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.

PDF Download

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.

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

PDF Download

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.

¹Division of Dermatology, McGill University, Montreal, QC, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada
³Division of Clinical Dermatology & Cutaneous Science, Dalhousie University, Halifax, NS Canada
⁴Probity Medical Research, Waterloo, ON, Canada
⁵Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
⁶Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁷Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁸Division of Hematology, Department of Medicine, McGill University, Montreal, QC, Canada
⁹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
¹⁰Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest: Elena Netchiporouk has received grants, research support from Novartis, Sanofi, Sun Pharma, AbbVie, Biersdorf, Leo Pharma, Eli Lilly; speaker fees/honoraria from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma and consulting fees from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma. Irina Turchin served as advisory board member, consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Mallinckrodt, Novartis, Pfizer, Sanofi, UCB. Wayne Gulliver received grants/research support from AbbVie, Amgen, Eli Lilly, Novartis and Pfizer; honoraria for advisory boards/invited talks from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant and clinical trial (study fees) from AbbVie, Asana Biosciences, Astellas, Boehringer-Ingelheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, UCB. Gizelle Popradi has received honoraria or speaker fees from Jazz Pharma, Seattle Genetics, Abbvie, Kite Gilead, Pfizer, Taiho, Servier, Novartis, Merck, Kyowa Kirin, Abbvie, Avir Pharma, Mallinckrodt. Robert Gniadecki reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Charles Lynde was a consultant, speaker, and advisory board member for Amgen, Pfizer, AbbVie, Janssen, Novartis, Mallincrodt, and Celgene, and was an investigator for Amgen, Pfizer, AbbVie, Janssen, Lilly, Novartis, and Celgene. Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Topics included in this article were based on, but not limited to, broad discussions at an advisory board meeting, which was sponsored and funded by Mallinckrodt, Inc. Consultancy fees were paid to meeting participants (EN, IT, WG, JD, MK, RG, CL and IVL). All other authors declare no existing competing interests.

Abstract:
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions. ECP was initially approved by the US FDA in 1988 for the treatment of Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma (CTCL). Although CTCL remains the only FDA-approved indication, ECP has since been used off-label for numerous other conditions, including graft-versus-host disease (GvHD), systemic sclerosis, autoimmune bullous dermatoses, Crohn’s disease, and prevention of solid organ transplant rejection. In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis. Herein, we review the current concepts regarding ECP mechanism of action, treatment considerations and protocols, and efficacy.

Key Words:
extracorporeal photopheresis, cutaneous T-cell lymphoma, S.zary syndrome, systemic sclerosis, graft-versus-host disease, safety.

Introduction

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions (Figure 1).^1,2 ECP was initially approved by the Food and Drug Administration (FDA) in the United States in 1988 for the treatment of S.zary syndrome (SS), a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course, characterized by a triad of circulating neoplastic T-cells, erythroderma, and lymphadenopathy.¹ Although CTCL remains the only FDA-approved indication, ECP has since been used as an off-label treatment for numerous other conditions, including graft-versus-host (GvHD) disease, systemic sclerosis (SSc), autoimmune bullous dermatoses, Crohn’s disease, and to prevent solid organ transplant rejection.^1,2 In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis (Tables 1-2). The goal of this article is to review the current concepts regarding ECP mechanism of action, treatment considerations as well as suggested treatment protocols and efficacy in CTCL, GvHD, systemic sclerosis and other skin diseases.

Table 1. The use of ECP by hospital and by city in Canada in 2020.

Table 2. The use of ECP by city and by indication in Canada in 2020.

ECP involves placing a catheter to gain access to the venous circulation and collecting blood via continuous or discontinuous cycles, which is then centrifuged to create a leukocyte-rich buffy coat. The isolated leukocytes are then placed in a sterile treatment cassette, injected with liquid 8-methoxypsoralen (8-MOP) and exposed to ultraviolet A (UVA) radiation. Afterwards, the photochemically-altered white blood cells are returned to the patient’s venous circulation (Figure 1).^1,2 The Therakos^® ECP machine (the only available unit for this treatment) represents an automated closed system. Each treatment lasts approximately 1.5-3 hours, and the scheduling and frequency of treatments depend on the disease being treated.

The exact mechanism of action of ECP remains unknown, however, in CTCL, it is believed that the procedure leads to DNA-crosslinking and apoptosis of pathogenic T cells induced by 8-MOP with UVA exposure, the differentiation of monocytes to dendritic cell that present tumor antigens from apoptotic lymphocytes, stimulation of anti-tumor immune responses, and shifting of immunoregulatory cytokines to Th1 cytokine profile, such as interferon-gamma and tumor necrosis factor (TNF) alpha, thus restoring the Th1/Th2 balance.^1-4 In particular, ECP targets mostly tumor cells since the absolute number of normal T cells remains relatively stable after the procedure.¹ Given its therapeutic benefit in transplant rejection and autoimmune diseases, ECP is also believed to have unique immunomodulatory properties generating needed responses in an autoimmune setting, which are thought to be similarly mediated by DNA-crosslinking and apoptosis of autoreactive leucocytes (natural killer (NK) and T cells) and induction of T-regulatory cells after treatment, although this phenomenon was not observed in patients with SS.² However, unlike immunosuppressive therapies, ECP is not associated with an increased risk of opportunistic infections.² In fact, ECP is overall well-tolerated, with no reports of post-treatment Grade III or IV side effects, as per the World Health Organization classification.² In particular, ECP is not associated with side-effects that are observed with skin systemic psoralen with UVA (PUVA) therapy, since the psoralen is not ingested orally nor applied to the skin.² The side-effects are primarily related to fluid shifts and the need for a central catheter. Rare side-effects of ECP include nausea, photosensitivity, transient hypotension, flushing, tachycardia, congestive heart failure and thrombocytopenia.^1,2 Contraindications to the use of ECP are summarized in Table 3. Currently, ECP is available in over 200 treatment centers across the world treating numerous diseases.² The use of ECP by hospital, region and indication in Canada is summarized in Tables 1-2. Unfortunately, treatment access is limited in Canada and significant knowledge gaps are recognized (i.e., paucity of randomized clinical trials and real-world evidence) amongst physicians and patients. As a result, this treatment may be significantly underused in Canada.

Table 3. Summary of contraindications to the use of ECP

CTCL

CTCL represents a group of lymphoproliferative disorders where there is an accumulation of malignant T-cell clones in the skin.² The most commonly recognized forms of CTCL are mycosis fungoides (MF) and SS. There are currently no curative treatments for CTCL, except for allo-transplantation which has been successful in select patients.² ECP is often used as a first-line treatment for SS, as well as for patients with erythrodermic MF or advanced CTCL.¹ Its use in early stages of CTCL remains controversial and impractical in Canada as many other effective treatment modalities are available (Table 4).^5,6 ECP can be used as monotherapy or it can be safely given in combination with phototherapy (narrow band or broadband UVB), radiotherapy, total skin electron beam (TSEB), systemic retinoids, interferons, anti-CCR4 monoclonal antibodies, histone deacetylase inhibitors, methotrexate, and/or other treatments.^1,2 One meta-analysis of 400 patients with all stages of CTCL showed a combined overall response rate (ORR) of 56% both when ECP was used as monotherapy and in combination with other therapies.² The complete response (CR) rates were 15% and 18% for monotherapy and combination therapy, respectively.² However, the ORR and CR were 58% and 15%, respectively, in erythrodermic patients, and 43% and 10% in patients with SS.² The CR was defined as a complete resolution of clinical evidence of disease and for normalization of CD4/CD8 ratio for at least 1 month. The partial response (PR) was defined as greater than 25% but less than 100% decrease in lesions and no development of new lesions for at least 1 month. ORR was defined as a sum of PR and CR. Furthermore, the United Kingdom consensus statement analyzed 30 studies between 1987 to 2007 and determined that the mean ORR and CR rates were 63% (range 33-100%) and 20% (range 0-62%), respectively, with higher response rates observed in erythrodermic patients. Many factors can explain the variability in the results of these studies, such as patient selection bias, stage of the disease, ECP treatment schedule, prior treatments, and end-point definitions.² In addition, there is a significant amount of inter-subject variability in response rates to ECP and factors that predict treatment response, as summarized in Table 5.²

Table 4. Treatment options for CTCL (MF)

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.

Different countries have varying guidelines with respect to the use of ECP in CTCL. Most recently, the European Dermatology Forum (EDF) published new recommendations in 2020. They recommend considering ECP as first-line therapy in patients with MF clinical stages IIIA or IIIB (erythroderma), or MF/SS stages IVA1 or IVA2 (Tables 6-7). Treatments are recommended every 2 weeks for the first 3 months, then every 3-4 weeks, with a treatment period of at least 6 months or until remission is achieved, followed by a maintenance period (Table 8).² ECP can take 3-6 months before a clinical response is appreciated, and therefore, no conclusions regarding its success should be drawn before that timeframe in erythrodermic patients.^1,2

Table 6. TNMB classification of MF and SS

Table 7. Clinical staging for MF and SS.

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.

GvHD

GvHD can be either acute or chronic based on clinical presentation and time to disease development.¹ Classic acute GvHD (aGvHD) occurs within 100 days of the transplantation with typical features, whereas chronic GvHD (cGvHD) presents after 100 days. However, persistent, recurrent or lateonset aGvHD can occur after 100 days with typical features of aGvHD. If features of both aGvHD and cGvHD are present, it is considered an overlap syndrome.⁷ cGvHD occurs in 30- 50% of patients receiving an allogenic transplant, involves multiple systems and most commonly presents with mucosal, skin, gastrointestinal and liver involvement.² First-line therapy consists of systemic glucocorticosteroids with or without a calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, imatinib, ibrutinib and rituximab.² Notably, phase III randomized clinical trials evaluating ruxolitinib versus best available therapy for steroid refractory or dependent cGvHD demonstrated superiority of this drug when compared to ECP and other agents (ORR 50% vs. 26%, p<0.001).⁸ The average response rate to ECP is approximately 60% and studies have shown ORR rates ranging from 36-83%. In addition, CR in the skin, oral disease, and liver ranged from 31-93%, 21-100% and 0-84%, respectively.² Best responses using ECP are seen in skin followed by gastrointestinal and then hepatic GvHD. The EDF recommends considering ECP as an additional secondline therapy in patients with cGvHD that is steroid-dependent, steroid-intolerant, or steroid-resistant, as well as for those with recurrent infections or with a high-risk of relapse (Table 8). Also, steroid-dependent patients (i.e., inability to reduce corticosteroid dose to <0.5 mg/kg/day without recurrence of Grade II or worse cGvHD) could benefit from ECP.

Similarly, systemic glucocorticoids are currently used as firstline therapy for aGvHD.² However, response rates are <50%.² In 2019, the US FDA approved ruxolitinib for steroid-refractory aGVHD in adult and pediatric patients ≥12 years of age. This approval was based on an open-label, single-arm, multicenter study of ruxolitinib that enrolled 49 patients with steroidrefractory aGVHD Grades II-IV occurring after allogeneic hematopoietic stem cell transplantation.⁹ Clinical trials have shown the superiority of ruxolitinib therapy when compared to ECP and other treatments (ORR 62% vs. 39%, p<0.001).¹⁰ In these patients, ECP may serve as an additional second-line treatment with ORR of 65-100% in the skin, 0-100% in the liver, and 40-100% in the gastrointestinal tract.² As such, the EDF recommends adjunct ECP, as second-line therapy, in patients not responding to appropriate doses of systemic corticosteroids (Table 8). Interestingly, it is also showing promising results as a prophylaxis therapy to prevent cGvHD.¹ This treatment option may be considered by dermatologists consulting on these patients in acute setting in the hospital especially at times when the diagnosis is uncertain, as ECP is recognized as not being an immunosuppressive therapy.

SSc

SSc is a multisystemic connective tissue disease characterized by collagen deposits in the skin and other visceral organs.^1,11 Although there are currently no FDA-approved treatments for cutaneous involvement in SSc, limited studies have investigated the use of ECP and have shown promising results.¹¹ For example, one multicenter trial showed that ECP was well-tolerated and improved disease severity, the mean percentage of skin involvement (-7.7% from baseline after 10 months, p=0.01) and the mean oral aperture measurements (+2.1 mm from baseline after 10 months, p=0.02).^11,12 Other studies have shown that ECP leads to improvement in dermal edema and skin elasticity, normalization of collagen synthesis, and improvement of extracutaneous symptoms, and that ECP-treated patients with SSc have a favorable long-term survival.^1,13 Further, one study found that, in most patients, ECP leads to a reduced usage of corticosteroids and other immunosuppressive agents, which have numerous adverse effects.¹⁴ The EDF currently recommends ECP as second-line or adjuvant therapy for SSc, either as monotherapy or in combination with other treatments (Table 8).¹¹

Other Cutaneous Conditions

ECP has been studied in numerous other cutaneous diseases, including atopic dermatitis (AD), immunobullous diseases, eosinophilic fasciitis and others. Although there are many other treatment options for AD, including emollients, topical therapies, phototherapy/photochemotherapy, immunosuppressive medications, targeted therapies¹⁵ and monoclonal antibodies, several small open-label trials have shown that ECP is beneficial in patients with severe AD, including erythrodermic AD, that are not responding to standard therapy. Although previous guidelines have not recommended routinely treating AD with ECP given the lack of consistent findings and the multiple other treatment options available, the EDF’s revised guidelines recommend its use as second-line therapy in patients that meet specific criteria (Table 8).¹¹ However, as new effective treatments are emerging for the treatment of AD, ECP should only be reserved for exceptional patients. Studies have also shown promising results for the use of ECP in pemphigus. One study of 11 patients with severe treatment-resistant pemphigus vulgaris or foliaceus showed an OR rate of 91% and CR rate of 73%.¹¹ As such, the EDF recommends ECP in patients with pemphigus vulgaris or foliaceus that is recalcitrant to conventional first- and second-line therapies.¹¹ Further, the EDF recommends considering ECP for severe epidermolysis bullosa acquisita (EBA) and erosive oral lichen planus that is refractory to conventional topical and/or systemic therapies.¹¹ Low level evidence suggests a possible role for ECP in the treatment of lupus erythematosus, however, further controlled clinical trials are needed to assess its efficacy. For this reason, no official recommendations for the use of ECP in lupus erythematosus have been published to date.¹¹ Studies have also investigated the use of ECP in other cutaneous diseases, including psoriasis, nephrogenic fibrosing dermopathy, morphea and scleromyxedema, however, the results have been inconclusive.¹¹

Pediatric Population

Many studies support the use of ECP in a pediatric population. It has been used as an off-label treatment for various conditions, including aGvHD and cGvHD.¹¹ In this patient population, the ECP protocol is adapted and can vary depending on the patient’s weight. Importantly, very few side effects are reported in this population, which further supports the favorable safety profile of ECP.¹¹

Conclusion

In conclusion, ECP has been used on- and off-label for decades to treat numerous diseases, including SS, CTCL, GvHD, and SSc, among others. Results from multiple studies have shown promising response rates, and ECP has an overall excellent safety profile with very few adverse events reported.^2,11 Unlike many other immunomodulatory therapies, an increased risk of infection has not been observed with ECP, which can be a significant cause of morbidity and mortality for patients on other immunosuppressive therapies.¹¹ Although ECP is still being studied for multiple diseases, in Canada clinicians should restrict its use to the diseases that have been extensively studied, as per the EDF guidelines.

Funding: The genesis of the paper was initiated at a meeting organized by a pharmaceutical company (Mallinckrodt Inc.) and EN, IT, WG, JD, MK, RG, CL and IVL were provided honoraria to attend that meeting. No funding bodies or other organizations had any role in data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgment: We thank RBC Consultants for editorial support, facilitating the preparation of tables, and coordinating the review of the manuscript.

Purchase Article PDF for $1.99

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.

PDF Download

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.

References

1. https://cdn.cancer.ca/-/media/files/cancer-information/resources/publications/2021-canadian-cancer-statistics-special-report/0835-2976-2021-canadian-cancer-statistics-en.pdf?rev=8e016fe8c5ea4c23b05ea08bf1018ca6&hash=C5BAEC543E496EDD8460CBBF6D44A010&_ga=2.47880293.391373246.1644172159-1100777747.1644172159
2. Canadian Cancer Society; 2021. Available at: https://www.cancer.ca/en/cancer-information/cancer-101/cancer-statistics-at-a-glance/
3. Mittmann N, Liu N, Cheng SY, Seung SJ. Health system costs for cancer medications and radiation treatment in Ontario for the most 4 most common cancers: a retrospective cohort study. Can Med Association J Open 2020;8:E191-8. Epub 2020 March 16 doi: https://doi.org/10.9778/cmajo.20190114
4. Dine J, Gordon R, Shames Y, et al: Immune checkpoint inhibitors: An innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4:127-135.
5. American Society of Clinical Oncology (ASCO). Understanding immunotherapy therapy. Accessed at https://www.cancer.net/ navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy on January 16, 2022.
6. Haslam A, Gill J, Prasad V: Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open 2020;3:e200423.
7. Malviya N, Tattersall IW, Leventhal J, et al. Cutaneous immune-related adverse events to checkpoint inhibitors. Clin Dermatol 2020;38:660-678.
8. Lacouture ME, Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails. Am J Clin Dermatol. 2018 Nov;19(Suppl 1):31-39.
9. Haanen J, Carbonnel F, Robert C, et al. management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(7) (suppl_4):119-142.
10. Schneider BJ, Naidoo J, Santomasso BD, et al. management of immunotherapy-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology (ASCO) guideline update. J Clin Oncol 2021;39(12):4073-4126. PIMD: 34724392.
11. Thompson JA, Schneider BJ, Brahmer J et al. NCCN Guidelines insights: Management of immunotherapy-related toxicities, Version 1.2020. J Natl Compr Cancer Netw. 2020;18(3):230-241.DOI: 10.6004/jnccn.2020.0012
12. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010 March 10;28(8):1351-7.
13. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
14. Ricciuti B, Genova C, de Giglio A, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab. J Cancer Res Clin Oncol. 2019 Feb;145(2):479-48
15. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018 Jun;19(3):345-361.
16. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44(2):158-76.
17. Tang SQ, Tang LL, Mao YP, et al: The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat 2021;53:339-354.
18. Druyts E, Boye M, Agg H, et al. Immune-related adverse events and efficacy outcomes in patients treated with immunotherapy: A systematic review and meta-analysis. J Clin Oncol 2020;38.
19. Patel AB, Pacha O: Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol 2018;995:117-129.
20. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol 2020; 83:1255-1268.
21. Kaul S, Kaffenberger BH, Choi JN, et al. Cutaneous adverse reactions of anticancer agents. Dermatol Clin 2019;37:555-568.
22. Wang LL, Patel G, Chiesa-Fuxench ZC, et al. Timing of onset of adverse cutaneous reactions associated with programmed cell death protein 1 inhibitor therapy. JAMA Dermatol 2018;154:1057-1061.
23. Simonsen AB, Kaae J, Ellebaek E, et al. Cutaneous adverse reactions to anti-PD-1 treatment—A systematic review. J Am Acad Dermatol 2020;83:1415-1424.
24. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors—A systematic review and meta-analysis. Cancer Treat Rev 2021;92:102134.
25. Raschi E, Gatti M, Gelsomino F, et al. Lessons to be learned from real-world studies on immune-related adverse events with checkpoint inhibitors: A clinical perspective from pharmacovigilance. Target Oncol 2020;15:449-466.
26. National Cancer Institute: Common Terminology Criteria for Adverse Events Version 5.0. NIH Publication, Bethesda, MD, 2018
27. Schaberg KB, Novoa RA, Wakelee HA, et al. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 2016 Apr;43(4):339-46.
28. Voudouri D, Nikolaou V, Laschos K, et al.Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer. Nov-Dec 2017;41(6):407-12
29. Rofe O, Bar-Sela G, Keidar Z, et al. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol. 2017 Apr;42(3):309-12.
30. Vivar KL, Deschaine M, Messina J, et al. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J Cutan Pathol. 2017 Apr;44(4):381-84.
31. Puzanov I, Diab A, Abdallah K et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations for the Society for immunotherapy of Cancer (SITC) Toxicity Management Working group. J Immuno Therapy Cancer 2017;5:95 DOI 10.1186/s40425-017-0300-z
32. Teulings HE, Limpens J, Jansen SN et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015 March 1;33(7):773-81.
33. Eggermont AMM, Kicinski M, Blank CU et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo. A secondary analysis of a randomized clinical trial. JAMA Oncol. 2020;6(4):519-527. Doi: 10.1001/jamaoncol.2019.5570 PMID: 31895407
34. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non‐small‐cell lung cancer (KEYNOTE‐010). Lancet 2016;387:1540–1550.
35. Bai X, Hu J, Betof Warner A et al. Early Use of High-Dose Glucocorticoid for the management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res. 2021 Nov 1;27(21):5993-6000. doi: 10.1158/1078-0432.CCR-21-1283. Epub 2021 August 10. PMID: 34376536.
36. Hua C, Boussemart L, Mateus C et al. Association of virtiligo with tumor response in patients with metastatic melanoma treated with pemobrolizumab. JAMA Dermatol. 2016;15(1)45-51. Doi: 10.1001/jamadermatol.2015.2707
37. Sauder MB, Addona M, Andriessen A, et al. The role of skin care in oncology patients. Skin Ther Letter; 2020 S Oct(10):1-12.
38. Sauder MB, Andriessen A, Claveau J, et al. Canadian skin management in oncology (CaSMO) algorithm for patients with oncology treatment-related skin toxicities. Skin Ther Letter; 2021 S March 21:1-10.
39. Hijal T, Sauder MB, Andriessen A, Claveau J, Lynde CW. Canadian Skin Management in Oncology Group (CaSMO) algorithm for the prevention and management of acute radiation dermatitis. Skin Ther Letter; 2021 S.
40. Brouwers M, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in healthcare. Can Med Association J 2010,182:E839-42
41. Trevelyan EG, Robinson N. Delphi methodology in health research: how to do it? Eur J Integrative Med 2015;7(4):423-428.
42. Smith Begolka W, Elston DM, Beutner KR. American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency. J Am Acad Dermatol.2011 Jun;64(6):e105-12. doi: 10.1016/j.jaad.2010.10.029.
43. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
44. Digklia A, Duran R, Homicsko K et al. Cancer Immunotherapy: A Simple Guide for Interventional Radiologists of New Therapeutic Approaches. Cardiovasc Intervent Radiol. 2019 Sep;42(9):1221-1229. doi: 10.1007/s00270-018-2074-1.
45. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
46. Belum VR, Benhuri B, Pastow MA et al. Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60(6) 12–25. doi:10.1016/j.ejca.2016.02.010.
47. Lacouture ME, Choi J, Ho A et al. US cutaneous oncodermatology management (USCOM) a practical algorithm. J Drugs Dermatol 2021; 20(9)(Suppl):s3-19.
48. Larkin J et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.
49. Anforth RM, Blumetti TCMP, Kefford RF, et al. Cutaneous manifestations of dabrafenib in patients with metastatic melanoma. Br J Dermatol. 2012 Nov;167(5):1153-60.
50. Shi VJ, Rodic N, Gettinger S et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell dealth 1 and anti-programmed cell death ligand 1 immunotherapy. J Am Med Assoc Dermatol 2016; 152: 1128–1136.
51. Tetzlaff MT, Nelson KC, Diab A et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients Am J Dermatopathol 2017; 39: 121–129.
52. Koelzer VH, Buser T, Willi N et al. Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer 2016;4(8): 47. DOI: 1186/s40425-016-0151-z
53. Boada A, Carrera C, Segura S, et al. Cutaneous toxicities of new treatments for melanoma. Clin Transl Oncol. 2018;20:1373-1384.
54. Bayer V, Amaya B, Baniewicz D, et al. Cancer immunotherapy: An evidence-based overview and implications for practice. Clin J Oncol Nurs 2017;21:13-21.
55. Keiser MF, Patel AB, Altan M: Cutaneous toxicities in lung cancer patients on immune checkpoint inhibitor therapy. Clin Lung Cancer 2021;22:195-e1.
56. Ala-Leppilampi K, Baker NA, McKillop C, et al. Cancer patients’ experiences with immune checkpoint modulators: A qualitative study. Cancer Med 2020;9:3015-3022.
57. Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017; 8:49.
58. Prior LM et al. Toxicities in immunotherapy: Can they predict response? J Clin Oncol. 2016;34(15 suppl):e14534-e14534.
59. Muntyanu A, Netchiporouk E, Gerstein W, et al. Cutaneous immune-related adverse events (irAEs) to immune checkpoint inhibitors: A dermatology perspective on management. J Cutan Med Surg 2021;25:59-76.
60. Ai L, Gao J, Zhao S et al. Nivolumab-associated DRESS in a genetic susceptible individual. J Immunother Cancer 2021;9:e002879. doi:10.1136/jitc-2021-002879
61. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7:306
62. Matsubara T, Uchi H, Takamori S et al. Acute Generalized Exanthematous Pustulosis Caused by the Combination of Pembrolizumab Plus Chemotherapy in a Patient With Squamous-Cell Carcinoma. Clin Lung Cancer 2020;21(2):e54-e56.
63. Ständer S, Pereira MP, Yosipovitch G et al. IFSI-guideline on chronic prurigo including prurigo nodularis. Itch 2020;5:e42 http://dx.doi.org/10.1097/itx.0000000000000042
64. Elmariah S, Kim BS, Yosipovitch G, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol 2021;(3):747-760. doi.org/10.1016/j.jaad.2020.07.025
65. Guven DC, Kilickap S, Guner G, et al. Development of de novo psoriasis during nivolumab therapy in a patient with small-cell lung cancer. J Oncol Pharm Pract 2020;26:256-258.
66. Voudouri D, Nikolaou V, Laschos K, et al. Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer 2017;41:407-412.
67. Choi Y, Jang D, Byun HJ et al. Psoriasiform dermatitis related with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains inhibitor in a patient with non-small-cell lung cancer. Ann Dermatol 2020;32(2):172-174. PMID: 33911733 | PMCID: PMC7992544
68. Amaris N, Geisler BS, Lacouture ME et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Acad Dermatol 2020;83(5):1255-1268.
69. Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019;37:2746–2758.
70. Kato Y, Otsuka A, Miyachi Y, Kabashima K. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol. 2016;30:e89–e91.
71. Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016;152:590–592.
72. Brahmer JR, Lacchetti C, Schneider BJ, et al. management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36:1714–68.doi:10.1200/JCO.2017.77.6385
73. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019; 80: 1073–113. x
74. Siciliano MA, Dastoli S, d’Apolito M et al. Pembrolizumab-Induced Psoriasis in Metastatic Melanoma: Activity and Safety of Apremilast, a Case Report. Front. Oncol. 2020;10:579445. doi: 10.3389/fonc.2020.579445
75. Fattore D, Annunziata MC, Panariello L, Marasca C, Fabbrocini G. Successful treatment of psoriasis induced by immune checkpoint inhibitors with apremilast. Eur J Cancer 2019;110:107–9. doi: 10.1016/j.ejca.2019.01.010
76. Frieder J, Kivelevitch D, Menter A: Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9:5-21. 1177/2040622317738910
77. De Bock M, Hulstaert E, Kruse V, Brochez L: Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor: case report and literature review. Case Rep Dermatol. 2018;10:190-197. 10.1159/000491572
78. Martinez-Domenech A, Garcia-Legaz Martinez M, Magdaleno-Tapial J, et al. Digital ulcerative lichenoid dermatitis in a patient receiving anti-PD-1 therapy. Dermatol Online J 2019;25.
79. De la Paz Sarasola M, Taquez Delgado MA, Medina VA et al. Histamine in cancer immunology and immunotherapy. Current status and new perspectives. Pharmacol Res Perspect. 2021;9(5):e00778.
80. Tziotzios C, Lee JYW, Brier T, et al. Lichen planus and lichenoid dermatoses. J Am Acad Dermatol 2018; 79: 789–818.
81. Tattersall IW, Leventhal JS: Cutaneous toxicities of immune checkpoint inhibitors: The role of the dermatologist. Yale J Biol Med 2020;93:123-132.
82. Lynde CW, Bergman J, Fiorillo L, et al. Clinical insights about topical treatment of mild-to-moderate pediatric and adult atopic dermatitis. J Cutan Med Surg. 2019 May/Jun;23(3_suppl):3S-13S.
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.
89. Kubicki SL, Welborn ME, Garg N, et al. Granulomatous dermatitis associated with ipilimumab therapy (ipilimumab associated granulomatous dermatitis). J Cutan Pathol 2018;45:636-638.
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.
92. Joly P, Roujeau JC, Benichou J et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346:321-327
    DOI: 10.1056/NEJMoa011592
93. EsfahaniK, Elkrief A, Calabrese C, et al. Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 2020;17:504–15. doi:10.1038/s41571-020-0352-8
94. Fatima S, Veenstra J, Antonyan AS et al. Severe recalcitrant morbilliform eruption from dual immune checkpoint blockade. JAAD Case Rep 2018;4(6):593-595. PMID: 29955646
95. Aizman L, Nelson K, Sparks AD, et al. The influence of supportive oncodermatology interventions on patient quality of life: A Cross-Sectional survey. J Drugs Dermatol. 2020May 1;19(5):477-82.

PDF Download

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.

Charles W Lynde MD, FRCPC¹, James Bergman MD, FRCPC², Loretta Fiorillo MD³, Lyn Guenther MD, FRCPC⁴, Marissa Joseph MD, FRCPC, FAAD⁵, Jill Keddy-Grant MD⁶, Ian Landells MD, FRCPC⁷, Danielle Marcoux MD, FRCPC⁸, Catherine McCuaig MD, FRCPC⁹, Michele Ramien MD¹⁰, Wingfield Rehmus MD MPH FAAD¹¹

Introduction

Atopic dermatitis (AD) is a lifelong pruritic, inflammatory skin disease associated with altered immune function and epidermal barrier dysfunction.^1-3 The chronic and recurring cyclic waxing and waning nature of AD leads the patient to treatment fatigue and imposes a significant burden on both the patients’ and caregivers’ quality of life (QoL).¹ AD frequently appears early in childhood and affects over 20% of children and up to 3.5% of adults.^2,3 Measurements of the prevalence of AD can differ, and this variability can be impacted by geographic location, population studied, and definition of AD used. A Canadian study showed that the adult prevalence of AD is up to 3.5% and that AD may be more prevalent among First Nations populations.² This research further revealed that men were less affected than women and that AD decreases with age. Additionally, the study noted that the severity of AD varies per region.² In many countries, the prevalence of AD is on the rise, especially in young children from developing lower-income countries in South East Asia and Latin America.⁴ Although the role of race and ethnicity in the pathophysiology of AD remains unclear, a higher incidence of AD was observed in Black American children (17.3%) compared to White children (10.4%).⁴

The pathophysiology includes skin barrier defects, inflammatory cytokines, and immune abnormalities. ADs’ etiology is multifactorial and involves an incompletely understood interaction between genetic factors, immune system dysfunction, skin barrier disorders, genetic and environmental stressors.^5,6 Most of the patients with AD have mild disease; however, 10% – 20% of children with AD are categorized as severe, and these rates are slightly higher in adults.²

There is a need for a variety of therapeutics targeted to different levels of severity.^6,7 A treatment paradigm that recognizes that patients may oscillate between degrees of severity and integrates topical and systemic therapies may align more closely with clinical reality.^8,9 AD treatment is often challenging due to the disease itself, treatment fatigue, and patient/caregiver concerns. Patients and caregivers frequently have concerns about medication safety and adverse events (AEs) as well as the long-term use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).⁹ Crisaborole ointment is an effective and safe alternative to TCS and TCI.⁹ Sharing best clinical practice standards, addressing challenges in treatment application, and methods to improve patient adherence to therapy may improve treatment results.⁹

This paper aims to review best clinical practices in treating AD patients, explore optimal use of crisaborole in mild to moderate disease, and provide expert guidance for the real-world use of crisaborole ointment to improve patient outcomes. This papers’ target audience is general practitioners, pediatricians, pediatric dermatologists, and dermatologists who treat patients with AD.

Methods

The project used a modified Delphi communication technique for interactive decision-making for medical projects, adapted from face-to-face meetings to suit a virtual platform.^10-12 The meeting was virtually convened on May 8, 2021, and the expert panel consisted of eleven dermatologists, including nine pediatric dermatologists from diverse geographical regions within Canada, who commonly treat patients with AD. In preparation for the meeting, a literature review surrounding crisaborole for the treatment of mild-moderate AD was conducted, and the panel members were surveyed regarding the use of crisaborole ointment for the treatment of AD.

The literature review and the pre-meeting survey results were presented at the virtual meeting. During the meeting, the experts were divided into three breakout groups to discuss and adopt draft recommendations for the real-world use of crisaborole ointment that were prepared from the literature searches by CWL and AA. The three groups presented their adapted versions of the recommendations to the larger group following the breakout session. The adapted recommendations were then collated and edited if necessary. The panel then voted and adopted the recommendations using evidence coupled with expert opinion based on the clinical experience of the advisors. The meeting summary and subsequent review of the manuscript were performed online (Figure 1).

Literature Review

Searches for English-language literature [2015– 2020] took place on April 14, 2021, on PubMed and Google Scholar as a secondary source. The data gathered by the literature review prioritized clinical studies published on the use of crisaborole, articles describing the current best practice in AD, and the most recent clinical guidelines, consensus papers and, algorithms. Excluded were duplications, articles of insufficient quality [small sample size, flawed methodology], and the most recent reviews were used in the case of review articles.

The searches yielded sixty-two papers deemed clinically relevant to current best practices of crisaborole use in AD. After removing duplicates and articles of insufficient quality, thirty publications remained: Four on epidemiology, ten reviews, three consensus papers and algorithms, four guidelines, five clinical studies, and four systematic reviews, meta-analyses, or posthoc analyses.

Results

The literature review indicated that the guidelines, algorithms, and consensus papers for topical AD treatment had not changed significantly over the past decade apart from adding crisaborole ointment and removing the black box for topical calcineurin inhibitor (TCI) treatment.^{7-9, 13-21}

A consensus paper and algorithm that explored the need for practical solutions to improve AD care was developed and published by the authors’ panel.⁸ The consensus statements and algorithm for topical treatment and maintenance of AD were integrated into the panels’ recommendations presented in this publication.

The DERMA (D: Diagnosis/Distribution; E: Education/Emollients; R: Red/Itchy; M: Medication/Maintenance; A: Assessment /Adherence) AD Algorithm targets a broad base of health care professionals treating patients with AD. The consensus statements and DERMA AD algorithm for topical treatment and maintenance of AD reflected current practice and were integrated into the panels’ recommendations (Figure 2).

Clinical Evidence of Crisaborole

Crisaborole is a small molecule, anti-inflammatory nonsteroidal PDE4-I inhibitor for the treatment of AD, which has demonstrated safety and efficacy in patients with mild-to-moderate AD.^22-30 Two percent crisaborole ointment was first approved by the American Food and Drug Administration (FDA) in December 2016 and then in 2018 by Health Canada for mild-to-moderate AD patients aged 2 years and over and in March 2020 (USA) and May 2021 (Canada) for patients aged 3 months and over.²⁵

The efficacy and safety studies on crisaborole used various clinical assessment scales such as Investigator Static Global Assessment (ISGA), Atopic Dermatitis Severity Index (ADSI), Eczema Area, and Severity Index (EASI) score, and Patient-Oriented Eczema Measure (POEM).

A randomized, double-blind, intra-patient controlled study (for the first 14 days) was continued as an open-label study applying crisaborole to all lesions. The study, including 40 patients of 18 years-old and older, demonstrated significant changes from baseline in crisaborole-treated lesions, ISGA, and pruritus NRS improvement from day fifteen assessment onwards.²³ The study also showed normalization of the genomic skin profile (approximated normal skin), inhibition of inflammatory genes known to be induced through degradation of cAMP by PDE4, and reduction in epidermal hyperplasia and TEWL.²³

The safety and efficacy of crisaborole treatment over 28 days were shown in two identical randomized, double-blind, vehicle-controlled studies including 1,522 patients with mild-to-moderate AD of 2 years and over.²² Significantly more patients treated with crisaborole than vehicle reached the primary endpoint (ISGA: clear, almost clear) than those treated with the vehicle at day 29 assessment.²² A long-term, open-label, single-arm 48 weeks safety study that included 517 patients of 2 years and over showed similar safety results as in a previous study that included adult AD patients.^22,24 In the long-term open-label study, nine patients (1.7%) withdrew due to AEs such as a stinging sensation after applying the ointment.²⁴ Another phase four open-label, single-arm study on 137 infants aged 3 months to less than 24 months of age demonstrated that crisaborole is safe and effective. ISGA of clear or almost clear was achieved at day 29 assessment by 30.2% of patients.²⁵ The study further indicated that improvements exceeded the minimal clinically significant difference in total POEM score at day eight and day twenty-nine.²⁵ The POEM subscale data further revealed improved sleep and pruritus, markedly improving patients’ and their caregivers’ quality of life.²⁵ Crisaborole yielded a rapid and statistically significant reduction in pruritus within four days.^26-28 Notably, in two vehicle-controlled studies, the vehicle effect on pruritus was considerable.^26,28

A pooled analysis of four studies of mild-to-moderate AD patients demonstrated efficacy and local tolerability of crisaborole treatment. After crisaborole use, most patients had mild to no pruritus from the first assessment through the remainder of treatment.²⁷

In a further study, treatment with crisaborole resulted in a marked improvement in QoL for patients and their parents, caregivers, and families.²⁸

A post hoc analysis of 2 phase 3 studies showed the effectiveness of crisaborole compared to the vehicle in significantly alleviating mild-to-moderate AD severity (per ADSI), and percentage of body surface area (%BSA) affected.²⁹

Finally, a systematic literature review and network meta-analysis comparing efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments for mild-to-moderate AD showed crisaborole was superior to vehicle and pimecrolimus 1% cream, and comparable to tacrolimus, 0.1% or 0.03% ointments, concerning ISGA 0/1 at 28-42 days.³⁰ Additionally, the systematic review showed that the AEs rates for application site burning/stinging were much higher for TCIs than for crisaborole.³⁰ The studies included different patients, and endpoints varied, so comparative assessment of medications from this meta-analysis is difficult. Head to head comparative studies are needed to see objective scientifically-grounded efficacy comparison.

Crisaborole works better for mild than moderate disease, where it provides a faster reduction of pruritus and other AD symptoms relieve.^9,25-30 Crisaborole is not typically used with TCI due to potential irritation, but the combination may be suitable for steroid-phobic patients and those at high risk of sequelae.⁹

It is advisable to avoid crisaborole application on significantly flared skin due to possible irritation. Crisaborole ointment can be beneficial for dermatitis of the hands and feet due to the potential for deeper penetration into inflamed, thicker lichenified skin as a result of the smaller molecular size of crisaborole. There appears to be less irritation of the hands and feet, and the good safety profile of crisaborole justifies application in infants and children.^9,25-30

Statements and Recommendations

Statement 1: Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function. When AD is not controlled by behavioral measures such as skincare and avoidance of triggers, treatments such as TCS, TCI, and more recently, PDE4-I should be considered. It is important to use topical agents in conjunction with moisturizers and gentle cleansers.

The complex multifactorial pathogenesis of AD includes genetic and environmental factors.⁵ The skin barrier in AD is dysfunctional, and this defective skin barrier leads to water loss from the skin and the ingress of irritants, pathogens and allergens resulting in further inflammation.⁷ As the dysfunctional barrier at baseline is further disrupted, an inflammatory immune response is upregulated, which further disrupts the barrier leading to a feedback loop.^6,31,5,6

AD presents clinically as recurrent scaly erythematous and pruritic papules and plaques of skin with varying severity. This morphology, in addition to pruritus and family history of atopy, are important diagnostic criteria.^7,32 Specific signs of AD include oozing, scaling, crusting, erythema, edema, and lichenification, which, together with the body surface area involved and the impairment of daily activities, help determine AD severity (Figure 3-5).
Most patients with AD present with mild disease and can be adequately treated with frequent moisturization and topical therapy such as TCS, TCI, or crisaborole.^{3,5,7,8,12-21}

Educating patients and caregivers about the condition, avoiding triggers, and daily skincare regime, including gentle cleansers and moisturizers, is a vital part of the approach.^{7-9, 13-21}

AD is a chronic disease, and as a result, adherence to therapy is a major obstacle. Education and patient support and can improve adherence and, in turn, outcomes. It is important to remember that AD education is not a one-and-done phenomenon. Ongoing reinforcement of the treatment plan and goals is needed. Clinicians need to explain the condition, the rationale for treatment, optimal treatment use, and demonstrate the application process in their office.^8,9 During the detailed conversation, solicit the patients’ or caregivers’ input and questions to enable their active role in the process.⁹ This will help manage expectations, adherence to treatment, and maintenance of the lifelong chronic disease.⁹ Actions to improve patient adherence with treatment include detailed but easy to follow information and options to revisit the information by reading materials or trusted websites (Box 1).^8,9,15,19

Box 1: Patient and caregivers information and education about crisaborole

Statement 2: Crisaborole, 1% ointment, is a nonsteroidal anti-inflammatory PDE4-I with demonstrated efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any body site. It may be especially beneficial for:

• Sensitive areas prone to thinning from TCS such as the face, intertriginous areas, and genitals
• Hand, feet, palms, and soles, where the small molecular size may allow potential deeper penetration

A previous publication by the panel reviewed various cases that reflect real-world clinical use of crisaborole aimed to clarify its optimal use as monotherapy, combination therapy, sequential therapy, and maintenance therapy.⁹ Crisaborole can provide a good and safe alternative to TCS and TCI, such as in cases of steroid or TCI avoidance, and can be used in mild-to-moderate AD patients from 3 months of age upwards.²⁵

The case studies discussed in the article suggested that crisaborole treatment was effective and well-tolerated for pediatric AD of the face, hands, and feet of infants, toddlers, young children, and adults where therapy with TCS or TCI had failed.⁹ One of the cases was a 5-year-old boy with moderate-to-severe AD of his hands that was painful and severely impacting daily activities, such as playing and interacting with other children. After eight weeks of crisaborole use, his hand palms and wrists involvement had almost entirely cleared.⁹

The advisors recommend that the smaller molecular size of crisaborole may allow better penetration into the skin to the site of inflammation.⁹ The advisors also indicated that there might be a cumulative effect of adding crisaborole for hands and feet that can benefit from its optimal penetration as part of a combination regimen with TCS and TCI in moderate-to-severe AD cases.⁹

Statement 3: Crisaborole may be used as a first-line topical agent and is also a good choice when previous treatment has yielded suboptimal results when TCS side effects constitute a significant concern, and in the case of TCS/TCI phobia.

TCS and TCI hesitancy exists among all cultures and likely contribute to AD treatment failure.³³ Widely available biased unreliable, and inaccurate sources of information about eczema and topical therapies such as TCS and TCI are not helpful for AD patients and hinder physicians ability to educate and treat appropriately.³³ Clinicians must inquire about and if present must thoroughly discuss the patients and caregivers’ concerns about TCS and TCI and emphasize that these treatments are vital and, if used appropriately, safe and effective.^{5,7,8,9,12-21} Providing the patient with trusted websites can give balanced information, thus addressing the issues that are adding to patients concerns, especially in those with TCS and TCI phobia.^15,19

If patients or caregivers continue to have safety concerns surrounding TCS/TCI treatment, then crisaborole can offer a safe alternative even in infants as young as three months of age.²⁵ In this situation, offering a safe and effective alternative to TCS or TCI may improve treatment adherence and patient outcomes.⁹

Statement 4: When starting topical therapies such as crisaborole, consider the following:

• Test the patients’ tolerability with a sample before a prescription to determine the degree of stinging
• Avoid its initial use on severely inflamed or open areas of skin
• Limit its use to areas less likely to sting/burn
• Use the product in combination with a refrigerated moisturizer

The recommendations are supported by the advisors’ clinical experience⁹, a post hoc analysis of 2 phase 3 studies²⁹, and a systematic literature review comparing efficacy and safety profiles of crisaborole and other topical treatments in mild-to-moderate AD.³⁰ Crisaborole is used in mild-to-moderate AD, but it is best to avoid application on severely inflamed and open areas if possible to minimize stinging.^29,30

Testing the patients’ tolerability in-office before prescribing crisaborole provides an opportunity to teach the patient about the appropriate application of the medication and identifies the uncommon patient who has more prominent stinging and thus may not tolerate the medication. The application also helps to identify the patient who has mild discomfort. Proper education and guidance can minimize the symptoms and allow then to get past the short-term symptom. Application in the office and identifying these subgroups will instill greater confidence in the medication and make it more likely that the prescription will be filled and utilized rather than abandoned after one application.

Improved knowledge about the central roles a defective skin barrier and dry skin may play in AD increasingly recognizes the benefits of daily and ongoing use of mild cleansers and moisturizers.³⁴ The use of a gentle cleanser that employs advanced vehicles with a near-physiologic pH (4.0–6.0) may help maintain skin barrier function by optimizing skin surface pH levels.³⁴ Utilizing moisturizers to optimize the barrier decreases water loss, decreases inflammation, and improves the skin’s barrier and natural moisturizing factors. Moisturizers that contain skin lipids such as ceramides have shown benefits over standard emollients when used for AD patients.³⁵

In an algorithm for South and East Asian AD patients, moisturizers were included as a standard measure when using topical treatments for AD, such as pimecrolimus.³⁶ A refrigerated moisturizer used in combination with crisaborole ointment may prevent irritation, burning, or stinging.⁹

Statement 5: TCS, TCIs, and PDE4-I may induce application site pain such as burning and stinging. Information and education on measures to prevent or treat these side-effects, such as testing/limiting application sites and concomitant use of a refrigerated moisturizer, can help optimize results and decrease skin irritation.

Few AEs such as irritation, burning, and stinging were reported in clinical studies using crisaborole but seem to be occurring more frequently in clinical practice.^16,9

Clinical trials report stinging or burning occurring in up to 8%, but the symptoms are usually transient, and 1.7% of patients withdrew due to these symptoms. In practice, clinicians have anecdotally noted that the rate of stinging seems to be greater than that reported in clinical trials, but generally, the stinging is mild and transient.^16,9 Topical medications can sting due to the stabilizers and preservatives in the vehicle cream or due to the medication itself. TCIs can sting, and this stinging is often correlated to the degree of inflammation in the area. Clinicians often apply TCS initially to calm down the AD, after which the TCI is better tolerated. Whether this technique applies to crisaborole is not clear but should be answered by future reports/ studies.^8,9

Before starting crisaborole therapy, inform and educate the patient and caregiver on measures that may prevent or quickly resolve irritation, burning, or stinging if it occurs.⁹ Best practice tips of the panel include the use of crisaborole with daily skincare, such as a gentle cleanser and a refrigerated moisturizer.⁹ Apply a patient age-appropriate regimen and patient education.⁹ Identifying patients prone to skin irritation may benefit from an in-office trial with a sample before prescribing the ointment.

Survey Results

A pre-meeting survey was conducted among the panel to share best practice standards and clinical pearls they use in prescribing crisaborole to mild-to-moderate AD patients. All eleven advisors completed the survey. Demographics, number of visits of AD patients, the severity of AD, and treatment are shown in Table 1. When asked: If Crisaborole is not your first choice, indicate why not? stinging (63% [7]), burning (40% [4]) and costs (91% [10]) were frequently mentioned. Six physicians also answered crisaborole was not used for other reasons, which included: Lack of payer coverage, Need to be off-flare to initiate the treatment to get a good response, It is not as effective and does not work as quickly as TCS or TCI, Other medications are effective and more readily available and with which there is more clinical experience. The advisors noted to specifically use crisaborole for various body locations such as the face (72% [8]), hands (91% [10]), eyelids (55% [6]), intertriginous areas (63% [7]), genitals (63% [7]), and feet (81% [9]). According to the advisors, they hypothesize that the small molecular size of crisaborole appears to allow better penetration on areas with thicker skin.

Table 1: Pre-meeting survey results
N=11
Topical corticosteroid (TCS), atopic dermatitis (AD)

When asked the main reasons to prescribe crisaborole, all (100% [11]) answered that there is a need for a nonsteroidal alternative. Other answers included TCS phobia (91% [10]) and TCI phobia (63% [7]) and suboptimal results with previous therapy (63% [7]).

When stinging or burning occurred with crisaborole use, the advisors discontinued the treatment more frequently in children than adults. For preventing and managing AEs, the advisors provided education before starting crisaborole treatment. Some tested patients’ tolerability to the treatment in the office prior to a prescription to determine the degree of stinging. Further, they recommended measures to reduce stinging, such as concomitant use of a gentle cleanser and refrigerated moisturizer, cooling the ointment in the fridge, and concomitant TCS or TCI use (Figure 6). Finally, the advisors agreed to avoid the application of crisaborole on severely flaring skin.

When asked about the patients’ response to crisaborole treatment within four weeks, forty percent of responders noted that on average, 20-50% of patients had improved, and 50% of the panel noted an improvement in over 50% of their patients (Figure 7 and 8).

Limitations

Measures to reduce burning and stinging that may occur when using crisaborole were developed using the authors’ expert opinion and clinical experience, and further studies are needed to support the possible benefits of these measures.

Conclusions

The review explored best clinical practices of crisaborole for mild to moderate AD patients and provided expert guidance for the real-world use of crisaborole ointment.

Atopic dermatitis is a common chronic inflammatory disorder in which patients experience a waxing and waning disease state that is punctuated by episodes of flares. If their disease is quiescent, then the patient continues good skincare by utilizing moisturizers and avoiding irritants. Patients will escalate and add topical medications at the first sign of a flare. Since every patient has a distinct disease course, some patients may never be fully clear while others clear between episodes. Recognition that patients with AD have a disease that often varies in severity and location on their body allows physicians to choose the appropriate treatments based on their clinical experience. The physician needs to educate their patient to escalate therapy accordingly at the first sign of disease in order to prevent severe flares. An eczema treatment plan is a necessity to ensure a smooth transition of therapy from baseline to flare. For mild to moderate AD patients, three topical options can be prescribed to control inflammation. Traditionally these medications have been divided into first and second-line therapy. However, the expert panel believes that the choice of a specific agent should be decided by the clinician based on factors such as disease severity, location, physician experience with the product, cost, and patient preference.

Crisaborole is a nonsteroidal PDE4-I with demonstrated safety and efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any cutaneous non-mucosal body site. It may be especially beneficial for areas with thicker skin, such as hands and feet, possibly due to improved penetration to the site of inflammation as a result of its small molecular size. There are no concerning serious safety signals associated with crisaborole. Crisaborole does cause a burning sensation in 8% of patients, but this is usually transient and may be minimized by the concomitant application of cool moisturizers. Consideration of in-clinic test site application of crisaborole to high-risk individuals may help identify those at risk and allow patient education, which may decrease the side effect and in turn improve adherence and outcome.

¹Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Lynde Institute for Dermatology (Private Practice), Markham, ON, Canada
³Division of Dermatology, University of Toronto, ON, Canada

Funding Sources: None

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Charles Lynde has acted as a principal investigator, speaker and/or consultant and/or advisory board member for AbbVie, Amgen, AnaptysBio, Arcutis, Avillon, Bristol-Myers Squibb, Celgene, Cipher, Eli Lilly, Galderma, Genentech, GlenMark, Incyte, Janssen, Kyowa, Leo Pharma, L’Oréal, Merck, Novartis, Pfizer, Sanofi and Valeant. Patrick Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Amgen, Aralez, Bausch Health, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, L’Oréal, Novartis, Pfizer, Sanofi-Genzyme and UCB.

Abstract:
Hair removal practices have evolved from adhering to social, cultural, and religious traditions to meeting aesthetic standards. Hair removal methods can be divided into two categories: 1) depilation, which involves removing the hair shaft and includes shaving and chemical depilatories, and 2) epilation, which involves removing the hair shaft, follicle, and bulb, and includes plucking, threading, waxing, sugaring, lasers, intense pulsed light system, electrolysis, and photodynamic therapy. Furthermore, an eflornithine hydrochloride 13.9% cream (Vaniqa®, neither an epilatory or depilatory technique), has been US FDA- and Health Canada-approved to slow the rate of facial hair growth and to be used in combination with other hair removal methods. Most methods are temporary except for electrolysis and laser therapy for some individuals, and each technique has advantages and disadvantages in terms of efficacy and adverse events. Importantly, most studies examining the efficacy of hair removal techniques are limited to darker hair and fairer skin, and further research is required especially for those with light-colored hair.

Key Words:
chemical depilatories, depilation, electrolysis, epilation, hair removal, laser hair removal, photodynamic therapy, plucking, shaving, sugaring, threading, Vaniqa, waxing

Introduction

Hair removal methods fall under two categories of depilation and epilation, each with distinctive advantages, disadvantages, and adverse events (Table 1).¹ Depilation removes the hair shaft and includes techniques such as shaving and chemical depilatories. Epilation removes the hair shaft, follicle, and bulb, and includes techniques such as plucking, threading, waxing, sugaring, lasers, intense pulsed light system (IPL), electrolysis, and photodynamic therapy (PDT).¹ In the 2000s, eflornithine hydrochloride cream 13.9% (Vaniqa®) was US FDA and Health Canada approved. Topical eflornithine is not considered an epilatory or depilatory technique but slows the rate of facial hair growth when used in conjunction with other methods.²

Table 1: Hair removal methods – advantages, disadvantages, adverse events, and permanency

Hair Removal Methods

Depilation

Shaving

Shaving is a cost-efficient and popular technique for male facial hair and female underarm and leg hair removal.^1,3 The two methods include: 1) wet shaving with a safety razor and 2) dry shaving with an electric razor.^1,3 The first razors used in the 17th century had straight, fixed blades made of tempered steel which were dangerous to use and required regular maintenance (honing and stropping). In 1903, the revolutionary King Camp Gillette T-shape razor was introduced with the first double-edged disposable blade which did not require honing and stropping, but still needed direct handling for blade replacement. In the 1920s, the disposable injector blade was introduced, a safer and more convenient method without direct handling. In 1931, the razor blade was again revolutionized by the electric razor blade, which was costlier, but provided enhanced safety (the blade never directly touched the skin) and convenience (long-lasting and eliminated the need for shaving cream).^3,4 Finally, in 1970, hoe-shaped safety razors with disposable cartridges were launched, and in 1975, the disposable razor was introduced. Both were safe to use, inexpensive, and convenient, with the disposable razor the most convenient of all models.⁵

Shaving (wet or dry) does not interrupt the anagen phase and, therefore, is a temporary hair removal method that necessitates frequent treatment.^1,6 Shaving is convenient and inexpensive, but may cause irritation, skin abrasions, and pseudofolliculitis.^1,7 Moreover, shaving does not change hair thickness or growth rate and leaves a blunt tip that appears to be thicker than uncut hair;³ thus, it is uncommon for facial hair removal in females.¹

Chemical Depilatories

Chemical depilatories are made as powders, pastes, creams, or lotions,^1,6,8 and used for the legs, bikini area, and face.³ Examples include detergents, hair-shaft-swelling agents, adhesives, pH adjusters, and bond-breaking agents, which disrupt disulfide bonds within keratin and provide temporary hair removal.³ The most common chemical depilatories are substituted mercaptans, 2% to 10% thioglycolates, mixed with 2% to 6% of sodium hydroxide or calcium hydroxide to increase pH.^3,6,8 Sulfide depilatories and sodium hydroxide depilatories are unpopular as they cause greater irritant dermatitis and skin damage.³ Depilatories are applied to hairs for 3 to 15 minutes to dissolve the hair shaft, and are then washed off with soap and water.^6,8

While chemical depilatories are easy to use, painless, have a slower regrowth than shaving, and do not result in stiffness of hairs post-treatment,³ they have unpleasant odors and may cause irritant contact dermatitis due to the alkalinity and allergic contact dermatitis due to fragrances.^3,7 Thus, less than 1% of patients find facial application tolerable.⁷ Moreover, chemical depilatories are less effective in removing darkly pigmented and coarse hair.³

Epilation

Plucking

Plucking with tweezers temporarily removes hairs in small areas, and is most effective at removing terminal as opposed to vellus hairs, with the latter tending to break near the skin surface.^1,3 Plucking is simple, inexpensive, causes minimal skin damage, and affords a longer regrowth period (2 to 12 weeks).³ However, plucking does not alter hair growth rate unless hairs are in the anagen phase, and can be a tedious process, making it impractical for use over larger areas.¹ Plucking can cause discomfort or pain, and its efficacy is dependent on user tolerance and technique.¹ Other drawbacks include folliculitis, follicular distortion, hyperpigmentation, erythema, and scarring.^6-8

Threading

Threading involves the use of a twisted loop of cotton thread, with ends held by hand and teeth,³ that is pressed against the skin to trap and pull hairs.^1,6 Threading is used in men to remove cheek, ear, and forehead hairs, and in women to remove facial hair.^1,3, Threading is a temporary hair removal technique widely practiced in the Middle East and dates back to antiquity, also known as fatlah in Egypt, that has gained popularity in Western cultures due to its precision in shaping eyebrows.¹ Threading, however, can be painful, tedious, and typically requires an esthetician with expertise.¹

Waxing

Waxing is a popular, temporary hair removal method resulting in hair-free skin for 2 to 6 weeks depending on the individual’s hair growth rate and body site.^1,3,7 Waxing is commonly used for larger areas.⁹ Wax is composed of beeswax and rosin with additives, essential oils, chemicals, and preservatives. Hot wax is preferred over cold wax especially in beauty salons⁹ as the heat dilates the follicular opening to facilitate hair removal.^1,3,7 Once the wax cools and hardens, the strip is removed quickly in the direction opposite of hair growth.^1,9

Waxing removes both vellus and terminal hairs in large areas, and is longer-lasting than shaving or chemical depilatories as hairs are removed from the bulb.^1,3 Repeated waxing can cause follicular trauma and reduce hair regrowth over time.^7,9 Other adverse events include folliculitis, thermal injury, skin irritation, scars,^7,9 and allergic reactions to the additives.^1,7 Patients using systemic retinoids are advised not to wax due to increased risk of scarring.

Sugaring

Sugaring is an ancient hair removal technique used in the Middle East and Egypt¹ involving a paste composed of sugar, lemon juice, and water¹⁰ applied to skin in the direction of hair growth, then removed in the opposite direction with cloth.¹⁰ Sugaring has a similar application to waxing, but may remove shorter hairs (1/16 inch versus ¼ inch) as water-based pastes can more easily penetrate follicles.¹⁰ Moreover, sugaring is safe (utilizes natural ingredients), cost-effective, hydrating, painless, and can be used for larger areas,⁷ and reduces the risk of skin redness, trauma, and scarring compared to shaving or hot waxing.¹⁰ However, sugaring may cause skin irritation and allergic reactions¹ and can only remove hairs of sufficient length.

Lasers

Laser hair removal can be permanent for some individuals,¹¹ and involves selective photothermolysis that emits a light at a specific wavelength (nm), pulse duration, and fluence, causing thermal injury without damaging the skin.^1,12 Light is either directly absorbed by melanin within the hair bulb and shaft⁶ or by an exogenous chromophore applied topically then absorbed by the follicle.^1,6,12 Lasers are more effective when the pigmented hair shaft is intact; thus, plucking and waxing are discouraged, whereas depilation (e.g., shaving) is recommended pretreatment.^1,12

Laser types include the ruby laser (694 nm),^1,6,13 diode laser (800 nm),^1,6,13-21 alexandrite laser (795 nm),^1,18,22,23 and neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (1064 nm),^6,12,24,25 and efficacy depends on laser fluence, spot size, number of treatments and individual factors (e.g., skin type, hair type and hormonal status).26 Lasers work best for dark, thick terminal hairs, light/fair skin, and a normal hormonal status, but are ineffective for thin vellus hairs, and white, grey, or red hairs.²⁶ Longer wavelengths reduce epidermal damage due to poor absorption and are therefore safe and effective in darker skin types. Cooling devices should also be used to reduce skin damage.¹⁶ Adverse events include immediate erythema,¹³edema, first- and second- degree burns,^19,20 folliculitis,^22,23 skin damage, pigmentation changes, blisters, and crust formation, and are more likely to occur in darker skin types [Fitzpatrick skin type (FST) III to VI].^6,24

Intense Pulsed Light (IPL) System

The IPL system is a non-laser source of polychromatic light (550 nm to 1200 nm)⁶ tailored to individual skin type and hair color.^1,6,24 Multiple treatments are typically required,¹ however, results (60% hair reduction) may last up to 12 weeks after one session.²⁷ For optimal results, individuals should avoid tanning but should shave prior to treatment to prevent conducting thermal energy to adjacent epidermis.¹ IPL is most effective in individuals with the combination of darker hair and lighter skin.¹

IPL has several advantages, including lower cost compared to laser hair removal and the ability to treat large surface areas (back, chest, and legs). However, IPL is generally less effective than laser hair removal, requires more treatment sessions,²⁸ and the IPL device is bulky, heavy, and difficult to maneuver as it houses a lamp and cooling device.¹⁸ Adverse events include pain, edema, erythema, hypopigmentation, and hyperpigmentation.^1,18,24 IPL devices can emit inconsistent fluence and wavelengths from pulse to pulse, making it difficult to predict efficacy.¹⁸

Electrolysis

Electrolysis is a permanent method of hair removal,^1,6,8 but patients with hirsutism will experience conversion of vellus to terminal hairs in treatment areas. The three types of electrolysis [1) galvanic (direct current) electrolysis, 2) thermolysis (alternating current), and 3) combination/blend method] all involve inserting a probe to deliver electric currents that destroy and prevent regrowth of hair follicles.¹

Galvanic electrolysis treatment is slow (15 seconds to 3 minute application per hair) with multiple treatments required; however, it can reduce the number of active hair follicles by 80% to 90%.¹ This technique is tedious, time-consuming, painful, and can cause post-inflammatory hyperpigmentation and scarring, and is not recommended for larger areas requiring hair removal.⁸ In contrast, thermolysis is faster than galvanic electrolysis due to a shorter skin contact time, but generally less effective – hair has been found to regrow in 20% to 40% of follicles post-treatment.¹ The blend method (combination of galvanic electrolysis and thermolysis) is considered the most effective form, as it is as fast as thermolysis and less painful than galvanic electrolysis.¹

Adverse events of electrolysis depend on current type, duration, and intensity, but include pain, scarring/keloid formation in susceptible patients, and post-inflammatory hypo- or hyperpigmentation. Topical anesthetics can be offered before treatment, however maintaining sensation is preferred as pain is related to skin damage.⁶ Erythema and edema are common but transient, and crusting or follicular nodules may form with repeated insertion of a needle into the same follicle. There is also risk of local infection if instruments are not cleaned properly; operators should wear gloves at all times and apply antibacterial ointment to the area post-treatment.⁶ The efficacy of electrolysis depends largely on the operator’s skills, and unfortunately there is no standardization of licensure to practice this technique.^1,6

Photodynamic Therapy (PDT)

PDT involves the application of a topical photosensitizer⁶ and subsequent exposure to nonionizing radiation of red light (635 nm) through a projector, broadband light device, or laser.²⁹ Light is absorbed by a photosensitizer, subsequently forming singlet oxygen that causes lipid peroxidation of follicular cell membranes and protein damage,^6,8 resulting in phototoxic effects on hairs.³⁰ The most common topical agents used for PDT are 10% or 20% topical 5-aminolevulinic acid (5-ALA) and methyl aminolevulinate – prodrugs that lead to the formation of a photosensitizer, protoporphyrin IX (PPIX). PDT treatment duration is dependent on the incubation time of 5-ALA, which should be sufficient to allow for its conversion to PPIX. The incubation period for 5-ALA is typically 3 hours²⁹ followed by brief light exposure.³¹ PDT can be used in all skin and hair types as its mechanism of action is independent of melanin concentration and has minimal side-effects.³⁰ Uebelhoer et al. described a 40% hair reduction at 6 months of wax epilated areas after ALA application for 3 hours with one treatment of irradiation with continuous wave 630 nm red light.³² Moreover, in a recent study by Comacchi et al. on the use of PDT in idiopathic hirsutism and hypertrichosis, two to five treatments (with a 1 month period between treatments) led to a 75% hair reduction at 12 months.³⁰ Since PDT is primarily used to treat cutaneous malignancy, its use in hair removal is limited and further investigations are required.^8,12

Other

Topical Eflornithine Hydrochloride

Eflornithine hydrochloride 13.9% cream (Vaniqa®), is a topical prescription medication that is not meant to be used alone and should be combined with another hair removal technique. Topical eflornithine does not fall under epilation or depilation as it does not remove hair but rather slows facial hair growth, and inhibition of ornithine decarboxylase is the postulated mechanism of action. If applied twice daily at least 8 hours apart, results may be seen as early as 4 to 8 weeks. Adverse event rates include acne, folliculitis, stinging or burning, dry skin, itching, tingling, redness or irritation, indigestion, rash, and dizziness. Patients should consult their physician before using eflornithine if pregnant, planning pregnancy, or breastfeeding.²

Conclusion

This article is a general overview of hair removal practices, which have evolved from utilizing waxes and blades, to advanced lasers and electrolysis, with further advancements still being studied.¹ Residual, unwanted hair is a common problem for many individuals and traditional methods of hair removal (e.g., shaving and waxing) have provided temporary solutions and unsatisfactory results. Laser therapy is a safe modality that can produce permanent results in some individuals.^11,12 Electrolysis is a permanent hair removal method but can be tedious and associated with several adverse events. A relatively recent FDA and Health Canada approved treatment, eflornithine hydrochloride 13.9% cream, can be used in combination with another hair removal technique to slow the rate of facial hair growth. Importantly, studies examining hair removal efficacy are limited to individuals with darker hair and fairer skin, whereby precautionary measures such as cooling devices are recommended for safe treatment. Further research is required to develop safe and effective treatments for those with lighter-colored hair.¹²

Purchase Article PDF for $1.99

¹Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada

Conflict of interest:
Funding sources: None. Conflicts of interest: Sara Mirali has no conflicts of interest to declare. Patrick Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Amgen, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, L’Oréal, UCB, Janssen, Novartis, Pfizer, and Sanofi-Genzyme. Charles Lynde has acted as a principal investigator, speaker and/or consultant and/or advisory board member for AbbVie, Amgen, AnaptysBio, Avillon, Arcutis, Bristol-Myers Squibb, Celgene, Cipher, Genentech, GlenMark, Incyte, Janssen, Leo Pharma, L’Oréal, Kyowa, Pfizer, Merck, Novartis, and Sanofi.

Abstract:
During the COVID-19 pandemic, prolonged usage of personal protective equipment (PPE) and frequent handwashing has exacerbated or caused skin diseases, particularly amongst frontline workers. Skin conditions, such as atopic dermatitis, irritant contact dermatitis, and hand eczema, affect patients’ quality of life and their ability to work. These conditions can be managed by frequent moisturization and washing with gentle cleansers. In this review, we discuss the properties of effective moisturizers and cleansers for patients with skin diseases related to enhanced infection control procedures.

Key Words:
COVID-19, personal protective equipment, PPE, skin pH, eczema, atopic dermatitis, irritant contact dermatitis, acne, hand eczema

Table of Content:

1. Introduction
2. PPE-related Dermatitis
3. Moisturizers
4. Hand Eczema
5. Cleansers
6. Conclusion

Introduction

During the COVID-19 pandemic caused by the novel coronavirus SARS-CoV2, health authorities advised frontline workers and the public to take infection control precautions. Current evidence suggests that COVID-19 is transmitted through respiratory droplets and contact with contaminated surfaces.¹ To prevent transmission, frequent handwashing and prolonged usage of personal protective equipment (PPE), such as goggles, masks, face shields, and gloves, are recommended. These enhanced precautions can cause or exacerbate inflammatory skin conditions, which impact patients’ quality of life and, in some cases, their ability to work.² Moreover, associated symptoms, such as pruritis affecting the face, increase the risk of transmission.

Recent studies have shown that 75-97% of healthcare workers (HCWs) treating COVID-19 patients suffered from adverse skin reactions, including contact and pressure urticaria, rosacea, perioral dermatitis, contact dermatitis, or aggravation of preexisting skin disorders. The most commonly affected areas were the hands, cheeks, and nasal bridge.^2,3 These adverse effects are not restricted to HCWs4 and are mainly caused by the hyperhydration effects of PPE, friction, epidermal barrier breakdown, and contact reactions. All of these can aggravate preexisting skin diseases or cause new skin diseases, many of which can be controlled with proper moisturization. In this review, we discuss the role of moisturizers and cleansers in the management of skin conditions caused by frequent handwashing and PPE.

PPE-related Dermatitis

Atopic dermatitis (AD) and irritant contact dermatitis (ICD) are common types of eczema that are characterized by pruritus, eczematous lesions, xerosis, and lichenification. AD is a chronic relapsing inflammatory skin condition that often develops at a young age, while ICD is caused by direct contact of the skin with environmental, chemical, or physical agents that disrupt the epidermal barrier.^5,6 AD and ICD can be exacerbated or caused by wearing PPE for long periods of time.^2,3

Prolonged usage of PPE can also exacerbate or cause acne vulgaris.^7,8 The tight seal and humid environment created by masks, particularly N95s, aggravates acne (also known colloquially as maskne). This is likely because pressure on the skin can rupture comedones and block pilosebaceous ducts. Moreover, the humid microclimate within the mask is ideal for bacterial growth and prevents filaggrin (FLG) breakdown, which contributes to skin barrier disruption.^8,9 In addition to AD and acne, masks can exacerbate other inflammatory skin disorders, such as rosacea and perioral dermatitis.^7,8

Moisturizers

Moisturizers are widely used to treat AD and ICD. Moisturizers treat damaged skin by repairing the stratum corneum, increasing hydration, and reducing transepidermal water loss (TEWL). In addition to restoring the skin barrier and relieving symptoms, frequent use of moisturizers can reduce the need for topical steroids.¹⁰ While steroids may reduce inflammation, they can also compromise the skin barrier and increase TEWL.¹¹

An effective moisturizer should contain an occlusive barrier, humectants, and emollients (Table 1). Occlusives block TEWL by forming a film on the surface of the skin, while humectants retain moisture by attracting water from the environment and from the dermis. Emollients soften the skin by repairing the stratum corneum’s lipid-rich matrix and filling the spaces between desquamating corneocytes.

Table 1: Basic properties of an effective moisturizer

PCA = pyrrolidine carboxylic acid; TEWL = transepidermal water loss

Treatment with moisturizers is largely based on patient compliance. Consumer preferences must be taken into account as compliance will likely be poor if patients are unsatisfied with the treatment.¹² An ideal moisturizer should be non-irritating, hydrating, cosmetically appealing, pH balanced, and contain ceramides.^10,13,14 Moreover, an ideal moisturizer should be inexpensive and widely available.

Non-irritating

Sensory reactions are a common adverse effect of moisturizers. Sensory reactions consist of burning or stinging sensations without evidence of inflammation.¹⁵ Although urea, lactic acid, and pyrrolidine carboxylic acid (PCA) are clinically effective humectants, they cause irritation in some patients, particularly in those with damaged skin.^12,16,17 In contrast, the humectant glycerin is well-tolerated.¹⁶ Preservatives, such as benzoic acid and sorbic acid, can also cause irritation (Table 2).^12,17

Table 2: Side effects of moisturizers and potential causes

Adapted from Lynde et al.²³
PCA = pyrrolidine carboxylic acid
MCI/MI = methylchloroisothiazolinone/methylisothiazolinone

Fragrances are the most common allergen found in moisturizers and are the most frequent cosmetic cause of allergic contact dermatitis.^18,19 Fragrances can also cause photo contact dermatitis and contact urticaria.²⁰ Moisturizers should be fragrance-free and fragrance-related allergens, such as benzyl alcohols, essential oils, and biologic additives should also be avoided.¹⁸ dermatitis and contact urticaria.²⁰ Moisturizers should be fragrance-free and fragrance-related allergens, such as benzyl alcohols, essential oils, and biologic additives should also be avoided.¹⁸

Moisturizers may contain or be used alongside treatments for acne vulgaris, such as retinoids and benzoyl peroxide. These compounds can disrupt the skin barrier and cause further irritation, particularly if patients recently integrated them into their skincare routine.²¹ To prevent maskne, skincare routines should be limited to a pH-balanced gentle non-soap cleanser and mild moisturizer free of irritants. Products with a physiological skin surface pH (4.0-6.0) should be used to reduce inflammation and improve skin barrier function.²² Changes in skincare routine (i.e., addition of a retinol) should be incorporated with caution because mask occlusion may worsen irritation from new products. Likewise, cosmetic products should not be used as mask occlusion will intensify product delivery to the skin, increasing irritation and maskne.

Hydrating Properties

Moisturizers derive their hydrating properties from humectants that attract water from the dermis and from the external environment. Within the stratum corneum, corneocytes contain natural moisturizing factors (NMF), a humectant mixture derived from amino acids and salts. NMF are made of amino acids produced by the breakdown of the protein FLG, which retains water within the corneocytes and maintains skin hydration.²⁴ Patients suffering from AD are deficient in FLG, resulting in increased TEWL and impaired skin barrier function.²⁵ Moisturizers containing FLG breakdown products have been shown to improve barrier function in AD patients.²⁶

Commonly used humectants include the FLG breakdown products lactic acid and PCA, as well as urea. Another frequently used humectant is hyaluronic acid, which has been shown to be efficacious in mild-to-moderate AD.²⁷ If patients are sensitive to these humectants, a moisturizer with glycerin should be considered. Glycerin is an effective humectant that is inexpensive and well-tolerated.¹⁶ Because humectants draw up water from the dermis, they must be used in combination with an occlusive agent to prevent TEWL.²⁸

Cosmetically Appealing

Moisturizers are formulated to be non-greasy, non-comedogenic, and smoothing. The consistency of a moisturizer depends on its emulsification. Creams are available as water-in-oil (W/O) or oil-in-water (O/W) emulsions. O/W emulsions are less viscous compared to W/O emulsions, which have an oil content between 15-30%. A higher oil content retains more moisture but increases the greasiness of the product.¹⁵

New emulsion technologies allow for better delivery of active ingredients. Multivesicular emulsions (MVE^®) are multi-lamellar emulsions with a series of concentric spheres containing oil and water. Ingredients are stored within the oil or water phases and layers are released slowly over time. While traditional emulsions release all of their ingredients at once, MVEs^® allows for sustained release, increasing the effective duration of the product.²⁹

pH Balanced

Normal physiological skin surface pH ranges from 4.0-6.0 but is elevated in AD, ICD, and acne.^30-32 Elevated skin pH can result in inflammation, disrupted stratum corneum cohesion, and impaired skin permeability. Moreover, for individuals with acne-prone skin, high pH moisturizers can interfere with the efficacy of topical acne treatments.^22,33 To improve skin barrier function, moisturizers at physiological skin surface pH (4.0-6.0) should be used, although there is limited clinical evidence directly linking low pH moisturizers and reduced irritation.

Ceramide Content

The stratum corneum’s lipid-rich matrix is composed of approximately 50% ceramides, 25% cholesterol, and 10-20% fatty acids.³⁴ Ceramides are synthesized in keratinocytes and play an important role in skin barrier maintenance, cell adhesion, and epidermal differentiation. Reductions in ceramide correlate with clinical irritation and barrier disruption.³⁵ Natural ceramides are expensive to synthesize but moisturizers containing synthetic ceramides have been shown to reduce symptoms and improve quality of life in patients with AD and ICD.^10,13,14,36

Hand Eczema

Hand eczema (HE) is the most common form of ICD.³⁷ Anionic surfactants, commonly found in hand soaps, disrupt the stratum corneum by damaging proteins and the processing of new lipids, allowing for greater penetration of irritants and TEWL.³⁸ Likewise, extended exposure to water disrupts the stratum corneum’s lipid structure and increases skin permeability.³⁹ Other irritants, such as organic solvents used in hand sanitizers, strip away lipids from the stratum corneum, although they are less damaging compared to harsh detergents.⁴⁰

Cleansers

Cleansers are mainly available as soaps, combars, and synthetic detergents (syndets) (Table 3 & Table 4). Soaps are typically very alkaline and range from pH 9.0-10.0. In contrast, syndets contain synthetic detergents and are acidic or neutral (pH 5.5- 7.0). Combars are a combination of soaps and syndets.⁴¹ While soaps are more effective at removing soluble proteins and lipids, their high pH disrupts the skin barrier and causes irritation.⁴² Fragrance-free, hypoallergenic, non-soap cleansers that are neutral to low pH are recommended.⁴³ Frequent handwashing with low pH cleansers is preferred as they have been shown to be less irritating.⁴⁴

Table 3: Cleanser categories

Table 4: Allergens in cleansers

Adapted from Rundle et al.⁴⁰

Conclusion

Prolonged PPE usage and frequent handwashing increases the risk of developing or aggravating skin diseases, such as AD, ICD, acne, and HE. Routine moisturization with non-irritating, pH-adjusted, ceramide-based products and gentle cleansing with a pH-adjusted cleanser can treat the unique dermatological challenges posed by COVID-19 (Table 5).

Table 5: Ideal characteristics of moisturizers/cleansers and summary of recommendations

AD = atopic dermatitis; FLG = filaggrin; PCA = pyrrolidine carboxylic acid; TEWL = transepidermal water loss

Purchase Article PDF for $1.99

¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, University of Toronto, Toronto, ON, Canada
³The Lynde Institute of Dermatology, Markham, ON, Canada

Conflict of interest:
All of the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract:
Prurigo nodularis (PN) is a chronic, recalcitrant inflammatory skin condition characterized by the presence of pruritic nodules. The exact pathogenesis of the disease is unknown, although immune and neural dysregulation are indicated in driving the itch-scratch cycle. Specifically, interleukin-4 and interleukin-31 pathways have been recently implicated in transmission of the pruritic sensation. There are currently no US FDA-approved targeted therapies for the treatment of PN. This article aims to review our present understanding of the disease pathogenesis and treatments, with a focus on emerging therapeutics. Specifically, this article explores the developing use of monoclonal antibodies nemolizumab and dupilumab, opioid receptor modulation and cannabinoids as potential treatments for PN.

Key Words:
prurigo nodularis, nemolizumab, dupilumab, chronic pruritus

Clinical Presentation

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Lesions vary in size from a few millimeters to 2-3 cm in diameter, and range in number from a few to hundreds.¹ Nodules may be flesh-colored, erythematous, or hyperpigmented (depending on skin type), and are typically located in symmetric linear arrangements along extensor surfaces.¹ PN has some predilection for elderly patients and individuals with dark skin, particularly persons of African ancestry.^2,3 Although the disease affects patients of either sex, some research suggests women may be disproportionately affected in terms of frequency, age of onset, and severity.⁴ Numerous risk factors have been elucidated prior to development of PN, including eczemas, psychiatric diagnoses, and chronic medical diseases such as malignancy, liver failure, chronic renal failure, diabetes and human immunodeficiency virus (HIV) infection.^3,5-7

Pathophysiology

The pathogenesis of PN is thought to be characterized by a cutaneous reaction pattern due to chronic itching and repeated scratching, otherwise termed the “itch-scratch cycle.” Although the exact pathogenesis of PN is unknown, immune and neural dysregulation drive the pruritic cycle.⁸

Histopathologic studies investigating the immune response of PN have demonstrated increased infiltrate in the dermis of PN lesions consisting of increased T lymphocytes, mast cells and eosinophilic granulocytes.^8,9 The intense itch is created by an inflammatory response in the skin through mediators such as interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins and neuropeptides.^8,9 Specifically, eosinophils and IL-31 are particularly implicated in the pathogenesis of the disease through their increased expression and pathologic mechanisms in the dermis of PN lesioned skin.^8-13

Neuronal dysregulation has also been demonstrated in PN; studies have shown differences in nerve fiber density between the dermis and epidermis in individuals with PN.¹¹ Further, dysregulation of neuropeptides has been implicated in the pathogenesis, with particular increases in calcitonin gene-related peptide and substance P in dermal PN skin.^8-11,14 Although these changes may be secondary to repeated mechanical scratching, they still contribute to the pruritic cycle through regulation of eosinophils, mast cells, effects on endorphins and mu- and kappa-opioid receptors.^8,9,11

Regardless of the aforementioned potential triggering pathologies, central nervous system functioning is essential for transmitting the itch signal from the periphery. Recent seminal findings by Oetjen and colleagues have demonstrated that the IL-4 receptor is directly expressed on sensory neurons in the dorsal root ganglia of both humans and mice. This receptor is directly activated by expression of type 2 cytokines, such as IL-4, IL-13 and IL-31.¹⁵ Most importantly, the authors demonstrated that ablating the IL-4 receptor in a mouse model significantly diminished chronic pruritus, and treating human patients with recalcitrant chronic itch that failed other immunosuppressive therapies with inhibitors of the type 2 cytokine pathway (Janus kinase – JAK – inhibitors) markedly improved their symptoms.¹⁵ Taken together, therapeutics targeting the inhibition of this central nervous system pathway may potentially be groundbreaking in the treatment of PN.

Current Treatments

Currently, there are no US Food and Drug Administration (FDA) approved targeted treatments for PN. Although the treatment goal is to break the itch-scratch cycle to allow the nodules to heal, there is a high degree of variability between providers and treatment regimens in the use of off-label therapies.^8,16 A recent systematic review assigned level of evidence ratings to the current treatment options for PN (Table 1). The review found that many current therapies have low efficacy or a high frequency of side effects, limiting their effectiveness. Further, there was a paucity of randomized control trials (8 RCTs, with only 3/8 having >22 participants with PN) and quality studies looking at treatment of PN. Overall, topical agents, including corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin, had the highest evidence ratings, with some beneficial effects.¹⁷ The majority of studies investigating phototherapy and photochemotherapy reported mild side effects and demonstrated good partial response rates, as did thalidomide, although it had poorer quality studies and a large side effect profile. Antiepileptics and antidepressants, such as pregabalin, amitriptyline, paroxetine, fluvoxamine, and neurokinin-1 receptor antagonists had strong evidence ratings with promising treatment results and low risks of side effects. Lastly, systemic immunomodulatory therapies, such as cyclosporine and methotrexate, demonstrated some benefit in a limited number of low evidence level studies. However, these systemic treatments had poor safety profiles.¹⁷

The lack of success with current treatments is likely due to the heterogeneity of disease and dearth of regimens addressing the immunologic and neural pathophysiologic components of PN.^8,17

Emerging Treatments

Currently, several new treatments are being explored for itch pathogenesis in PN (Table 2).

Nemolizumab

Nemolizumab is a new drug designed to interrupt the itch-scratch cycle in PN. Considering that up-regulation of IL-31 messenger RNA has been reported in PN lesions compared to healthy skin biopsies, a drug interrupting this increase could be beneficial.¹³ Nemolizumab was designed as a humanized anti-human IL-31 receptor A monocloncal antibody. This monoclonal antibody disrupts the binding of IL-31 to its receptor, and in doing so inhibits part of the cascade of inflammatory events causing the itch sensation.^18,19

Results of a phase 2 trial of nemolizumab on adults with moderate-to-severe PN were recently published. Moderate-to-severe PN was defined as 20 or more nodules, while severe PN was characterized as a mean score of at least 7 (range 0-10) for the worst daily intensity of pruritus. PN patients were randomly equally assigned to receive subcutaneous injections of nemolizumab 0.5 mg/kg (n=34), or matching placebo (n=36).²⁰ Three total injections were administered at baseline, week 4 and week 8, with three more visits at weeks 12, 16 and 18. At week 4 there was a 53% reduction from baseline in peak pruritus score (4.5 points) in the nemoluzimab group, compared to a 20% reduction in the placebo group (1.7 points). Reductions were maintained throughout the trial period.²⁰ The mean number of prurigo lesions decreased by a greater proportion in the nemolizumab group compared to the placebo group at week 12. Other secondary outcome measures such as assessments investigators’ global assessments, sleep quality and Dermatology Life Quality Index also demonstrated greater improvements in the nemolizumab group compared to placebo.²⁰ Nemolizumab was associated with more side effects than placebo, namely abdominal symptoms such as abdominal pain and diarrhea, as well as nonspecific musculoskeletal symptoms.²⁰

Based on these strong and promising results for treatment of PN, the FDA recently approved nemolizumab for Breakthrough Therapy status, thus expediting its development and approval process.²¹ Phase 3 trials are currently underway (NCT03989206).

Dupilumab

Similar to nemolizumab, dupilumab is a monoclonal antibody antagonist of the IL-4 receptor, another integral component of the neural pathway for pruritus.¹⁵ Further, it has already been approved by the FDA for three indications including treatment of moderate-to-severe atopic dermatitis.²²

The largest recently published case series has demonstrated the benefit of dupilumab in the treatment of chronic pruritus. Twenty recalcitrant pruritus patients at a tertiary care center were treated with off-label dupilumab at standard atopic dermatitis dosing. Promising results were observed, with complete resolution obtained in 12/20 patients and an overall mean reduction of 7.⁵⁵ points on the numeric rating scale for itch intensity (range 0-10). Specifically, 9 patients in this series had PN, and reported a mean reduction in itch ratings of 7.89. Further, the drug was well tolerated in all patients and no significant adverse events were reported.²² The same authors have also reported success in its specific use for PN in a previously published case series.²³ Several other case series and reports all published within the last year have also described the benefit of dupilumab for treatment of PN.^24-28

Further, a recent retrospective cohort study examined the effectiveness of dupilumab in treating adults affected by persistent atopic dermatitis with clinical features of generalized PN. A total of 90 atopic dermatitis patients were treated, of which 9 patients demonstrated generalized PN. Significant improvements in Eczema Area and Severity Index, Dermatology Quality of Life Index, and pruritus visual analogue scale score were observed after treatment.²⁹ Another recent retrospective cohort study of 16 adult patients with chronic PN refractory to multimodal treatment regimens reported similar results.³⁰ Taken together with the evidence from the case series, the use of dupilumab in treatment of PN shows promise, and warrants further research with randomized control trials.

Opioid Receptor Modulation: Nalbuphine, Butorphanol, Naloxone and Naltrexone

Other research has examined the efficacy of opioid receptor modulating drugs in the treatment of pruritus. Considering that imbalances between mu- and kappa-opioid signalling have been indicated in generalized itch pathogenesis, mixed kappa-opioid agonist/mu-opioid antagonists may interrupt this cycle.³¹ The mechanisms of nalbuphine and butorphanol both act as such, and each have been demonstrated to have some beneficial effects on reducing pruritus. Specifically, one study examined the effects of nalbuphine in hemodialysis patients on treating uremic pruritus, and found discernable reductions in measures of itch severity with increasing dosage.³² Further, case investigations examining the effects of butorphanol on intractable pruritus have also demonstrated its benefit.³¹ Importantly, a recent multicenter, double-blind randomized control trial examined the effects of nalbuphine on itch severity in PN, as well as evaluated the safety and tolerability of the drug in this population. Phase 2 results have been released, but not yet published, and demonstrated promising beneficial effects of nalbuphine in reducing pruritus (NCT02174419).

Intravenous naloxone and oral naltrexone, both mu-opioid receptor antagonists, have also demonstrated antipruritic effects in select PN patients.^33,34 A double-blind, randomized control trial investigating the use of naloxone infusions in patients with pruritus of cholestasis (n=29) found that it was associated with reduced pruritic perception and actual reduction of scratching.³⁵ Further, another trial of 65 patients examined the effects of naltrexone on pruritus, and found significant benefits including lesion healing and symptom reduction.³⁶ Further studies examining the efficacy of opioid receptor modulation in pruritic pathways are warranted given these promising combined results.

Cannabinoids

Cannabinoid receptor (CB)1 and CB2 are expressed on cutaneous nerve fibers, with agonists of these receptors diminishing histamine-induced excitation and leading to reduction of itch.^37,38 As such, these cannabinoid receptors are thought to contribute to the pruritic sensation. A recent systematic review examined the efficacy of cannabinoids for the treatment of chronic refractory pruritus. Only 5 studies were included in the analysis, but all reported a reduction in itch intensity following cannabinoid therapy.³⁹ Considering the recent growth in acceptance of use and favorable legislation of medical marijuana, further research is warranted to explore its potential use in PN.⁴⁰

Conclusion

Novel therapeutics are currently being explored for the treatment of PN. It is important for treatments to consider targeting both the neural and immunologic components of the itch-scratch cycle. Nemolizumab and dupilumab both demonstrate promise in inhibiting specific central nervous system pathways responsible for transmission of the pruritic sensation. Moving forward it is important for clinicians to better understand the pathogenesis of PN, and apply an integrated approach to treatment of this chronic, recalcitrant condition.

Purchase Article PDF for $1.99

PDF Download

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.