakage, and subsequent hair loss.¹⁰ Androgenic alopecia typically presents as female pattern hair loss, with diffuse thinning over the scalp and the “Christmas tree pattern” along the center part.¹³

Most cases of alopecia associated with hormonal therapy are grade 1, which is defined as hair loss of less than 50% of normal for that individual that is not obvious from a distance.¹³ Alopecia associated with hormonal agents is generally reversible, but it tends to last for the duration of treatment.^10,13 While HCPs may view hair loss as a temporary or cosmetic issue; alopecia can be very distressing to cancer patients and survivors.¹⁵ Even low-grade alopecia has been associated with decreased quality of life and negative emotional impact.¹³

Before starting hormonal therapy, providers need to discuss the risk of alopecia with patients and encourage them to report any increase in hair loss that is not normal for them.³⁰ Although there are currently no preventive strategies for alopecia caused by endocrine therapies, it is essential that diagnosis and treatment start as soon as possible to improve prognosis. Once patients seek medical help for alopecia, the goal of treatment is to stop or reduce hair loss. Patients must be educated on their prognosis and understand that therapy focuses on maintenance, not hair regrowth.¹⁵

When a patient on hormonal therapy presents with alopecia, it is important first to rule out other causes, such as thyroid dysfunction or low iron, vitamin D, or zinc levels.¹⁰ Occasionally, scalp biopsy can be helpful to exclude early scarring alopecia or telogen effluvium, especially when patients present with alopecia that does not follow the typical androgenetic pattern.^10,31 After ruling out other contributing factors, patients with mild alopecia can use topical minoxidil 2% to 5% twice daily.¹⁰ Camouflaging sprays, powders, wigs, or extensions may also help conceal low-grade hair loss. Spironolactone may be considered after discussion with the oncologist for cases refractory to topical or oral minoxidil.^13,32 In abundance of caution, finasteride is not recommended for use in breast cancer patients or survivors.¹³ Although supplementation is recommended for patients with alopecia and low levels of vitamin D and iron, there is insufficient evidence to support the use of most other vitamin supplements. Of particular interest, the use of biotin supplements is not recommended because of a lack of supporting data and the fact that it can interfere with lab results.³³

Rosacea

Rosacea, an inflammatory dermatologic condition characterized by facial flushing that persists for at least three months, is classified into several subtypes based on clinical signs and symptoms (Table 4).³⁴

Table 4. Treatment for Rosacea

Patients with rosacea need to identify exacerbating factors to avoid these triggers.³⁴ Patients should be instructed on the importance of using mild, fragrance-free, non-alkaline cleansers and moisturizers that contain emollients and occlusives. Additionally, daily use of sun protection using a broad-spectrum sunscreen with SPF 30 or higher is recommended.^19,35

Treatment of rosacea varies according to the presentation. To treat erythema and inflammation, patients can use topical metronidazole, azelaic acid, ivermectin, or brimonidine.³⁵ Additionally, vascular laser therapy can treat erythema and telangiectasias. Patients who present with papulopustular rosacea can use the above treatments alone or in combination. Anti-inflammatory doses of doxycycline can also be used as monotherapy or in combination with topical treatment. If oral therapy with low-dose doxycycline is ineffective, other options include antimicrobial doses of doxycycline, various other antibiotics, or oral isotretinoin.

Hirsutism

Hirsutism is reported in less than 10% of breast cancer survivors receiving hormonal therapy¹⁵; however, this AE is likely underreported (Table 5).³⁰ For mild hair growth (grade 1 hirsutism), local therapies such as plucking, waxing, and electrolysis may be helpful.^15,36 For prominent thick hairs that are associated with psychosocial impact (grade 2), laser therapy or pharmacologic treatment may be considered. Eflornithine (Vaniqa) topical cream can slow terminal hair growth rates on the face and under the chin.³⁷ It is applied to affected areas of the face and chin twice daily, at least 8 hours apart, and can be combined with local hair removal methods.^36,37 Spironolactone up to 200 mg per day can be considered, but this decision should be made in consultation with the oncologist due to the potential risk of hormonal stimulation in patients with hormone-positive breast cancer.³⁶ Finasteride should not be used in breast cancer patients or survivors.^13,32

Table 5. Treatment for Hirsutism

Other Eruptions

Aside from the above cAEs that are commonly observed with hormonal therapy for breast and prostate cancer, some of the individual medications can cause other skin toxicities.

Especially, a newer androgen receptor antagonist, apalutamide has been associated with high rates of dermatologic reactions. An analysis of 303 patients with prostate cancer treated with apalutamide showed that 23.4% experienced a dermatologic AE of any grade, most commonly maculopapular rashes, and xerosis.³⁸ In both the SPARTAN and TITAN trials, apalutamide was associated with a higher incidence of skin rash compared with placebo (23.8% vs. 5.5% for SPARTAN and 27.2% vs. 8.5% for TITAN).³⁹ An integrated analysis of data from Japanese patients in these two studies, plus the PCR1008 study, indicated that the incidence of rash with apalutamide was nearly double in the Japanese population compared with the global population. Rash associated with apalutamide was easily managed with drug interruptions, dose reductions, and supportive medication, including oral antihistamines, topical corticosteroids, or systemic corticosteroids. The median time to resolution was one month. Treatment discontinuation was required in 14.3% of the integrated Japanese population, 9.9% of the global SPARTAN population, and 8.5% of the global TITAN population. Rash, pruritis, and xerosis can occur with AI therapy.⁴⁰ There have also been rare reports of cutaneous vasculitis, erythema nodosum, subacute cutaneous lupus erythematosus, lichen sclerosus vulvae, erythema multiforme, and erythema multiform-like eruption associated with use of AIs.

While tamoxifen is generally well tolerated, it has been associated with a wide range of less frequent dermatologic AEs. Approximately 19% of patients receiving tamoxifen will experience a cAE during treatment.⁴¹ These reactions can vary from the common occurrence of flushing to the rare and serious development of Stevens-Johnson syndrome. Other potential skin toxicities that have been associated with tamoxifen include urticaria, vasculitis, hypersensitivity reactions, and subacute cutaneous lupus erythematosus. Cutaneous reactions typically occur within the first couple of weeks to months after initiating therapy, but there have been reports of delayed reactions that present years after starting tamoxifen. Treatment for cAEs includes discontinuation of tamoxifen and use of antihistamines, topical corticosteroids, or systemic corticosteroids when appropriate. Depending on the severity of the reaction, tamoxifen may be gradually restarted under close observation, or the patient may be switched to another hormonal therapy.

Combination Treatment:

The risk of dermatologic AEs is even higher when hormonal therapies are combined with other anticancer treatments.⁴² Targeted therapies, such as phosphoinositide 3-kinase (PI3K) inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, and cyclin-dependent kinase (CDK) inhibitors, are often used in combination with hormonal therapy and can contribute to skin toxicities.

Rash is common when patients begin treatment with the PI3K inhibitor alpelisib in combination with fulvestrant. Therefore, the ESO-ESMO guidelines recommend the use of a nonsedating antihistamine for the first four weeks of therapy.²² Alpelisib labeling includes a warning for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Alpelisib should be held when patients present with signs or symptoms of SCARs and should be permanently discontinued if SCARs are confirmed.⁴³ Additionally, when alpelisib is added to fulvestrant, the rates of stomatitis, rash, alopecia, pruritis and xerosis are increased compared with fulvestrant plus placebo.⁴³

mTOR inhibitors can cause paronychia and stomatitis.¹³ To prevent paronychia, patients should be instructed on gentle nail care, including regular trimming, avoiding manicuring, and wearing shoes that fit correctly. Topical corticosteroids can be used to treat chronic paronychia, and topical antibiotics and antiseptic washes can be used for bacterial infections. Oral or intravenous antibiotics may be necessary to treat more serious secondary infections. A steroid mouthwash containing dexamethasone can be used to prevent stomatitis.²² Treatment delays and dose reduction should be considered for stomatitis higher than grade 2. Additionally, dental steroid paste can be considered for the treatment of ulcers.

A high incidence of alopecia was seen in studies involving the CDK 4/6 inhibitors palbociclib, abemaciclib, and ribociclib.⁴⁴ Other dermatologic AEs observed with CDK 4/6 inhibitors include mild rash, as well as rare cases of Stevens-Johnson syndrome.

Corticosteroid-related cAEs:

High-dose corticosteroids are frequently used in the treatment of cancer and are associated with various adverse effects, including cAEs. The use of systemic corticosteroids can cause acne, skin atrophy, impaired wound healing, and ecchymosis.⁴⁵ Additionally, corticosteroids can result in hirsutism or thinning of hair.

Conclusion

Patients receiving cancer treatment and survivors live longer. They require information on risk factors of clinically significant events, preventive strategies, and treatment, which would contribute to the optimal care of patients with cancer. This algorithm aims to provide HCPs with information on various skin toxicities associated with hormonal therapies for breast and prostate cancer, including preventing and treating these AEs. With this knowledge, providers will be better equipped to manage cAEs in this population, thereby contributing to improved quality of life, treatment outcomes, and therapy adherence.

¹Diplomate of the American Board of Dermatology, Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Medicine University of Toronto, Onco-dermatologist, Princess Margaret Cancer Centre, Director, Toronto, ON, Canada.
²Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine, Division of Dermatology, Laval University, Director Melanoma and Skin Clinic, Le Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Quebec City, QC, Canada.
³Medical Oncologist, Medical Oncology Disease Site Lead for Melanoma/Skin Oncology, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre. Assistant Professor, Department of Medicine, University of Toronto, Associate Member, Department of Immunology, University of Toronto, Toronto, ON, Canada
⁴Radboud UMC, Nijmegen and Andriessen Consultants, Malden, The Netherlands.
⁵Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Oncology, McGill University; Director, Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
⁶Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine University of Toronto, Toronto, ON, Canada, Lynderm Research, Markham, ON, Canada.

Abstract
The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) quality of life by offering tools to healthcare professionals for preventing, reducing and/or managing cutaneous adverse events (cAEs).
Immunotherapy, specifically immune checkpoint inhibitors (ICIs), for cancer patients is both increasing in indications and use. Similarly, the incidence and onset of cutaneous immunotherapy-related adverse events (cirAEs) vary based on the class and dose of immunotherapy administered, the type of cancer, and factors related to the patients. Dermatologists will increasingly see side effects from immunotherapy.

The CaSMO advisors developed a practical primer on prevention, identification, and treatment, including skincare for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.
A modified Delphi approach was used for the cirAEs practical primer’s development. Recommendations given by the CaSMO advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions.

According to the CaSMO group, the management of cirAEs starts with physician awareness and patient education on the occurrence of toxicities, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before immunotherapy begins and ongoing thereafter as part of the lifestyle.

Keywords: Immunotherapy, cutaneous adverse events, immune checkpoint inhibitor, skin toxicity, psoriasis, pruritus, morbilliform, eczema, bullous pemphigoid

Disclosures
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the manuscript, reviewed it and agree with its content and publication.

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Introduction

In 2021 an estimated 229,200 Canadians were diagnosed with cancer.¹ In Canada, of the four most commonly diagnosed types of cancer (lung, breast, colorectal, and prostate), excluding non-melanoma skin cancer, lung cancer is the most lethal and expected to cause more deaths than the other types combined.^2,3

Immunotherapy activates the body’s immune system to fight cancer. Immune checkpoint inhibitors (ICIs) prevent the deactivating signal by blocking the T-cell shut-off receptors and ligands from binding to each other, thereby disrupting signaling so that T cells remain active and can then recognize and attack cancer cells.^4,5 ICIs are approved for treatment across almost every type of solid-organ tumors, many hematologic malignancies, and in many instances, first-line therapy.^4,5 In 2019, in the United States, approximately 40% of oncology patients were eligible for treatment with immunotherapy.⁶ ICIs may be administered as a single agent (anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab, and avelumab)) or as combination immunotherapy (ipilimumab and nivolumab) and even as a combination with other agents.^4-6

Oncology patients treated with immunotherapy may experience cutaneous immunotherapy-related adverse events (cirAEs) at any time during and after the cancer treatment, severely impacting the quality of life (QoL) and potentially cancer treatment outcomes.^7-24 The incidence and onset of cirAEs vary depending on the drug class, the type of cancer, and factors related to the patient.²⁵ Adverse skin reactions occur in 14%–47% of patients treated with ICIs, ranging from mild and localized to debilitating and widespread in 1%–3% of patients and even potentially causing death.^15,16,26-30 Nivolumab-related cirAEs, including isolated pruritus, occurred in approximately 13–20% of patients, of which 0.7% of patients reported grade three or higher cAEs.^29-33 Pembrolizumab-induced cirAEs occurred in 9%–27% of patients, of which 1%−4% of patients reported grade three or higher cirAEs.^34,35

Frequently occurring cirAEs include pruritus without primary dermatologic findings (isolated pruritus), lichen planus or lichenoid drug eruptions, psoriasiform reactions, eczematoid eruptions, morbilliform eruptions, and bullous diseases, primarily bullous pemphigoid.^7-24  

The cirAEs may indicate a therapeutic response. A multicenter retrospective study on patients with non-small-cell lung carcinoma (NSCLC) receiving nivolumab showed that AEs and cirAEs were a strong predictor of survival outcomes, and those presenting with more than 2 AEs showed more benefit than patients with fewer AEs.¹⁴  Vitiligo occurs in some patients with melanoma receiving ICIs (Figure 1), and this is significantly associated with both progression-free-survival (PFS) and overall survival (OS) which indicated a two to four times lower risk of disease progression and death.^32,36

Major guidelines^10-12 recommend the use of systemic steroids for grade 2 or higher “rash” contrary to evidence showing the use of systemic steroids reduces the anticancer effect of ICIs.³³  A secondary analysis of a randomized trial on stage III melanoma patients with cirAEs showed that patients who received treatment with systemic steroids for 30 days or longer had lower OS than those without steroid treatment.³³  Another multicenter retrospective analysis of patients treated with anti-PD-1 therapy showed that high-dose glucocorticoids used to treat AEs were associated with poorer PFS and OS.³⁵

Scope of the Canadian Skin Management in Oncology Project

The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) QoL by offering tools for preventing and managing cAEs.^37-39 A general management algorithm to reduce the incidence of all cutaneous toxicities and maintain healthy skin using general measures and over-the-counter agents³⁸ and an algorithm to reduce and treat acute radiation dermatitis³⁹ were previously published. These algorithms aim to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and other medical providers.^38,39 The next step in the project was to develop a practical primer on prevention, identification, and treatment for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.

Table 1: Immunotherapy classes, molecules, and indications

CTLA-4 impinges on many features of T-cell biology.^43,44  The CTLA-4 signaling pathway and the PD-1/PD-L1/PD-L2 signaling pathway are critical checkpoints that are used to down-regulate the body’s immune system that tumors often exploit and activate, thereby evading the body’s immune system.^43,44 CTLA-4 dampens T-cell responses via cell-intrinsic and extrinsic pathways. Intrinsic events include, among others, inhibition of protein translation, recruitment of phosphatases, activation of ubiquitin ligases, inhibition of cytokine receptor signaling, and inhibition of lipid microdomain formation on the surface of T-cells. Cell extrinsic events include the competition for CD28 in binding to its ligands CD80/86, the removal of CD80/86, the release of suppressive indoleamine-dioxygenase, and the modulation of Treg function. Antibodies to CTLA-4 may facilitate T-cell tumor entry and alter the movement in tumors and rates of egress.^43,44

cirAEs can present as almost any dermatologic condition, but most are inflammatory dermatoses.^7-11,26 The median time to onset of cirAEs is four weeks but has a broad range from 2 to 150 weeks, including beyond treatment discontinuation.^15,17,45

cirAEs of any grade have been reported at 30-40% of patients receiving PD-1/PD-L1 and approximately 50% of patients treated with ipilimumab.³¹  Maculopapular rash and pruritus are common cirAEs related to these treatments.³¹

A systematic literature review on cancer treatment with pembrolizumab and nivolumab observed that the most frequently occurring cirAEs were inflammatory dermatitis, pruritus, and vitiligo.⁴⁶ The rate of any-grade cirAEs with pembrolizumab and nivolumab was reported at 16.7% (RR=2.6) and 14.3% (RR=2.5), respectively.⁴⁶ The cirAEs may be associated with pruritus and comprised of erythematous macules, papules, and plaques, predominantly low-grade and localized to the trunk and extremities.⁴⁶ Challenges with reports of cirAEs are accurate descriptions and diagnoses of the specific dermatoses as many are simply reported as “rash”. Additional cirAEs comprised pruritus [incidence pembrolizumab and nivolumab was 20.2% (RR=49.9) and 13.2% (RR=34.5) respectively] and vitiligo [incidence, 8.3% (RR=17.5) and 7.5% (RR=14.6) respectively].⁴⁵ The researchers noted that knowledge of cirAEs is critical in delivering optimal cancer treatment, maintaining therapeutic agent dose, and health-related QoL.⁴⁶

The advisors agreed that cirAEs are likely an indicator of ICIs treatment efficacy and should be managed with topical treatment and judicious, ideally steroid-sparing systemic treatment where possible.^33,35-38

Approaches to the most common immunotherapy-related cAEs

The advisors discussed and selected the most common cirAEs: isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, morbilliform (maculopapular) eruptions, and bullous pemphigoid eruptions.^7-25,27-30

According to the advisors, the management of cirAEs starts with patient education on the occurrence of cirAEs, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before ICIs treatment begins and ongoing during survival as part of the lifestyle.^9-25

Diagnosis of cirAEs

When diagnosing the cirAEs, other etiologies such as an infection, an effect of other agents, or other skin conditions should be ruled out.^8-11 

Biopsies play a role in accurately diagnosing the cirAEs when morphology is not clear. Histopathologically, cirAEs can be categorized into four broad groups, group 1: Inflammatory skin disorders, which reflect acute, subacute, or chronic inflammation of various patterns associated with variable epidermal changes, including psoriasiform or lichenoid interface chronic dermatitis.^16,50-53 Group 2: ICIs-related bullous skin lesions such as bullous pemphigoid or dermatitis herpetiformis, group 3: Keratinocyte alteration—Grover’s disease⁵⁴/acantholytic dyskeratosis, and group 4: Immune-reaction mediated by alteration of melanocytes such as regression of nevi, tumoural melanosis, and vitiligo.^29,36,48-52 For this review, we will only be focusing on the selected cirAEs.

When assessing the severity of cirAEs, grading systems’ trial limitations need to be considered.⁹ The Common Terminology Criteria for Adverse Events (CTCAE) classification is typically used; however, in the case of clinical trials, clinicians should be cognisant of the version the trial is using as different versions of CTCAE have different definitions and categorizations.²⁶

A general approach to prevention or reduction of cirAEs as well as initial management of the previously published CaSMO algorithm is displayed (Figure 2) for reference.³⁸  

Isolated Pruritus

Immunotherapy-related isolated pruritus occurs frequently and has a significant impact on QoL (Figure 3).^{7-25,31,46,55-57}  Diagnostic criteria for pruritus have been described as core symptoms, including duration of pruritus (more than six weeks) and a history of signs of scratching.^63,64 Associated criteria comprise a range of clinical manifestations, symptoms, functions, and emotions. The function includes the extent of impaired QoL, sleep loss, and days of absence from work. Emotions include possible psychological reactions such as, depression, anxiety, anger, and helplessness.⁶⁴

Isolated pruritus should be a diagnosis of exclusion once other causes such as pre-bullous pemphigoid, bites, or other drug reactions are ruled out.

A stepwise approach includes starting with over-the-counter topical agents, topical prescription agents, systemic drugs, and phototherapy.^63,64 General principles before starting topical and/or systemic treatment comprise skincare using gentle cleansers and moisturizers, especially in the presence of xerosis.^63,48

The CaSMO algorithm educates on general measures such as avoiding skin irritants, scented products, temperature extremes, sun, and the use of sun-protective clothing (e.g., brim hats and sunglasses). The information should be provided before immunotherapy starts, and this is especially important for isolated pruritus.³⁸ The daily skincare regimen should be reinforced with emphasis on gentle cleansers, skin moisturization, and sun protection – similar counseling to a patient with atopic dermatitis.^37,38,47  

A prurigo nodularis 4-tier treatment ladder⁶⁴ addresses neutral and immunologic mechanisms that may be applicable to ICIs-induced pruritus.⁶⁴ Immunologic mechanisms are more likely to be the underlying mechanism in ICIs-induced pruritus. Patients can enter the treatment ladder at any tier and move up or down the ladder based on their clinical presentation.⁶⁴  Immunologic tier 1 is more likely mechanisms can be treated with TCS, TCI, or topical calcipotriol.⁶⁴  Moisturizers, including antipruritics such as pramoxine 1% or formulations with menthol or camphor, may be used as an adjunct therapy.⁶⁴ 

For tier 2 neural mechanisms of pruritus medications include selective nor­epinephrine reuptake inhibitors (SNRIs) (i.e., mirtazapine) and gabapentinoids (gabapentin and pregabalin), which have antipru­ritic properties.^63,64  Second-generation histamine H1 receptor antagonists were shown to be effective and safe for patients receiving ICIs.⁶⁴ 

Additional second-line systemic therapies such as neurokinin 1 inhibitors (i.e., aprepitant) and inhibi­tors of interleukins (ILs) 4, 13 may be considered for the tier 3 immunologic mechanisms approach.⁶⁴ When evaluating the need for systemic or topical treatment, possible interactions with cancer therapy are assessed together with concomitant conditions and cirAEs.^{9-11,15,16,23,24 37,38,47}

Clinicians should take caution using systemic steroids and immunomodulators for patients receiving cancer treatment with ICIs (Table 2).^9-11

Table 2: Isolated pruritus

Psoriasiform Eruptions

T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) drive the pathogenesis of psoriasis by orchestrating inflammation in the skin triggering proliferation of keratinocytes and endothelial cells.⁶⁵ Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation.^66-70  ICIs are thought to be driven through the TH17 pathway, and this may have implications on the development of psoriasis but also on the use of systemic psoriasis medications.^64,65,71,72

Immunotherapy with anti-PD1 and anti-PDL1 can exacerbate psoriasis, although more severe flares were noted in patients treated with durvalumab.^65-68,70,71

A personal or family history of psoriasis is a significant risk factor that should be identified before starting immunotherapy.^65,66,68 These patients require regular skin monitoring enabling early diagnosis and treatment of psoriatic exacerbations.^65,66,68 Prompt diagnosis can prevent a severe impact on QoL of this cirAE that may compromise therapeutic protocols and final cancer prognosis (Figure 4).^53,65,66 A skin biopsy to confirm the diagnosis, although not required, includes parakeratosis, hypogranulosis, regular acanthosis, suprapapillary plate thinning, and neutrophils at various layers of the epidermis.^68,70

Psoriasiform cirAEs can affect skin, nails, and joints and significantly impact QOL.^65-71 Psoriasis can be associated with arthritis as patients have a greater-than-expected incidence of psoriatic arthritis when it occurs as a cirAE of cancer treatment.^33,65,66 The choice of therapy takes many factors into account, including the extent and area of involvement, lifestyle, other health issues, and medications. First-line treatments include topical treatment with TCS, TCI, calcitriol, or a combina­tion of a super potent TCS with calcipotriol or tazarotene can be given.^65-71  For recalcitrant cases, consider adjuvant narrowband ultraviolet B therapy or oral treatment such as systemic retinoids [acitretin] or apremilast.^72-75  Although there is no direct evidence in ICIs treated cancer patients, methotrexate is immunosuppressive and may reduce the therapeutic effect of ICIs, similar to systemic steroids that have been shown to reduce RFS and OS.^32,33,35

Acitretin or apremilast is preferred over methotrexate; however, there is an absence of data for apremilast on the effect it may have on the anticancer treatment.^68-75  If the lesions persist, treatment with biologics may be required to treat psoriasiform cirAEs. IL-23 agents (gulselkumab, risankizumab, tildrakizumab) are considered most targeted and have the least direct evidence of immunosuppression (e.g. infection and TB reactivation). However, the risk/benefit needs to be considered before starting treatment with biologics (Table 3).^76-86

Lichen Planus

Immunotherapy-induced lichen planus is a pruritic, papulosquamous disease that can affect skin, hair, and nails (Figure 5). Treatment is required, especially if pruritic when it can severely impact QoL.^{7-19,27,33,46,63,77,78} When examining the patient exclude guttate psoriasis, mucositis, and bullous disease. Specific investigations include a detailed medical history and medication use, liver function tests including hepatitis C status, and, if required, a skin biopsy.⁷⁹

Pruritus may be treated with second-generation histamine H1 receptor antagonists (e.g., blistane, rupatadine, cetirizine and fexofendadine).^63,64,79 A retrospective analysis of clinical data investigating if commonly used medications might influence responses to checkpoint inhibitors. The researchers found that concurrent use of second-generation histamine H1 receptor antagonists correlated with significantly improved survival outcomes in those with melanoma or lung cancer. In addition, the antihistamine was effective for treating pruritus in cirAEs.^63,64,79 The choice of therapy takes many factors into account, including the extent and area of involvement, other health issues, and medications.^{8-11,67-69,78,80} First-line treatment includes moisturization and sun avoidance, antihistamines, TCS, and TCI.^80,81 Other second-line treatments include oral retinoids (acitretin), apremilast, sulfasalazine, metronidazole, hydroxychloroquine (especially for scalp or presentation with arthritis).⁸⁰ Additionally, narrowband or broadband UVB or PUVA may be used. Treatment with cyclosporine should be avoided as it may exert effects on the immune system (Table 4).^25,31,78

Table 4: Lichen planus

Eczematous Eruptions

Eczematous eruptions (EE) are associated with altered immune function, epidermal barrier dysfunction, genetic and environmental factors, and poorly understood interaction between these factors.^82-85 EE presents clinically as relapsing erythematous and pruritic patches of skin with varying severity (Figure 6).^9-11,82-85  Skin biopsies may be taken if the condition is extensive or not responding to therapy or if the diagnosis is in doubt.^9-11 Canadian and US guidelines for topical treatment of atopic dermatitis include education and avoiding triggers, routine skincare with gentle cleansers and moisturizers, and EE management foundation regardless of disease severity and prescription treatment.^82,83 Conventional moisturizers contain occlusives, humectants, and emulsions. Newer moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions.^{36,38,47,82,83} If EE is not controlled with a moisturizer alone, TCS, TCI, or crisaborole ointment, an anti-inflammatory inhibitor of PDE4, is recommended while continuing skincare.^9-11,82-86   Treatment with crisaborole ointment achieved early sustained control of atopic dermatitis flares (reduced pruritus, erythema, exudation, excoriation, induration/papulation, and lichenification).^84,85  The topical PDE4 inhibitor offered a safe alternative to TCS and TCI.^84,85

For those not adequately controlled with topical treatment, nbUVB may be considered.^82,83 Dupilumab is a humanized monoclonal antibody against the shared alpha subunit of IL-4 and IL-13 receptors, blocking these cytokines commonly found in atopic dermatitis-affected skin. The use of dupilumab may be considered for extensive, moderate-to-severe EE. Two large, long-term RCTs demonstrated its efficacy and safety.^{9-11,82,83,86}  

Another option is tralokinumab (IL-13 inhibitor) which was shown to be effective and safe for the treatment of severe atopic dermatitis.⁸⁷

Treatment with the biologic is preferred to methotrexate which is an immunosuppressive and may reduce the anticancer effect.^9-11 TCS, TCI, and crisaborole can be used with any systemic treatment to address an EE flare (Table 5).^82-85,93

Morbilliform (maculopapular) Eruptions

These cirAEs may present as pruritic, nontender, erythematous papular, and macular eruptions on various body locations.^37,38,46,47 Physical examination focusing on the morphology and the distribution, starting on the trunk and then spreading to limbs, of the presented morbilliform eruptions is required to distinguish between the various cirAEs (Figure 7).^37,38,46,47 Laboratory tests may be needed and include a complete blood count, electrolytes, renal and liver function, and inflammatory markers.^37,38,46,47 Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders (Table 6).^37,38,46,47  Mild to moderate conditions may be treated with general skin care measures, TCS, TCI, and oral histamine H1 receptor antagonists to reduce pruritus.^63,64,94 Generally, this condition can be managed with aggressive topical treatment; however, for very severe and symptomatic cases, ICIs-treatment may be held, and a short course of systemic corticosteroids may be indicated.⁹⁴ 

Table 6: Morbilliform eruptions

cirAE BP can occur at any time, including after discontinuation of ICI. The onset to developing BP is within days or weeks of ICI exposure or may be delayed several months after starting ICI.³¹ Upon diagnosis ICIs is to be held and may require permanent discontinuation.^3,15,46 In milder cases, aggressive topical treatments with class I TCS may be as effective as systemic steroids.⁹²  cirAE BP may require systemic treatment and temporary, if not permanent, cessation of immunotherapy.^3,15,46 Systemic corticosteroids may be used the achieve control quickly while waiting for steroid-sparing treatments to take effect.^88,90-92 Non-immunosuppressive systemic treatment includes oral tetracycline-class antibiotics combined with oral niacinamide 500 mg twice a day, omalizumab, IVIg, and dupilumab.^31,88,90-92 However, steroid-sparing agents that are immunosuppressive may be required in order to control BP ongoing, including methotrexate, mycophenolate mofetil or rituximab.⁹¹ While rituximab may be immunosuppressive, it works on B-cells and may not hinder the T-cell activation from ICIs. In patients with cirAE BP, obtaining disease control as quickly as possible is ideal not only for improved QoL, and decreased morbidity but also if treatment is to be reinitiated (Table 7).^93,95

Table 7: Bullous eruptions

Limitations

The details provided on the mode of action of ICIs were limited to what is clinically relevant for this primer on cirAEs. Clinical studies on prescription medications and skin care for cirAEs frequently are case reports, case series, or have small sample sizes. For this reason, grading the evidence resulting from the literature searches was irrelevant. Therefore, recommendations given by the CaSMO project advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions. More work is required to identify the best practice evidence-based management of cirAEs.

Summary and Conclusions

Immunotherapy for cancer patients is fast-developing into the standard of care for many malignancies. Although many publications are available on cirAEs, publications on the treatment using prescription medications and skincare are scarce.

The CaSMO practical primer focuses on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid. The practical primer addresses the need for physician awareness, patient education on the occurrence of cirAEs, prompt diagnosis, prevention, treatment, and ongoing skincare started before ICI.

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83. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116–132.
84. Yosipovitch G, Simpson EL, Tan H et al. Effect of crisaborole topical ointment, 2%, on atopic dermatitis–associated pruritus: an extended analysis of 2 phase 3 clinical trials. Itch 2019;4(1)p e12.
85. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.e6
86. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348
87. Wollenberg A, Blauvelt A, Guttman-Yassky E et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-449.
88. Fontecilla NM, Khanna T, Bayan CY, et al. Bullous pemphigoid associated with a new combination checkpoint inhibitor immunotherapy. J Drugs Dermatol 2019;18:103-104.
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90. Siegel J, Totonchy M, Damsky W, et al: Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018;79:1081-1088.
91. Lopez AT, Khanna T, Antonov N, et al. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol 2018;57:664-669.
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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.

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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.

Abstract:
Introduction: Cancer treatment has significantly improved overall survival and progression-free survival of patients; however, adverse cutaneous reactions are common. If not treated effectively, cutaneous sequelae may lead to severe morbidities that seriously affect the patients’ quality of life (QoL) and decrease cancer-treatment outcomes.

Objectives: The Canadian skin management in oncology (CaSMO) algorithm focuses on general skincare measures for cancer-treatment-related skin toxicity prevention and management to improve patient outcomes.

Methods: The CaSMO algorithm working group used an online procedure to reach a consensus on the algorithm, which was built using evidence from the literature combined with the panel’s opinion and experience.

Results: The algorithm has the following steps: Education on cancer treatment-related skin toxicities for clinicians and patients, prevention/reduction measures, evaluation of severity, skincare management, including general management. Prevention measures include daily and frequent skincare use, including cleansers and moisturizers to support skin hydration.

Conclusions: The CaSMO algorithm focuses on general skincare measures that may help prevent or reduce the severity of cancer-treatment-related skin toxicities, improving treatment tolerability leading to improved patient outcomes.

Key Words:
cancer treatment-related cutaneous toxicities; skincare

Introduction

Due to increased cancer incidence and improved 5-year survival rates in Canada, a growing number of people are living with cancer and the sequelae of cancer treatment, including cutaneous sequelae.^1-2 Depending on the cancer type, stage, and patient-related factors, cancer treatment may include surgery, radiation therapy, chemotherapy, targeted therapy, hormonal treatment or stem cell transplantation, and more recently, targeted therapy and immunotherapy.^3-8 Although technology and agents used for cancer treatment have significantly improved overall survival and progression-free survival, adverse cutaneous reactions are common.^3-10 Clinicians and healthcare providers are focused on the tumor’s clinical response and potentially life-threatening side effects.⁸ After life-threatening reactions are ruled out; skin toxicity-related adverse events may lead to morbidities that significantly affect the patients’ quality of life (QoL).^8-14 Additionally, cutaneous side effects may hamper optimal cancer treatment due to treatment reduction, interruption, or discontinuation.¹⁵ Over 50% of cancer patients experience a treatment interruption due to dermatologic adverse events that can ultimately lead to treatment discontinuation.^8-15

A review of one-hundred thirteen dermatology consultations over a two months period in 2015 of patients with cancer treatment-related skin toxicities showed a high discordance between referring clinicians and dermatologists.¹⁵ Of the 79 patients receiving hematologic cancer-treatment, 41 (52%) patients had their treatment interrupted. Of the ten cases where discontinuation of therapy was recommended, the dermatologists agreed on one case. The study illustrates the importance of dermatological consultations for these patients.¹⁵

A retrospective study of outpatients with cancer treatment-related skin toxicities seen by a dermatologist reported a high frequency of positive cancer treatment outcomes with a low recurrence of skin toxicity, overall indicating fewer cancer-treatment interruptions.¹⁶

Few studies have evaluated the impact on QoL of cancer treatment-related skin toxicity. A study by Lee et al. evaluated 375 patients who received cancer treatment for breast cancer (136 [36.27%]) or colorectal cancer (114 [30.40%]). It showed that clinicians’ observations on the impact of cutaneous toxicities on QoL might differ from what patients report, and the patients’ age did not affect skin toxicity-related QoL. However, the type of cancer treatment and the duration of the therapy reduced patients’ QoL.⁸ In line with findings from other researchers, the study demonstrated that the symptoms such as itching, dry skin, easy bruising, pigmentation, papulopustular rash on the face, periungual inflammation, nail changes, and palmoplantar lesions particularly lead to a reduction in QoL.^8-14

A survey evaluating patients’ quality of life resulting from cutaneous toxicities demonstrated a reduction in QoL but concluded that dermatologic care resulted in improved patient satisfaction outcomes. However, patients were unsure if dermatologic interventions aided in improved cancer-treatment adherence.¹⁷

Before starting cancer treatment, patients should be counseled on the potential skin adverse events and ideally review preventative measures that include a basic skincare regime.^18-25 Oncologists, family physicians, oncology nurses, pharmacists, and dermatologists have the opportunity to join forces to care for oncology patients with skin reactions and to share evidence-based knowledge.²⁵ Among physicians, there may still be a bias against using skincare in the context of oncology treatment. Hesitation to use skincare may stem from earlier experiences with potentially harmful products (e.g., fragranced, elevated pH, etc.).²³ Currently, there are gentle cleansers, moisturizers, and sunscreens available that this group believes are ideally suited for oncology patients.^23,24

Scope

The CaSMO project aims to improve patient outcomes by preventing and managing cancer treatment-related skin toxicities. A review article by the CaSMO working group²⁶ discussed a holistic approach to cancer patients’ treatment, including patient education, therapeutic relationship, and frequent, open communication between the patient and the oncology team. The working group further recommended measures for preventing and treating skin toxicities using a skincare regime involving hygiene, moisturization, and sun protection.²⁶

The current CaSMO algorithm is designed as a first in a series and focuses on general skincare measures for cancer-treatment-related skin toxicity prevention and management. The clinical algorithm is easy to apply also by non-dermatologists. It targets all healthcare providers dealing with oncology patients, including specialist physicians, primary and palliative care physicians, nurses, pharmacists, and radiation technologists.

This algorithm will be followed by other algorithms developed for specific cancer treatments and related skin toxicities, e.g., radiation, traditional chemotherapies, targeted therapies, and immunotherapy.

Methods

The CaSMO algorithm working group, a panel of clinicians treating oncology patients, was to convene for a one-day meeting; however, due to the COVID-19, a web conferencing meeting took place on March 29, 2020. The algorithm was developed following the AGREE II instrument²⁷ using a modified Delphi approach. A concept algorithm based on the literature selected before the web conference was discussed and adopted using clinical evidence coupled with the expert opinion and experience of the CaSMO working group members. An online procedure was then used to reach consensus through blinded reiterations and votes to define the final algorithm. The CaSMO working group’s consensus on the algorithm was established as an eighty percent agreement was obtained.

Literature Review

A literature review included guidelines, consensus papers, and publications on the management of oncology treatment-related skin toxicities, clinical and other research studies published in the English language from January 2010 to January 2020.

Excluded were articles with no original data (unless a review article was deemed relevant), not dealing with skincare for prevention and treatment of oncology treatment-related skin toxicity, publication language other than English. A dermatologist and a physician/scientist conducted the searches on January 30 and 31, 2020, on PubMed and Google Scholar as a secondary source of the English-language literature, using the terms:

Skincare regimes for prevention and treatment of cutaneous toxicities associated with radiation treatment, chemotherapy, targeted therapy, immunotherapy, hormonal treatment, prevention, management, maintenance of cutaneous toxicities, health-related quality of life, and skincare

The results of the searches were evaluated independently by two reviewers; discrepancies were resolved by discussion. The searches yielded two-hundred and thirty-six publications. After the exclusion of duplicates (n = 94) and articles (N = 109) that were deemed not to be relevant for the algorithm (other subjects, low quality, a small number, case studies), thirty-three papers remained. Twenty-three were review articles, including one guideline, two algorithms, and two systemic literature reviews, of which one was a meta-analysis. Additionally, we selected eight clinical studies and two books (Figure 1).

Cancer Treatment-Related Skin Toxicities

Each type of cancer treatment is associated with specific skin reactions. A recently published review article by the CaSMO working group gives a more detailed description of cancer treatment-related cutaneous toxicities.²⁶ Specific reactions are beyond the scope of this article and may be featured in future articles from the CaSMO group.

The CaSMO Algorithm

Features of a Medical Algorithm

For the development of the CaSMO algorithm, the unpublished mnemonic RECUR (Reliable, Efficient, Clear instructions, Understandable, Remember easily) was used.

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.²⁷ The best algorithms have inputs and outputs, precisely defined specific steps, and uniquely defined results that depend on the preceding steps.²⁷

The current algorithm focused on preventing or reducing and managing skin side effects of cancer treatment using skin care measures. The algorithm has the following steps: education on cancer treatment-related skin toxicities for both clinicians and patients, prevention/reduction measures, evaluation of severity, initial dermocosmetic management, and eventual reaction specific management (Figure 3A and 3B).

Education on Cancer Treatment-Related Skin Toxicities

Education on cancer treatment-related skin toxicities is essential for both clinicians and patients.^8,26 The panel agreed that before initiating cancer treatment, the first step is building a therapeutic relationship with the patient enabling active participation of the patient in their cancer treatment plan. The plan should be viewed holistically, with attention to health determinants such as education, mental health, income, social status, access to resources, and geographic location.^3,5,26

A detailed discussion between the patient, treating physician and nurse, or other team members, if applicable, includes explaining the treatment protocol, potential side effects, hospital visits, diagnostic tests, management of AEs, and prophylactic and preventative measures.^3,5,26

Strategies suggested by the panel include:

1. Educating patients on the skin changes that may occur by giving both verbal information and print or online references (Table 1).^3,5,26
2. Informing the patient on who to contact when they experience an AE.²⁶
3. Establishing proactive contact with the patient, especially in the early stages of treatment.²⁶
4. Addressing AEs early^3,5,26

Patients often underreport their skin changes or confuse them with reactions related to other factors, i.e., allergies, weather, diet, stress, or they do not want to be a bother.⁵ (Box 1: Information)

• Establish a proactive contact with the patient from the start of the treatment.
• Encourage frequent communication, develop a rapport and trust, and ensure open communication between the patient and the team.
• Have a detailed discussion with the patient, treating physician and nurse, or other team members explaining the treatment protocol, AEs, hospital visits, diagnostic tests, management of AEs, prophylactic, and preventative measures.
• Provide detailed patient education on the skin changes that may occur before starting the cancer treatment.
• Explain to the patients that they should always report their skin changes, regardless of severity.
• Reinforce that prevention and early treatment of AEs lead to better cancer-treatment outcomes and quality of life.

Box 1: Information and patient education

The panel stressed that fluid, ongoing, and frequent communication is essential while checking if the patient’s information is processed and understood. The clinician should emphasize the importance of early and detailed reporting by the patient of new and worsening AEs during the treatment period and the follow-up, explaining that it is much easier to manage or resolve AEs when detected early.^5,23,24,26 Moreover, low-grade AEs may not initially seem severe to patients who frequently fear discontinuing their cancer treatments.^23-25

Prevention Measures Using Skincare

The focus of the initial steps of the algorithm is on skincare measures. The over-the-counter (OTC) skincare regime should start before the cancer treatment begins to prevent skin toxicities ^3,5,26 It is essential to inform the patient about the importance of good skin hygiene and barrier maintenance.³ At the same time, provide education on general measures such as avoiding skin irritants, scented products, temperature extremes, sun avoidance, and the use of sun-protective clothing (e.g., brim hats and sunglasses).²⁶ The daily skincare regime should contain products addressing hygiene with gentle cleansers, skin moisturization, and sun protection.^22-26

The skincare formulations for patients undergoing cancer-therapy should be safe, effective, free of allergens and irritants such as common preservatives causing allergy, fragrances, and perfumes.²⁶ Skincare formulations should also have a near physiologic skin surface pH.^24-26,28 A physiological skin surface pH is acidic (4.0–6.0), while a high skin surface pH may lead to skin irritation, dryness, and elevated inflammation.^26,28 Soaps, surfactants, and detergents, especially those with an alkaline pH, may excessively remove natural moisturizing factors and skin lipids, elevating skin surface pH, which is explicitly damaging for cancer patients and those at risk for cancer treatment-related skin toxicities.^26,28 A skin cleanser with a near physiologic skin surface pH (4.0–6.0) is less aggressive than alkaline soaps and has demonstrated benefits when used for inflammatory skin conditions.²⁸

Daily and frequent use of a non-occlusive moisturizer to support skin hydration is generally accepted practice, although there is a lack of evidence to support their use.²³ Moisturizers form a barrier that retains water by preventing transepidermal water loss (TEWL). Additionally, moisturizers may have hydrophilic humectants, such as glycerol, propylene glycol, butylene glycol, alpha hydroxyl acids (AHAs), including lactic, glycolic, and tartaric acids. Use AHA’s with caution as they can change the pH and be irritants.²³ An example of a hydrophilic matrix substance is hyaluronic acid, a mucopolysaccharide found in the dermis that functions as both a humectant and a penetration enhancer.²³ (Box 2: Skincare using cleansers and moisturizers) A review of topical agents for treating radiation therapy-related skin toxicities concluded that emollients containing aloe vera, chamomile, ascorbic acid, pantothenic acid, dexpanthenol, and trolamine lacked therapeutic effect²⁹ and may cause irritation or allergy. (Box 3: Criteria for moisturizers)

• Use gentle cleansers such as those with a near-physiological skin pH (4.0 – 6.0).^28,26
• Avoid the use of soap and cleansers with an alkaline pH (> 7), which may excessively remove skin lipids, elevating skin surface pH, and compromise the skin barrier function further.^28,26
• Apply moisturizers to the face, hands, feet, neck, and back daily.²⁶
• Choose a moisturizer vehicle based on skin condition, level of xerosis, and patient preference.,²⁶
• Apply moisturizers liberally and frequently.²⁶

Box 2: Skincare using cleansers and moisturizers

• Skincare formulations should be safe, effective, free of additives, fragrances, perfumes or sensitizing agents.²⁶
• Skincare formulations should have a physiologic skin surface pH.^23-25,28
• Moisturizer effectiveness depends on the formulation, the vehicle, frequency, and compliance of applications.^23,26
• Skincare product choices depend on the skin condition, availability, costs, and individual preferences.^23,26

Box 3: Criteria for moisturizers

A study on the efficacy and tolerability of thermal water containing skincare regime (La Roche-Posay) consisted of two types of cleansers, a moisturizer, a healing baume, and an SPF50+ sunscreen.²⁶ The skincare was used for preventing skin toxicity 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 heavy users who daily used the total skincare regime showed significantly (p ≤ 0.0001) less severe skin toxicities than those with lower skincare regime use who used parts of the regimen from time to time.²⁶

Sunscreens are part of a complete program for sun protection that includes protective clothing and sun avoidance.³⁰ Sunscreens can be classified as UVB filters, UVA filters, or physical blockers.³⁰ A broad-spectrum sunscreen protects against both UVA and UVB light. UVA filters are active in the range of 320–400 nm, while UVB blockers are active in the range of 290–320 nm.³⁰ Sunscreens such as oxybenzone and octocrylene have UVA activity in the 320–340 nm range. Avobenzone, benzophenones, and dicamphor sulfonic acid are effective in most of the UVA range.³⁰ Most currently available sunscreen formulations aim for coverage of both UVA and UVB spectra. Physical blockers, including titanium dioxide and zinc oxide, are effective in both the UVA and UVB ranges.³¹ Most dermatologists recommend daily sunscreen of SPF 30 or higher, especially for sun-exposed areas, 15 minutes before sun exposure and every 2 hours after that. 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.³¹ (Box 4: Sunscreen)

• Sunscreens are one part of a complete program for sun
  protection that includes protective clothing, shade, and sun avoidance.²⁶
• Sunscreens and sunblocks may prevent photodamage
  and can be classified as UVB filters, UVA filters, or physical blockers.^26,30,31
• Sun protection factor (SPF) refers to UVB radiation, and broadspectrum refers to the sunscreen’s UVA radiation protection capacity.
• Apply daily sunscreen of SPF 30 or higher, especially for sunexposed areas, 15 minutes before sun exposure and every 2 hours after that.^26,31
• Special populations that are at higher risk for sun-induced
  toxicities and neoplasms are advised to avoid sun exposure by using UVA and UVB protection as well as sun-protective clothing.²⁰
• The recommended amount of sunscreen needed for one application to an adult is 2 mg/cm2 or about 35 g to cover an adult in a swimsuit.²⁶

Box 4: Sun protection

Assess for Life-Threatening or Dangerous Reactions

If, despite a preventative approach to skincare, cutaneous toxicities occur, clinicians must first assess if the reaction is dangerous or life-threatening. The patient’s demographic data, medical history, cancer characteristics, performance status, previous cancer therapies, past dermatological history, and concomitant skin conditions should be reviewed.⁶ Physical examination focusing on the morphology and the distribution of the presented cutaneous toxicity is important to distinguish between the various presentations (Table 2).^6,20,32-34

To ensure the skin toxicity is not dangerous or life-threatening, the clinician should check five significant symptoms:²⁶

1. Does the patient have a fever?
2. Are blisters or skin detachment present?
3. Is the skin painful?
4. Is there mucous membrane involvement (oral, ocular, or genital)?
5. Does the patient have abnormal laboratory blood values?

Laboratory tests should include a complete blood count, electrolytes, renal and liver function, and inflammatory markers, among others.³² Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders, and evaluation should seek to identify the cause and possible organ involvement.³²

Severe cutaneous toxicities include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), overlap SJS-TEN, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS).^6,7

The most significant cutaneous eruption is SJS, TEN, or SJS-TEN overlap characterized by extensive epidermal loss (<10% SJS, >30% TEN, 10-30% SJS-TEN overlap) with mucous membrane erosions and often presents as an impaired general condition.^35-36 Management requires immediate discontinuation of the offending agent, hospitalization ideally to a burn unit, early involvement of ophthalmology, gynecology, and urology to prevent permanent scarring.^35-36 The medical treatment of SJS, TEN, or SJS-TEN overlap varies by institution and typically involves high dose intravenous steroids as well as steroid-sparing agents.^6,35-36 The evidence for optimal treatment of this life-threatening condition is an evolving field and beyond the scope of this paper.

Patients with acute generalized exanthematous pustulosis (AGEP) present with fever and hundreds of non-follicular, sterile pustules on a background of edema and erythema. AGEP has a predilection for face and intertriginous areas that then progresses to become widespread. AGEP can be associated with neutrophilia, hypocalcemia, and transient renal dysfunction.^6,7,35-36

Patients with DRESS typically present fever, facial edema, lymphadenopathy, and morbilliform eruption with follicular accentuation, which may progress to erythematous rash and exfoliative dermatitis.^6,7,36 Hematologic abnormalities, including eosinophilia and atypical lymphocytosis, are a hallmark of the condition. Visceral organ involvement typically manifests as hepatitis but may include thyroiditis, nephritis, interstitial pneumonitis, or myocarditis.^6,7,36 Visceral organ involvement, especially thyroiditis and myocarditis, may develop up to a year after the initial reaction.³⁶

It is crucial to determine the cancer-treatment that caused the reaction and determine the correct diagnosis to prevent further risks and long-term sequelae.^6,7 Definitions and grading of cutaneous AEs may pose challenges and require consultation with a dermatologist to identify the AEs correctly.^20,34 For practical reasons, as the current algorithm focuses on skincare, skin toxicities were not graded. Future algorithms by the CasMo group discussing the various types of cancer treatment-related skin toxicities in detail will address grading.

Treatment Measures With a Focus on Skincare

Most skin rashes are mild-to-moderate, but some that are not dangerous or life-threatening can still be severe, leading to cancer treatment dose reduction, dose delay, or discontinuation.^6,20,32-34 Initial assessment of the cutaneous toxicity should establish if it exacerbates a pre-existing dermatologic condition or a new reaction.³² For exacerbation of a pre-existing skin condition, patients should initiate pre-existing plans for acute exacerbations of their condition.³² For example, a patient with atopic dermatitis may need to increase the frequency or strength of topical steroids or steroid-sparing agents during an acute exacerbation.^37-40 If they do not have pre-existing plans for acute exacerbation, follow-up with their healthcare provider most responsible for the management of their pre-existing condition is recommended.³² Condition-specific medical treatment is outside the scope of this paper.

In patients with new eruptions, this is most likely a result of the cancer treatment.^32,37-40 However, other causes should be excluded, such as concurrent over the counter products, medications, or infections.^32,37-40

Reinforcing general skincare measures discussed prior to treatment and then adapting the measures according to the clinical presentation and individual patient’s needs can aid in managing the eruption.²⁶ Depending on the condition, additional measures to skincare may be beneficial (Table 2).^3,5,26

Improving the diagnostic and symptomatic management of cancer treatment-related skin toxicities may limit dosage reductions or treatment discontinuations.²⁵ Moreover, when identified early, the impact on patients’ quality of life of the cutaneous AEs may be less severe.^23,32 It is therefore essential to describe the skin symptoms accurately and identify appropriate dermatological treatments to guarantee both the physical and psychological well-being of patients and optimum cancer treatment conditions.^23,30

The panel suggests that including dermatologists in the team and building cutaneous toxicities team(s) may be beneficial for providing urgent access to care, managing dangerous or life-threatening cutaneous symptoms, and improving quality of life.^25,26 Consultation with a dermatologist may also reduce the risk of disruption of oncologic treatment.^25,26

Chen et al. (2019) showed that patients were less likely to receive systemic steroids if a dermatologist was involved in treating cutaneous toxicities.^25,26

Implementation of the Algorithm

A multidisciplinary shared care model will be used when implementing the algorithm. The model will include medical oncologists, family practice/internal medicine, dermatologists, oncology nurses, advanced practice providers (APPs), nurse practitioner (NP), physician assistant (PA), and pharmacists. Additionally, oncology patient organizations need to be informed and included in the process.

Limitations

A few 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 spur more skincare studies to prevent and manage cutaneous toxicities.

Conclusion

The CaSMO algorithm focuses on general skincare measures to prevent or reduce the severity of cancer-treatment-related cutaneous toxicities. Increased awareness of cutaneous adverse events by the multidisciplinary team treating and guiding the cancer patient through their journey may improve treatment tolerance. Moreover, daily and frequent skincare use, including cleansers and moisturizers to support skin hydration, may help prevent cutaneous toxicities or reduce their severity, leading to improved patient outcomes.

Key Words:
antineoplastic agents, BRAF inhibitors, CTLA-4 antigen, immunomodulatory agents, lymphatic metastasis, melanoma, skin neoplasms

Background

The management of metastatic melanoma constitutes an important medical challenge, as it accounts for more than 80% of skin cancer deaths, and its incidence has increased over the past decades worldwide.¹ In 2013, an estimated 6,000 new cases of melanoma will be diagnosed in Canada and 1,050 deaths will be attributed to this disease.² Its ability to disseminate to regional and distal sites results in a poor prognosis.³

While surgical treatment of early stage disease is often curative, metastatic melanoma carries a significantly less promising outlook with a high associated health burden and economic cost. A multidisciplinary approach optimizes the management of metastatic melanoma. Patients, including those with metastatic disease, often view their dermatologist as an integral part of their multidisciplinary team and turn to them for information and guidance in decision making. Further, an increasing number of dermatologists are playing a key role in coordinating the care of their patients with melanoma. For this reason, it is crucial for dermatologists to remain informed about treatment options for metastatic disease in order to provide patients with current information and to participate in the management of dermatologic adverse events (AEs) of various therapies.⁴

New Therapies for Metastatic Melanoma

Until very recently, approved treatment options for patients with metastatic melanoma were limited to chemotherapy and interleukin-2 (IL-2).⁵ Chemotherapy, particularly with dacarbazine (DTIC), has failed to show a survival benefit over supportive care,⁵ and treatment with IL-2, while associated with some durable responses, has significant toxicity.⁶

As a result, metastatic melanoma has become a focus for the development of novel treatment approaches including targeted and immunoregulatory therapies. Targeted therapy is directed toward c-KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue), BRAF (v-raf murine sarcoma viral oncogene homologue B), MEK (mitogen-activated protein kinase kinase), and NRAS (neuroblastoma RAS viral (v-ras) oncogene homologue). Of recent interest is vemurafenib – a highly selective inhibitor of mutated BRAF protein kinase – that has demonstrated improved survival in patients with metastatic melanoma. Immunoregulatory therapy targets include CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD1 (programmed cell death-1), and PDL1 (PD-Ligand 1),⁷ whereby disabling these proteins enhance the immune system’s ability to recognize and attack cancer cells. In particular, ipilimumab is a monoclonal antibody against CTLA-4, an inhibitor of T-cell activation. Ipilimumab potentiates an immune response rather than targets the tumor itself.⁸

Vemurafenib has demonstrated activity in patients with metastatic melanoma who harbor the V600E BRAF mutation. In the pivotal phase III trial (BRIM-3) of previously untreated patients, an early analysis of the data demonstrated a statistically significant benefit in overall survival (OS) with vemurafenib compared with DTIC (hazard ratio [HR] of 0.37; 95% confidence interval [CI]: 0.26-0.55; p<0.001) while the median OS had not yet been reached at the time of publication.⁹ Based on these findings, vemurafenib received Health Canada approval in 2012 for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma.¹⁰ In a follow-up analysis of the BRIM-3 data with a data cutoff of February 1, 2012, the median OS for vemurafenib was 13.6 months versus 9.7 months for DTIC with an HR for death of 0.70 (95% CI: 0.57-0.87) in favor of vemurafenib.¹¹*

Ipilimumab, in a pivotal phase III trial, demonstrated OS benefit when compared with a glycoprotein 100 vaccine in pretreated patients with unresectable or metastatic melanoma. The median OS was 10.1 months (95% CI: 8.0-13.8) compared with 6.4 months (95% CI: 5.5-8.7) in patients receiving the vaccine.¹² In a second phase III trial of ipilimumab in treatment-naïve patients with unresectable stage III or IV melanoma, the OS benefit was reproduced when ipilimumab was combined with DTIC (median OS 11.2 months)¹³ resulting in approval by Health Canada in 2012.¹⁴

Adverse Events (AEs)

With the approval of vemurafenib and ipilimumab, and increased research into related compounds, their use will rapidly become more widespread. While use of these agents can result in significant clinical benefits, they also have unique AEs. Most AEs are mild and can be managed with supportive treatment, but some require special management strategies.¹⁵ Furthermore, as some of the AEs are cutaneous in nature, dermatologists will increasingly be called upon for their expertise in managing them.¹⁶ As a result, the timely coordination and follow-up between members of the multidisciplinary care team will be important.

Vemurafenib

In the phase III BRIM-3 trial, the most common AEs observed with vemurafenib included grade 2 and 3 arthralgias (18% and 3%), rash (10% and 8%), photosensitivity (12% grade 2 or 3), fatigue (11% and 2%), cutaneous squamous cell carcinoma (SCC) (12%), keratoacanthoma (KA) (2% and 6%), nausea (7% and 1%), alopecia (8% grade 2), and diarrhea (5% and <1%). AEs led to dose interruption or modification in 38% of patients enrolled in the study.⁹

Broader experience outside of a phase III setting has demonstrated that the cutaneous AEs associated with vemurafenib therapy include a toxic erythema-like eruption, a keratosis pilaris-like eruption (Figure 1), which have been documented in as many as 20% of patients at one institution, and hyperkeratosis of hands/ feet (Figure 2).¹⁷ Photosensitivity (Figure 3) and the development of secondary cutaneous SCC/KA (Figure 4) are also relatively common.¹⁶ SCC/KA usually develops between weeks 2 and 14.15 It is generally well-differentiated with no metastatic potential and can be treated with surgical excision.¹⁸ At baseline, patients should have a thorough skin examination and be monitored regularly throughout treatment. A dermatologist should be consulted when any new skin lesions develop and excisions should be arranged.¹⁵ As far as the rash is concerned, daily use of a moisturizing cream could be used as a preventive measure. Mild-to-moderate eruptions are usually managed with moderate strength topical steroids prescribed in a sufficient amount. If the rash becomes severe, a dermatologist should be consulted for treatment recommendations.¹⁵ Table 1 summarizes some of the cutaneous AEs associated with BRAF inhibition and suggests management options.

Figure 1: Keratosis pilaris-like eruption

Figure 2: Hyperkeratosis of feet

Figure 3: Photosensitivity

Figure 4: Secondary cutaneous SCC of the KA-type

Figure 5: Papillomas

Ipilimumab

With respect to ipilimumab treatment, the AEs are immune response-related (irAEs) and cover a wide range of systems including dermatologic, gastrointestinal, hepatic, and endocrine. Of the irAEs, dermatologic toxicity is the most common and appears in weeks 2-4 of treatment. Dermatologic irAEs include pruritus, rash, and vitiligo and are reported in over 40% of patients for all grades, while grade 3 and 4 events are seen in 1-3% of patients.¹⁵

Patients should be monitored for signs and symptoms of dermatitis, such as rash and pruritis. For mild-to-moderate events, topical moisturizers, antipruritics, and oatmeal baths can be used to manage symptoms. If there is no improvement within one week, topical or systemic corticosteroids can be administered (0.5 mg/kg/day of prednisone or equivalent). No dose interruption is necessary for mild events but may be considered for moderateto- severe events. Severe events should be treated with systemic corticosteroids at 1-2 mg/kg/day of prednisone or equivalent. For patients with Stevens-Johnson syndrome, toxic epidermal necrosis, or rash complicated by full thickness dermal ulceration or necrotic, bulbous, or hemorrhagic manifestations, ipilimumab should be permanently discontinued, patients should ideally be taken in charge by specialized units, and systemic corticosteroids administered at the same dosage used to manage severe events. Corticosteroid tapering should occur over 4-6 weeks once symptoms improve to mild severity or resolve.^14,15,24

A Paradigm Shift

As a result of the ability to identify specific mutations in a patient’s melanoma, the disease has recently earned the designation as “an unlikely poster child for personalized cancer therapy.”²⁵ The treatment paradigm for metastatic melanoma is changing with the novel agents now available for treating this disease. As these agents transition from the clinical trial context to widespread clinical practice, and as newer therapies and combinations thereof continue to be studied, the multidisciplinary team will face challenges not only in the optimal choice of therapy for their patients, but also in the timely and aggressive management of their AEs. As the development of new anticancer agents accelerates, education and awareness of these AEs across disciplines is essential in order to ensure the safety of patients being treated with these drugs.

Development of resistance to these new agents has been demonstrated. To overcome this, it is important to understand the mechanisms of resistance. Early evidence provides a rationale for the combination of immune modulation with ipilimumab and BRAF inhibition with vemurafenib.¹⁵ However, there are a number of overlapping toxicities with these agents, particularly dermatologic AEs. Effective management strategies for these AEs will need to be developed concurrently with clinical investigations of efficacy in order to optimize patient outcomes.

The improvements in accuracy of predicting response to therapy will undoubtedly lead to better disease control, resulting in a renewed sense of hope in a therapeutic area that has historically had poor outcomes.

Acknowledgements

The authors acknowledge medical writing support from Diana Stempak, MSc, PhD and Cathie Bellingham, PhD of New Evidence; this support was funded by Hoffmann-La Roche.

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