¹University of Central Florida/HCA Healthcare Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA
^* Co-first authors

Conflict of interest: None.
Funding sources: None.
Disclaimer: This research was supported in whole or in part by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Abstract:
Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin. Several factors can precipitate SD development, such as colonization of Malassezia, sebocyte activity, impaired immunity, and environmental influences. Topical antifungals, corticosteroids, and calcineurin inhibitors are the current mainstay treatment of SD. Recent clinical trials have validated the efficacy of non-steroidal roflumilast 0.3% foam for the treatment of SD. In this review, we analyze the safety and efficacy profile of roflumilast 0.3% foam.

Keywords: seborrheic dermatitis, treatment, roflumilast, PDE-4 inhibitor

Introduction

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin.¹ While clinical presentations may differ, typical findings include erythematous, pruritic plaques and patches with a yellow, greasy appearance.^1,2 This condition can significantly impact quality of life due to activity limiting symptoms and emotional distress exacerbated by cosmetic ramifications.³ SD affects approximately 5% of the global population, whereas its non-inflammatory counterpart, dandruff, likely impacts closer to 50%.⁴ Despite such high prevalence, the pathogenesis and exact mechanisms via which these yeasts cause inflammation have yet to be fully elucidated.

Malassezia is a part of the human microbiome, interacting with the innate and acquired skin immune system. Innate immunity plays a critical role in initiating the initial immune response against Malassezia.⁵ Sensitization to Malassezia can cause a type I hypersensitivity reaction leading to redness, itching, and scaling.⁶ Further studies point towards Malassezia causing an irritant, non-immunogenic stimulation of the immune system, leading to complement activation and a localized increase in NK1+ and CD16+ cells.^7,8

Currently, there are many mainstay treatments for SD. Due to the underlying mechanism of Malassezia proliferation, most commonly topical antifungals are used for long-term treatment and topical corticosteroids and calcineurin inhibitors for short-term treatment (Table 1).¹ Due to the chronicity of SD, ongoing maintenance therapy is often necessary to achieve low recurrence rates of visible signs of the condition, as well as alleviate associating symptoms, such as pruritus.

Table 1

Phosphodiesterase-4 (PDE-4) inhibitors, including roflumilast, represent a significant advancement in the treatment of SD and other inflammatory conditions. These drugs work by inhibiting the PDE-4 enzyme, which plays a role in modulating inflammatory responses by breaking down cyclic adenosine monophosphate (cAMP).^9,10 Elevated levels of cAMP result in reduced inflammation, making PDE-4 inhibitors effective in managing various ongoing inflammatory disorders such as chronic obstructive pulmonary disease (COPD) and asthma.¹⁰ In dermatology, PDE-4 inhibitors have received regulatory approval in the US and Canada for plaque psoriasis, psoriatic arthritis, atopic dermatitis and, most recently, SD. They have shown promise in off-label treatment of a myriad of other inflammatory skin conditions. Apremilast is an oral PDE-4 inhibitor FDA-approved for psoriasis and psoriatic arthritis in patients ≥6 years of age. Crisaborole is a topical PDE-4 inhibitor, currently FDA-approved for atopic dermatitis in patients ≥3 months of age. Roflumilast has also demonstrated safety and efficacy in managing chronic inflammatory skin conditions, with the regulatory approval status in the US and Canada summarized in Table 2. Compared to currently available PDE-4 inhibitors, apremilast and crisaborole, used to treat skin disease, roflumilast has demonstrated greater selectivity and potency.^9,10

Table 2

Herein, the review will focus on the treatment of SD with a particular emphasis on roflumilast 0.3% foam.

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE-4.⁹ Inhibition of PDE-4 leads to an increase in cAMP and subsequent decrease in pro-inflammatory mediators such as interleukin (IL)-17, IL-23, tumor necrosis factor alpha, and interferon gamma.¹⁰

Clinical Trials

Phase 2¹¹

The Phase 2a study design was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily roflumilast 0.3% foam. A total of 226 participants aged 18 or older were enrolled in the 8-week trial conducted at 24 sites in the US and Canada with a clinical diagnosis of SD for a 3-month long duration and affecting less than 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. Roflumilast 0.3% foam demonstrated a statistically significant increase in treatment success, with 104 participants (73.8%) achieving an Investigator Global Assessment (IGA) score of 0 or 1, compared to its vehicle. At week 8, 50 individuals (35.5%) attained an IGA score indicating clearance, while 54 patients (38.3%) achieved an IGA score signifying almost clear skin. In comparison, the vehicle group exhibited lower rates of improvement, with only 10 patients (15.2%) reaching clearance and 17 patients (25.8%) achieving almost clear status. Roflumilast patients exhibited significantly higher rates of erythema success, defined as an overall erythema score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline, compared to those treated with the vehicle. At weeks 2, 4, and 8, respective absolute differences were 16.6% (95% Confidence Interval (CI): 6.4%-24.8%), 25.2% (95% CI: 13.1%-34.9%), and 23.5% (95% CI: 9.6%-35.0%). Similar results were noted for scaling success, defined as overall scaling score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline. Statistically significant differences at weeks 2, 4, and 8: absolute differences were 11.8% (95% CI: -0.3% to 21.8%), 20.4% (95% CI: 6.8%-31.8%), and 28.8% (95% CI: 14.4%-41.0%), respectively. Overall, roflumilast 0.3% foam exhibited good tolerability, with a low occurrence of adverse events.

Phase 3¹²

The Phase 3 trial design was a parallel-group, double-blinded, vehicle-controlled, multicenter (50 centers) study with participants aged ≥9 years who were clinically diagnosed with SD affecting up to 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. 457 patients were randomly assigned in a 2:1 ratio to roflumilast (n = 304) or vehicle (n = 153). The primary endpoint was an IGA score of 0 (clear) or 1 (almost clear) and a ≥2-point improvement from baseline by week 8. The secondary endpoints included IGA success by weeks 2 and 4 and a ≥4-point improvement on the Worst Itch Numeric Rating Scale score (WI-NRS).

During this 8-week trial, a statistically significant amount of roflumilast treated patients (79.5%) achieved IGA success compared with vehicle (58.0%; P < 0.001). Roflumilast also demonstrated success at weeks 2 and 4, with percentages of IGA success of 43.0% versus 25.7% (P < 0.001) and 73.1% versus 47.1% (P < 0.001). At week 8, a higher percentage of patients treated with roflumilast (62.8%) achieved WI-NRS success compared to those treated with the vehicle (40.6%: P < 0.001), with improvement observed within 48 hours after the first application, respectively (Table 3).

Table 3

Safety and Tolerability

Overall, roflumilast 0.3% foam was well tolerated, and had similar rates of adverse events (AE) as the vehicle. During all phases of the study, there were no treatment emergent adverse events (TEAEs) reported as a direct result of roflumilast 0.3% foam treatment.^11,12 The most prevalent adverse reactions, observed in ≥1% of subjects across both Phase 2 and Phase 3 study groups included nasopharyngitis (1.5%), nausea (1.3%), and headache (1.1%).^11,12 Less frequent AEs included application site pruritus, application site pain, and diarrhea.^11,12 There were no significant differences between groups noted in clinical laboratory assessments. Vital signs, body weight, and body mass index indicated no clinically meaningful variations.¹² Moreover, evaluations for depression, suicidal ideation, and behavior revealed no safety concerns.¹²

Contraindications

Contraindications include individuals with a known hypersensitivity to roflumilast or any of the components in the formulation, as this can lead to severe allergic reactions. Additionally, patients with moderate to severe liver impairment (Child-Pugh B or C) should not use roflumilast, as it may exacerbate liver dysfunction.¹³ The coadministration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 may increase roflumilast systemic exposure and result in increased adverse reactions.¹³ It should be noted that no formal drug-drug interaction studies were done with topical roflumilast and these recommendations are based on oral roflumilast, which has a much greater bioavailability.

Regulatory Approval

The roflumilast 0.3% foam formulation was approved by the US FDA in December of 2023 and Health Canada in October 2024 for the treatment of SD in individuals aged ≥9 years.¹⁴ The medication is to be applied once daily to the affected areas, with the duration determined by the healthcare provider. One pressurized can of roflumilast 0.3% foam (60 g) contains 3 mg roflumilast per 1 g.

Discussion

Current first-line therapies for SD typically include topical antifungals and topical steroids (Table 1). These treatments are often readily available and affordable, leading to their widespread use. While these are effective in many cases, some individuals require a combination of multiple topicals for control which contributes to patient non-compliance due to complex treatment regimens.⁴ Moreover, these treatments may be ineffective in some individuals and can be associated with poor tolerability due to various AEs such as local skin reactions, burning, pruritus, and blistering.⁴

Roflumilast 0.3% foam provides an additional non-steroidal anti-inflammatory treatment option in those who have failed first-line therapies or prefer a once daily treatment regimen. It marks the first regulatory approved medication for SD with a novel mechanism of action in over two decades. This foam is uniquely formulated in a water-based emollient formula without skin irritating fragrances or alcohols such as, propylene glycol, polyethylene glycol, isopropyl alcohol, or ethanol.¹⁴ It is reported to be the first-in-class drug formulated with a novel emulsifier that lacks ceramide stripping properties. The hydrating features of the vehicle itself may add to its therapeutic effect. Moreover, the non-irritating, non-steroidal formula enables use anywhere on the body, including the eyelids and genitalia. The non-greasy foam formulation lends itself to use on hairy scalps.

Roflumilast may improve adherence and tolerance due to its once daily application, potent formulation, and minimal AEs. Its greater selectivity for PDE-4 than apremilast and crisaborole, likely contributes to its low side effect profile. Few patients reported stinging, burning, application site reactions, or application site pain with roflumilast.¹² Data from key trials reported IGA success, defined as IGA of 0 (clear) or 1 (almost clear) plus ≥2-point improvement from baseline in 80% of participants, with some reaching IGA success as early as weeks 2 and 4.¹² Pruritus, measured via the WI-NRS, improved as early as 48 hours after application. These results are in-line with other first-line therapies (Table 3).

With the continual push for more effective and safer therapies, roflumilast appears to be a useful agent added to the SD armamentarium.

Conclusion

Due to its minimal AEs and favorable tolerability, the novel roflumilast 0.3% foam offers a safe treatment for the erythema, scaling, and pruritus caused by SD. Its once daily application and potent formulation provides a convenient and effective treatment for SD. This treatment highlights the importance of continued advancement in the development of innovative therapies for SD as it is essential to improve outcomes and enhance the quality of life for individuals affected by this condition.

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Abstract

Background: Atopic dermatitis (AD) is a heterogeneous disease characterised by epidermal barrier dysfunction and immune dysregulation. It commonly presents with pruritus and eczematous lesions that significantly impact quality of life. Abrocitinib is a JAK inhibitor approved for treatment of refractory, moderate-to-severe AD in patients 12 years and older.

Objectives: This real-world case series intends to illustrate a variety of moderate-to-severe AD patient cases to help guide discussions around abrocitinib and describe its treatment strategies used by experts in the field.

Methods: Expert panel members were recruited from across Canada to discuss varying clinical AD phenotypes seen in their clinic. Guided by literature, the panel shared their opinions and insights to provide a holistic view of the overarching question, “Which patients are good abrocitinib candidates?”

Results: The panel reported on ten real-world patient cases that detailed the use of abrocitinib in biologic naïve patients, refractory AD patients, complex medical patients, and those with differing treatment goals. Cases aim to demonstrate the broad use of abrocitinib in patients with AD, offering a learning point with each real-world case.

Conclusions: Each presented real-world case reflects the panel’s clinical experience. Panel members concluded that abrocitinib is a fast-acting, safe, and efficacious therapy for a wide variety of AD patients with differing disease severities and comorbidities. Treatment with abrocitinib may cause transient nausea that frequently resolves by taking it with food. Overall, patients are highly satisfied with the treatment.

Keywords: atopic dermatitis, real-world cases, JAK inhibitor, abrocitinib

Disclosures and Acknowledgment: The authors conducted the real-world series, supported by an educational grant from Pfizer Canada. The authors acknowledge and thank Sophie Guénin, MSc, for her assistance in preparing this manuscript.

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Introduction

Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease characterized by epidermal barrier breakdown, immune dysregulation, and significantly reduced quality of life (QoL).¹ Approximately 3.5% of the total Canadian population and 25.4% of the pediatric Canadian population is affected with AD.^1,2 This relapsing condition may present as dry, erythematous, sensitive skin or pruritic, excoriated, eczematous, and painful patches with weeping erosions and prurigo nodules.¹ About one-third of AD patients are affected by atopic comorbidities such as asthma, food allergy, and hay fever.³

Patients with AD report impaired quality of life that limits their daily lives and social interactions.³ Pruritus is reported as the most burdensome symptom of AD, with 95% of patients reporting itch as the most important indicator of treatment response.⁴ Other burdensome symptoms included excessive dryness, scaling, inflamed skin, skin pain, and sleep disturbance.⁴ Impaired barrier function in AD is largely attributed to filaggrin dysfunction.⁵ Meanwhile, immune dysregulation in AD largely stems from T-helper (Th)2 cell cytokines, interleukin (IL)-4 and IL-13, in its acute phase and Th1 skewing in chronic disease.⁶ IL-22 and IL-17-producing T cells have also been implicated in the pathogenesis of AD.⁶

Systemic Treatment for Moderate-to-Severe AD

The consensus-based European guidelines for the treatment of AD recommend proactive therapy with topical calcineurin inhibitor (TCI) or topical glucocorticosteroids (TCS) for moderate AD along with narrow band (nb) UVB phototherapy, psychosomatic counseling, and climate therapy.⁶ For severe AD, the guidelines recommend hospitalization in specific cases, systemic immunosuppression with cyclosporine, short-course oral glucocorticosteroids, methotrexate, azathioprine, or mycophenolate mofetil.⁷ Biologic monoclonal antibody therapies such as dupilumab are also recommended for severe AD patients.⁷

Dupilumab is an anti-IL-4-receptor α monoclonal antibody that inhibits the signaling of both IL-4 and IL-13.⁶ Since the guidelines were published in 2018, an additional monoclonal antibody therapy, tralokinumab, an IL-13 inhibitor, has been approved for AD treatment in Canada, as well as two janus kinase inhibitors (JAK) inhibitors (JAKi): abrocitinib and upadacitinib.⁶

Newer topicals such as the topical PDE4 inhibitor, crisaborole, has also been recently introduced for AD treatment, and ruxolitinib, a topical JAK inhibitor, not yet available in Canada.^6,7

Abrocitinib & JAK Inhibitors (JAKis)

JAKis are a new class of systemic treatments for AD that function by blocking downstream cytokine inflammatory signaling.⁶ Abrocitinib and upadacitinib are once daily, oral JAK1 inhibitors that block IL-4 and IL-13, cytokines involved in the pathogenesis of AD, downstream.^8,9 Abrocitinib is available in three doses: 50 mg, 100 mg, and 200 mg, and is approved for moderate-to-severe AD patients aged 12 and older.⁹ In pivotal trials JADE MONO-1 and JADE-MONO-2, abrocitinib demonstrated significant pruritus reduction within two weeks.^10,11 In a phase 3 comparative clinical trial, JADE-COMPARE, abrocitinib 200 mg demonstrated greater IGA response and itch response at endpoint than dupilumab.¹² As with all JAK inhibitors, abrocitinib has inherited a black box warning for thrombosis, major adverse cardiovascular events (MACE), and malignancy. Despite this, clinical trial safety analysis at 48 weeks of both the 100 mg and 200 mg abrocitinib dosage groups showed only 0% to 0.3% incidence of the following: nonmelanoma skin cancer (NMSC), malignancy, MACE, or VTEs.¹³

Upadacitinib is approved for the treatment of AD, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondylarthritis.⁹ In refractory moderate-to-severe AD, upadacitinib is approved in Canada for ages 12 and up with two dosing options: 15 mg and 30 mg; recommendations suggest initiating treatment at 15 mg prior to titrating up to 30 mg.¹⁴

As more treatments become available, it will be important for clinicians to partner with patients in a treat-to-target (TTT) paradigm to identify the optimal AD treatment for each patient.¹⁵

Methods

Aim of the Project

This real-world case series illustrates a variety of patients with moderate-to-severe AD treated with abrocitinib. The cases outline the TTT paradigm and demonstrate patient-provider partnerships that highlight patient priorities and ideal treatment options. Expert panelists’ thought processes, reasoning, and rationales are detailed in the following patient cases to serve as a guide for licensed providers who treat patients with AD.

Steps in the Process

The project was conducted in the following five steps: 1) project definition and expert panel selection 2) data collection and preparation of patient cases, 3) patient case discussion and selection for publication 4) literature review to support selected cases 5) drafting, review, and finalization of the manuscript.

Role of the Panel

The panel consisted of 10 dermatologists practicing in Canada who commonly care for patients with AD. Panelists were chosen from 3 provinces in Canada to capture geographical and provincial differences in dermatological practice. During the Dermatology Update conference on April 30^th, 2023, in Vancouver, panelists met to report on and discuss clinical cases of AD patients who were suitable candidates for abrocitinib treatment.

The panel used the following template to gather insight through a case-based approach:

Panelists were asked to select two patient cases from their clinical practice to share and discuss. In the second half of the meeting, panelists examined and collaborated to select ten real-world cases for inclusion in the publication. Panel members agreed that real-world cases should focus on common AD scenarios encountered in the clinic. The publication was prepared and reviewed by the panel.

Experience Gathering and Atopic Dermatitis Outcome Measures

Suggested information and outcome measures to present included patient demographics, concomitant medications, comorbidities and Investigators’ Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS), and patient-reported Dermatology Life Quality Index (DLQI) at weeks 0, 2, and 4 (+/- 5 days) of abrocitinib treatment (Appendix 1). Panelists were also requested to report patient compliance, treatment satisfaction, and any adverse events experienced.

Results

Selected Real-World Cases

The panel selected ten cases to demonstrate the real-world use of abrocitinib in a diverse group of patients with varying skin concerns, past treatment failures, severity, and comorbidities. The findings reflect real-world clinical use of oral abrocitinib and patient treatment outcomes.

Case 1: The recalcitrant, severe AD patient with intense pruritus

A 31-year-old Caucasian, Fitzpatrick Skin Type (FST) 1, female struggling with severe, recalcitrant AD for the past 18 years presented with reported worsening anxiety, avoidance of social activities, and sleep interruption due to debilitating pruritus. Intense pruritus led to diffuse excoriations and multiple skin infections. Her EASI was 22, and DLQI 20. Over the years, the patient had tried TCS, TCI, crisaborole, nbUVB phototherapy, and systemic therapies: prednisone, methotrexate, and intramuscular triamcinolone injection. She had developed striae on her abdomen and arms from frequent TCS use and continued to suffer from intractable itch. The patient started dupilumab but discontinued it after three months due to repeated flu-like symptoms and nasopharyngitis. Having failed first, second-, and third-line therapies for AD, the patient was started on abrocitinib, 200 mg daily. The rationale for beginning abrocitinib at the higher dose was the failure of previous treatment and the patient’s primary complaint of incessant itch. Within eight weeks, she saw rapid improvement; her EASI was 8 and DLQI 4. At week 16, her EASI was 2 and DLQI 0. When asked about her experience, the patient reported that abrocitinib had “life-changing” effects after only one month of treatment. No adverse events occurred, and the patient was reduced to 100 mg abrocitinib daily without exacerbation.

Learning point: Abrocitinib is a fast-acting, effective, and safe treatment option for patients with longstanding, recalcitrant AD. It may be an option for patients who have failed many prior therapies. Abrocitinib therapy can improve patients’ QoL and reduce the need for TCS and other adjunct therapies, thereby sparing patients from the undesirable adverse effects of these treatments.

Case 2. The biologic-naïve patient

Since early childhood, a 55-year-old Caucasian (FST1) salesman with hypertension, hypercholesterolemia, and prediabetes had suffered from severe AD that affected extensive parts of his head, neck, trunk, and extremities. Since starting amlodipine and rosuvastatin for his comorbid conditions, the patient reported worsening xerosis and diffuse erythema.

While biologic naïve, he had previously tried various moisturizers, TCS, TCI, phototherapy, and oral antihistamines with only modest benefit. Despite the multimodal treatment approach, the patient continued to have frequent visits to the Emergency for infections and exacerbations. His condition greatly impacted his work and social interactions as well as his psychological and sexual health. Given his frequent business travel, busy family life, and needle aversion, the patient expressed interest in a convenient, effective treatment that would improve his worsening xerosis and eliminate the requirement for additional therapies. For these reasons, the patient was started on 100 mg abrocitinib. Within two weeks, the patient’s IGA score reduced from 3 to 2, EASI score from 4 to 2 and PP-NRS score from 8 to 3. Two weeks later, the patient saw continued improvement with an IGA score of 1, EASI score of 1, and PP-NRS score of 2. Rapid reduction in itch made the patient extremely satisfied with abrocitinib monotherapy. He did not experience any adverse events and was “thrilled” with his outcome. The patient remains on abrocitinib 100 mg with the option to increase to 200 mg, if necessary.

Learning point: JAKi is an option for biologic-naïve patients for whom self-injection does not correspond to their lifestyle. Patients who travel frequently or lead busy lifestyles may have difficulty transporting subcutaneous injections that must be stored in cool temperatures or having the proper setting to self-inject. Further, some patients are needle-phobic and would prefer an effective, oral treatment option.

Case 3. The patient with post-inflammatory hyperpigmentation

A 29-year-old Southeast Asian (FST4) female presented with sensitive skin, longstanding AD and significant post-inflammatory hyperpigmentation (PIH) around her eyes and on her arms. She had been treated with multiple courses of prednisone with a good response but would predictably flare 2-4 weeks after steroid discontinuation. Having suffered from AD since infancy, she reported the post-inflammatory hyperpigmentation from AD as her most bothersome symptom. Previous treatments included TCS, TCI, and crisaborole. She saw a slight improvement in her skin and pruritus with topical therapy in conjunction with oral antihistamines. Despite mild improvement, she was still desperate for a long-term, effective solution. Her primary care physician had recently made her aware of abrocitinib and encouraged her to seek evaluation by a dermatologist. As a young, single female without any plans for pregnancy in the near future, the patient was a good candidate for abrocitinib and was started on abrocitinib 100 mg. Her IGA was 3 at baseline, EASI score was 4, and PP-NRS score was 8. By week 4, her IGA, EASI, and PP-NRS scores were all 1, and she felt happy and hopeful that PIH marks would continue to fade with time. No compliance issues or adverse reactions were reported.

Learning point: Patients with skin of colour are at increased risk for PIH. Consistent AD treatment with abrocitinib and control of AD, results in PIH improvement and improved mood and QoL. It also reduces inappropriate, long-term use of oral corticosteroids. In females of childbearing age, it is also important to inquire about pregnancy and/or contraceptive use. Pregnancy is a contraindication for abrocitinib use. It should be recognized that contraceptive use may lead to low risk of VTE. Family planning should be discussed with all patients of childbearing potential who are contemplating treatment with abrocitinib.

Case 4. The atopic patient with barriers to treatment access

A 22-year-old (FST2) male with lifelong AD and comorbid atopic diseases (hay fever, asthma, and urticaria) presented with worsening pruritus. Physical exam revealed symmetric, generalized excoriated red, scaly patches with significant lichenification on his bilateral extremities, face, scalp, and back. Working as a dishwasher, the patient reported wearing gloves most of the day to protect his skin from irritating soaps or dryness. Despite his precautions, his skin began impacting his ability to work. He reported skin burning, discomfort, unbearable itch, and skin pain, which frequently disrupted his sleep. At presentation, while on methotrexate, his EASI was 23, IGA score 4, and DLQI 18, with 31% of his body surface area (BSA) affected by AD (Figure 1A [back – face]). Throughout his lifetime, the patient had tried lifestyle modifications such as fragrance-free, hypoallergenic detergent, gentle cleansers, moisturizer application every 2 hours as well as TCS, TCI, calcipotriol gels, oral antihistamines, systemic corticosteroids, and 1-year of methotrexate. Given the severity of the patient’s AD and worsening QoL, the plan was to begin biologic monoclonal antibody therapy. Unfortunately, the patient could not gain access to dupilumab or tralokinumab through his insurance, compassionate drug program, or patient assistance programs. Fortunately, the patient was able to access 100 mg abrocitinib and was thus started on this oral therapy in lieu of biologic therapy. The 100 mg dose was chosen since the patient and his mother were risk-averse and wished to try the 100 mg dose first, increasing to 200 mg only if the 100 mg dose was not sufficient. Two weeks prior to starting abrocitinib, the patient was given his first shingles vaccine. At his 11-week follow-up visit, the patient reported no skin pain and minimal itch with only slight residual erythema on his face (EASI 1.1, IGA 1) (Figure 1B [face – back]). He reported that he could sleep through the night and was able to stop using topical therapies and antihistamines. Of note, the patient experienced mild initial nausea and abdominal pain that abated within the first few weeks of treatment. He had his second shingles vaccine after commencing abrocinitib treatment.

Learning point: Abrocitinib is readily accessible to some patients who are unable to gain coverage for monoclonal antibody therapies such as dupilumab and tralokinumab. While addressing itch, abrocitinib also effectively targets skin pain. It is important to consider shingles vaccination prior to abrocitinib start. The second dose of the vaccine can be given 1-6 months later.¹⁶ Nausea may also be an important adverse effect to discuss with patients. Nausea is frequently transient and can be improved by taking abrocitinib with food.

Figure 1: 22-year-old male with severe AD
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 5. The complex medical patient with persistent AD-related pruritus

The retired aerospace worker, two-time widower, and former smoker the 63-year-old man, has atopic triad and comorbid anxiety, depression, hyperlipidemia, hypertension, and a history of stroke. He presented with persistent AD, severe pruritus, and atopic keratoconjunctivitis (AKC). His concomitant medications included: citalopram, atorvastatin, ezetimibe, perindopril, and clopidogrel. Despite his other conditions, the patient was most concerned with his pruritus as it had prevented him from sleeping, exercising, socializing, dating, and working. He had only slept through the night three times in the past year. Embarrassed by his skin, he has not been in a swimming pool for over ten years. His EASI was 50, DLQI 26, IGA 4, PP-NRS 10, and BSA 49% (Figure 2A [face – back – legs]).

Having tried numerous moisturizers, TCS, 12 years of nbUVB phototherapy, antihistamines (up to 4 times approved dosing), and multiple cycles of prednisone, he continued to suffer from his skin condition. He was enrolled in a lebrikizumab clinical trial, which helped his AD and pruritus but did not clear his face and neck. However, during the clinical trial, he suffered a non-treatment-related posterior cerebral artery infarct, which has deterred him from future biologic use. The patient redeveloped generalized erythema, lichenification, and scaling off the biologic.

The rationale for starting abrocitinib stemmed from numerous conversations with the patient, during which he highlighted his preference for QoL over mere survival. He was desperately seeking to sleep through the night and regain control of his life. Use of immunosuppressants such as methotrexate and cyclosporine were contraindicated in this patient due to his heavy alcohol use and hypertension, respectively. Given his AKC, dupilumab, and tralokinumab were eliminated as options to reduce the risk of worsening his ocular involvement. The lower perceived rates of MACE and VTE events with abrocitinib compared to upadacitinib led to the patient being started on abrocitinib. Two weeks prior to starting abrocitinib, he received his first dose of the shingles vaccine. The decision was made to start at 50 mg of abrocitinib to mitigate any potential risk for drug interactions or adverse cardiovascular events. He reported that during his first week on abrocitinib, he was able to sleep itch-free every night and noticed smoother skin texture. After one month of monitoring without any adverse events nor appreciable changes in blood values, the patient was increased to 100 mg abrocitinib. After two weeks on 100 mg abrocitinib, the patient’s EASI was reduced to 6.4, DLQI to 6, IGA to 2, PP-NRS to 1.5, and BSA to 10% (Figure 2B [face – back – legs]). The patient remains on 100 mg of abrocitinib with good control of AD, itch, and good tolerability.

Learning point: Assessment of risks and benefits with a patient remains an important consideration in the TTT paradigm for AD treatment. While extra precautions must be considered in a complex medical patient, their complexity does not preclude them from abrocitinib therapy. Titration of the abrocitinib dose, starting at 50 mg, may also help minimize any potential risk while simultaneously allowing patients to benefit from treatment.

Figure 2: 63-year-old medically complex male with anxiety, depression, hyperlipidemia, hypertension, and a history of stroke
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 6. The busy professional biologic naïve patient needing a fast-acting therapy

A 38-year-old lawyer of Asian (FST4) descent presented to the clinic in search of a rapid solution for his AD. He had no significant past medical history other than lifelong AD. At presentation, his DLQI was 28, EASI was 50, and IGA was 4 (Figure 3A [face – legs]). He had only previously tried betamethasone 0.1% cream and prednisone with mild, transient improvement after each therapy. Despite being naïve to systemic therapies beyond prednisone, he wanted a quick, easy solution to his skin condition that would not impact his busy schedule and allow him to enter conference rooms with confidence. Understanding the patient’s aggressive treatment goals, the provider started him on 200 mg of abrocitinib with concomitant use of tacrolimus ointment 0.1% twice daily, as needed. Four weeks later, the patient returned with 90% skin clearance, including complete clearance on his face and only post-inflammatory erythema remaining on his extremities (Figure 3B face – legs]. At his 6-month follow-up, he had clear skin (Figure 3C [legs]). While he was given the option to reduce to the 100 mg dose, the patient has been reluctant to decrease the dosage given his rapid, lasting response to the current abrocitinib 200 mg regimen.

Learning point: The 200 mg dose of abrocitinib may be an optimal first-choice therapy for select patients. The JAKi allows for fast results, and the ease of a once-daily pill makes it an ideal option for working professionals with hectic lives. The 100 mg and 200 mg abrocitinib dosing options also allow patients to choose how aggressively they would like to treat their AD while relying on their provider to help them weigh the risks and benefits.

Figure 3: 38-year-old biologic naïve male
(Photos courtesy of Andrei Metelitsa MD, FRCPC)

Case 7. The dupilumab failure AD patient

A 62-year-old (FST3) male with generalized AD since adolescence was initiated on 100 mg of abrocitinib therapy. Having struggled most of his adult life with daily TCS and emollient regimens, the patient was frustrated as his AD had a determinantal impact on his daily activity, social life, sports participation, and sleep. He had previously tried one year of dupilumab treatment with an inadequate response. Prior to starting abrocitinib, his EASI was 12, IGA 3, and PP-NRS 8. After two weeks on abrocitinib, the patient had an EASI of 3.2, IGA 1, and PP-NRS of 1. Despite reporting nausea from therapy, he expressed 8 out of 10 satisfaction, given his dramatic skin response. At his 4-week follow-up, the patient had an EASI of 2.1, IGA 1, and PP-NRS of 1, with resolution of his nausea and no further adverse events.

Learning Point: Abrocitinib is an ideal step-up therapy for patients who have an inadequate response to dupilumab. The differing mechanisms of action of abrocitinib and dupilumab make the trial of abrocitinib worthwhile in a patient who may have failed IL-4 receptor blockade. Nausea, when and if it occurs, often resolves spontaneously.

Case 8. The patient intolerant to dupilumab

Struggling with AD since childhood, a 47-year-old female (FST4) with mild asthma and severe AD presented after 16 months of dupilumab therapy. While dupilumab was effective for the first year, her skin failed to maintain its initial response. She had also developed persistent conjunctivitis secondary to dupilumab use. AD covered her trunk, face, and proximal extremities and often caused her to miss work and avoid romantic and social relationships. She struggled to sleep through the night without scratching. In the past, she had tried topical tacrolimus and clobetasol without any lasting improvements. The rationale for starting 100 mg abrocitinib was intolerance and failure to maintain response to dupilumab. On Day 0, her EASI was 35, IGA 4, and PP-NRS score 8. Upon starting abrocitinib treatment, the patient reported mild nausea that improved when the tablet was taken with food. By week 4, the nausea had resolved, and the patient had an EASI of 16, IGA of 2, and PP-NRS of 3. She reported feeling more confident in her skin, with reduced pruritus and improved sleep and quality of life. Without experiencing any other side effects, the patient remains on 100 mg of abrocitinib and is highly satisfied with the treatment.

Learning Point: The side effect profile for abrocitinib does not include conjunctivitis or any other ocular effects, making it ideal for patients sensitive to the adverse reaction of dupilumab or tralokinumab or patients with comorbid ocular conditions. Lastly, nausea is a common adverse effect of abrocitinib therapy that usually resolves with time and may be mitigated by taking the medication with food.

Case 9. The patient with adult-onset AD

The 49-year-old (FST2) male presented with a 4-year history of adult-onset AD. He had a remote history of alcohol-induced pancreatitis but no other comorbidities. Expressing high levels of frustration with his inadequate sleep and intractable itch, the patient wanted rapid control of his pruritic skin. He had tried TCS, TCI, and cyclosporine without sustained skin improvement, and he experienced deterioration of his kidney function from cyclosporine. His EASI was 25, IGA 4, and PP-NRS score 9. The rationale for starting abrocitinib was that the patient was desperate for rapid control. While upadacitinib was considered for rapid pruritus relief, the patient’s history of alcoholism made abrocitinib a safer option as it does not require monitoring of liver function tests. After four weeks of abrocitinib 100 mg daily use, the patient no longer required use of TCS and had an EASI of 1.2, IGA of 2 and PP-NRS of 4. He was extremely satisfied with treatment and tolerated the treatment without any adverse events.

Learning Point: Immunosuppressants such as cyclosporine and methotrexate have long been used to treat AD, although Health Canada does not approve them for treating AD. In addition, these immunosuppressants are often associated with kidney toxicity (cyclosporine), liver and bone marrow toxicity (methotrexate) as well as malignancy (both medications). Thus, long-term use of these immunosuppressants is not appropriate for long-term use in AD patients. In addition, the increasing availability of efficacious, safe, and targeted treatments for AD makes the use of broad immunosuppressants inappropriate.

Case 10. The AD patient switching from another JAK inhibitor

The 21-year-old (FST4) male university student presented with severe AD involving his torso and limbs. His AD first presented in childhood. He had a positive family history of atopic disease. Having tried TCS, crisaborole, and a 2-year course of methotrexate without improvement, the patient was started on upadacitinib. While the upadacitinib helped to significantly clear his skin, he developed acneiform lesions on his face which led to treatment cessation. His AD returned upon upadacitinib cessation (EASI 24, IGA 4, and BSA 30%). A healthy young man, the patient was offered to start at the higher 200 mg dose of abrocitinib, which should allow for faster control of his AD and a quicker return time to being more productive at school. At his 4-week follow-up, the patient had an EASI of 1.2, IGA of 2, and BSA of 3%, with the most considerable improvement on his face and neck. The patient reported mild nausea a few hours after taking abrocitinib; however, the nausea abated when he started taking it with food. Interestingly, he did not experience acne on abrocitinib.

Learning Point: Abrocitinib is a good treatment option for patients who had adverse reactions to another JAKi. There is a low risk of acne as an adverse reaction to abrocitinib versus upadacitinib. Thus, if a patient develops acne on one JAKi, it does not preclude them from trying abrocitinib.

Discussion

Real-world cases provide highly impactful insight into patient and provider experience with a new treatment. Without a cure, the AD treatment goal is aimed at reducing symptoms to a level that has minimal or no impact on patient QoL. In the patient cases discussed above, all patients had previously tried and failed topical therapies such as TCS, TCI, and various emollients and moisturizers. While some had tried systemic therapies, a few were naïve to systemic AD therapies prior to starting abrocitinib. Each patient discussed had a complete or near complete response by week 4 of abrocitinib therapy and reported significant satisfaction with treatment. This real-world case discussion provides invaluable insight into abrocitinib use in a diverse population of Canadian patients suffering from moderate-to-severe AD.

Biologic Naïve Patients

The 2018 consensus-based European guidelines for the treatment of adult AD only recommend the use of dupilumab in severe AD.⁶ While JAKi’s were not yet approved when these guidelines were released, clinical experience suggests that many practices do not recommend JAKi until a patient has failed all other standard therapies, such as dupilumab and other immunosuppressants. However, panel members discussed five cases of biologic-naïve patients with safe, efficacious, and accessible treatment with abrocitinib. The patients’ successful treatment with abrocitinib as a second-line therapy after topicals suggests that requiring a patient to cycle through a biologic prior to a JAKi may be unnecessary. Biologic naïve patients reported being “thrilled” and “very satisfied” with abrocitinib oral dosing that provided rapid itch relief and improvement in QoL.

Dupilumab Failed/Intolerant Patients

Another recurring rationale for initiating a patient on abrocitinib therapy was previous inadequate response or intolerance to dupilumab treatment. Three patients presented had previously been on dupilumab and stopped either due to inefficacy, failure to maintain response, or secondary conjunctivitis. Switching to abrocitinib after prior dupilumab therapy had no effect on the JAKi’s efficacy. Each patient saw near complete response to abrocitinib on either 100 mg and 200 mg dosing approaches. Failure to maintain response to dupilumab may stem from the monoclonal antibody’s ability to trigger the development of anti-drug antibodies (ADA).¹⁷ Some reports show a 7.61% ADA incidence in dupilumab studies, which may be higher in sporadic dupilumab injectors.¹⁸ Abrocitinib, a small-molecule JAK inhibitor, does not trigger the production of ADAs, which may contribute to greater maintenance of initial response.¹⁸ In one-year clinical trials, JADE EXTEND for abrocitinib and LIBERTY AD CHRONOS for dupilumab, 60.5% of patients on abrocitinib 200 mg exhibited an IGA 0/1 at week 48 while only 40% of patients on dupilumab 300 mg weekly and 36% of patients on dupilumab 300 mg biweekly exhibited an IGA score of 0/1 at week 52.^19,20

Jumping JAKi’s and Adverse Reactions

To date, two systemic JAKi’s, upadacitinib and abrocitinib, are indicated in Canada for AD treatment. The most common adverse reactions to abrocitinib include nasopharyngitis, nausea, headache, herpes simplex, increase in blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, and vomiting. Acne occurred in 4.7% of patients on 200 mg abrocitinib and 1.6% of patients on 100 mg abrocitinib in placebo-controlled trials.⁸ While upadacitinib shares many similar adverse reactions to abrocitinib, 16% of patients on 30 mg and 10% on 15 mg of upadacitinib developed acne during placebo-controlled clinical trials.¹⁴ Case 10 illustrates that patients who develop acne on upadacitinib may not have this adverse event on abrocitinib.

In the real-world cases presented, nausea was the most common adverse event experienced by four patients in the series. The nausea was reported to subside over time or when counseled to take abrocitinib with food. Reactivation of the varicella-zoster virus (VZV) has also been reported in approximately 1% of abrocitinib-treated patients.¹³ The panel suggests shingles vaccination in conjunction with JAKi use. Two presented cases reported that first dose shingles vaccination occurred two weeks prior to abrocitinib start.

Dosing Approach

Abrocitinib is unique in that it offers three potential dosing strategies: 50 mg, 100 mg, and 200 mg.⁸ Depending on preference, patients and providers may choose to start at a higher dose and titrate down or start at a lower dose and titrate up. Considering patient factors, disease factors, and concomitant medications, providers should work with their patients to choose the best dosing strategy for them.

Abrocitinib is predominately metabolized by CYP2C19 (~53%) and CYP2C9 (~30%); thus, co-administration of abrocitinib with a strong CYP2C19 and CYP2C9 inhibitor is not recommended and may increase the risk of adverse reaction to abrocitinib.⁸ Case 5 had a history of cerebral infarct and anxiety treated with CYP2C19 inhibitor, clopidogrel, and CYP2C19 substrate, citalopram, respectively. Despite his complex medical history, because of the impact of his severe AD on his QoL and sleep (he only slept three nights/year pre-abrocitinib), he was initiated on 50 mg of abrocitinib to assess safety. He tolerated the regimen without any adverse reactions. The 50 mg abrocitinib allows for further dose titration in patients with poor renal function or who are poor CYP2C19 metabolizers.

While extra caution must be taken, the panel agreed that patients with complex medical histories should not be excluded as potential candidates for abrocitinib without first evaluating the risks and benefits and having a thorough discussion with these patients.

Future Directions

The panel agreed that patient testimonials are highly impactful and educational. Patients are often enthusiastic about sharing their experiences. In the future, it will be important to direct discussions toward more complex AD cases to help healthcare providers choose appropriate dosing strategies and treatment regimens with the proper precautions. Further investigation into AD-associated PIH in individuals with sensitive skin may also help elucidate therapy plans for all skin types. Lastly, one panel member suggested further training of other medical specialties outside of dermatology in order to earlier recognize and appropriately treat AD patients. In particular, emergency medicine (EM) practitioners come in frequent contact with AD patients suffering from recurrent infections or exacerbations. Educating EM providers may allow for faster AD treatment and reduced patient suffering.

Conclusion

The real-world cases presented reflect the expert panel’s clinical experience with abrocitinib for the treatment of patients with moderate-to-severe AD. The panel’s cumulative insight suggests that abrocitinib is a safe, effective, and rapid-acting AD therapy that may be used in all Fitzpatrick skin types and disease stages. Through a multi-option dosing approach, abrocitinib fosters a TTT paradigm that allows patients and providers to form successful, individualized AD treatment plans.

Limitations

The presented cases represent real-world experience with abrocitinib. All outcome measures were reported from providers in the clinic and reflect real-life data rather than data from a controlled, clinical trial environment. Actual experience with abrocitinib may differ with each patient and/or provider. Our expert panel included general dermatologists and did not include specialized pediatric dermatologists. Thus, this discussion does not provide real-world experience in a pediatric setting. Off-label use of abrocitinib is up to the discretion of treating healthcare providers.

Abstract

Introduction: Advances in cancer treatment have contributed to a reduction in mortality but survivors and healthcare providers should be aware of the potential adverse effects of these advanced treatments.

Objectives: The Canadian skin management in oncology (CaSMO) practical recommendation was developed to improve the quality of life for cancer patients and survivors who experience targeted therapy-related cutaneous adverse events.

Methods: The CaSMO advisory board (advisors) identified four common cutaneous adverse events related to targeted therapy and gave practical recommendations for managing these cutaneous adverse effects based on the results of a literature search and clinical expertise.

Results: Papulopustular eruption, xerosis, paronychia, and hand-foot skin reaction were identified as common cutaneous adverse events related to targeted therapy. The advisors provide practical steps for preventing and treating these cutaneous conditions.

Conclusions: The CaSMO practical guidance is for all healthcare providers who treat oncology patients receiving targeted therapy and can be used to help prevent and manage common cutaneous adverse events, thereby improving treatment adherence, quality of life, and outcomes.

Acknowledgments and Disclosure:  This educational supplement to the Journal of Drugs in Dermatology was funded by La Roche Posay Canada.

Keywords: targeted cancer therapy, management of cutaneous adverse events

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Introduction

Improved understanding of the molecular basis of numerous cancers has led to the development of targeted therapies. Epidermal growth factor receptor (EGFR) inhibitors, multikinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors, mammalian target of Rapamycin (mTOR) inhibitors, BRAF inhibitors, and MEK inhibitors (Table 1) are all molecular targeted agents that have emerged as effective cancer treatments. As opposed to conventional chemotherapies which usually target rapidly dividing cells and are not specific to cancer cells, targeted therapies more selectively attack cancer cells by inhibiting specific molecules involved in tumor pathogenesis.

Table 1: Targeted therapy categories and specific agents

The increased specificity of these therapies leads to an improved safety profile compared with conventional chemotherapy, with fewer systemic side effects. However, the most prevalent side effect of targeted therapies are skin and appendage toxicities. The targeted therapy cutaneous adverse events (ttCAEs) profile is broad and differs for each specific agent. In general, most common ttCAEs include papulopustular eruption, xerosis, pruritus, hand-foot skin reaction (HFSR), paronychia, and mucositis. Targeted therapies can also lead to uncommon but serious toxicities such as morbilliform exanthema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

ttCAEs can lead to severe symptoms with profound effects on cosmesis, quality of life, and compliance with cancer medication. Common ttCAEs are not life-threatening toxicities by themselves but can lead to targeted therapy dose reduction, therapeutic holidays, or even permanent discontinuation, which may compromise cancer outcomes.

Targeted therapy toxicities generally are a positive prognostic sign to therapeutic response. CAEs incidence as well as severity are associated with a longer time to progression of cancer (TTP) and increased overall survival (OS).¹ Most data show a positive relation between papulopustular eruption incidence and severity and TTP and OS in patients receiving EGFR inhibitors.^2-5 The goal for dermatologists and oncologists should be to treat the dermatological toxicities prior to considering dose reduction, interruption, or discontinuation, whenever possible.

While ttCAEs are common, treatments and guidelines are mostly based on reviews, expert consensus, and case series. Very few controlled studies are published on specific treatments to prevent or manage these CAEs. Even more, in most published clinical trials studying targeted therapies, cutaneous side effects are reported as “rash” without details about the clinical appearance and management of specific cutaneous toxicities.

Mechanisms underlying these ttCAEs are poorly understood. Most explanations come from literature on EGFR inhibitors. EGFR is overexpressed in some cancer cells, but is also expressed in normal basal keratinocytes, the outer layers of hair follicles, sebaceous epithelium, and periungual tissues. It plays an essential role in skin physiology and differentiation and proliferation of these tissues. EGFR blockage induces upregulation of IL-1 and TNF-alpha and increases synthesis of other inflammatory chemokines and cytokines, leading to an inflammatory response.⁶ Apoptosis of normal keratinocytes, abnormal keratinization, and the subsequent inflammatory response could explain the occurrence of papulopustular eruption. EGFR inhibitor-induced xerosis results from abnormal keratinocyte proliferation and differentiation, leading to a deteriorated stratum corneum and a decrease in moisture retention.^{7, 8} Paronychia pathogenesis is unclear. It could be secondary to skin fragility, leading to onychocryptosis and subsequent paronychial inflammation.⁹ EGFR inhibitors induce an inflammatory response which could result in paronychia.¹⁰ EGFR inhibition-induced abnormal keratinocyte differentiation and proliferation lead to periungual stratum corneum thinning and fragility, resulting in piercing of paronychium and granulation tissue formation.¹¹ EGFR is also involved in the normal healing process, so EGFR blockage leads to abnormal healing which could contribute to excessive periungual granulation tissue.¹¹ Infection does not appear to play a consistent role in the pathogenesis of paronychia.⁹ HFSR pathophysiology is even less understood. In contrast to hand-foot syndrome induced by chemotherapy agents excreted in sweat, a study on sorafenib showed that this targeted therapy is not excreted through eccrine glands.¹²

In an era in which there is a growing number of targeted therapy indications and use, it is essential that dermatologists, oncologists, and other physicians know how to manage these common CAEs to enable patients to continue receiving these survival-prolonging therapies and improve their outcomes.

This review article discusses the management of four common CAEs induced by targeted therapy: papulopustular eruption, xerosis, paronychia, and HFSR.

Scope

The CaSMO project aims to improve the quality of life for cancer patients and survivors by offering tools to prevent and manage CAEs.^13-16 A general management algorithm to reduce the incidence of all CAEs and maintain healthy skin using general measures and skin care,¹⁴ an algorithm to reduce and treat acute radiation dermatitis,¹⁵ and an algorithm for the management of hormonal therapy-related CAEs¹⁶ were previously published. These algorithms aim to support all health care providers (HCPs) treating oncology patients, including physicians, nurses, pharmacists, and advanced providers. A practical primer followed on prevention, identification, and treatment, including skin care for immune-related CAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.¹⁷ The next step in the project was to develop practical guidance for the management of four common CAEs (papulopustular eruption, xerosis, paronychia, and HFSR) in oncology patients receiving targeted therapies.

Methods

The CaSMO advisors convened for a meeting to develop practical guidance for targeted therapy-related CAEs. The advisors used a modified Delphi approach following the AGREE II instrument.^18-20

Literature Review

Searches included literature describing current best-practice in improving comfort during targeted therapy, reducing/treating CAEs, and promoting healing of affected skin. Selected literature is clinically relevant to the practical guidance and included guidelines, consensus papers, reviews, and publications describing current best-practice in CAEs-related targeted therapy in the English language from January 2010 to May 2022. Excluded were articles with no original data (unless a review was deemed relevant), articles not dealing with prescription treatment, skincare for cAEs-related to targeted therapy, and publication language other than English.

A dermatologist and physician/scientist conducted searches on PubMed and Google Scholar for English-language literature on May 20 and 21, 2022, using the following AND OR search terms:

Group 1: TKIs OR MKIs OR tyrosine kinase inhibitors OR multikinase inhibitors OR EGFR inhibitor OR VEGF inhibitor OR FGFR inhibitor OR MEK inhibitor OR BRAF inhibitor OR PanRAF inhibitor OR BCR-abl inhibitor OR osimertinib OR afatinib OR dacomitinib OR erlotinib OR gefitinib OR lapatinib OR cetuximab OR panitumumab OR sunitinib OR bevacizumab OR Lenvatinib OR vandetanib OR regorafenib OR sorafenib OR axitinib OR pazopanib OR erdafitinib OR pemigatinib OR trametinib OR cobimetinib OR dabrafenib OR vemurafenib OR belvarafenib OR KIT OR PDGFR OR imatinib OR dasatinib OR nilotinib AND cutaneous adverse event

Group 2: paronychia OR hand-foot skin reaction OR papulopustular rash OR acneiform rash OR xerosis OR pruritus OR rash OR skin toxicities AND targeted therapy

Group 3: prescription medication OR skincare OR topical OR prevention OR treatment OR maintenance OR QOL OR quality of life OR adjunctive OR education OR communication OR communication strategies OR adherence OR concordance OR efficacy OR safety OR tolerability OR skin irritation AND cutaneous adverse event AND targeted therapy

Two reviewers independently evaluated the results of the literature search. The abstracts of 422 articles were reviewed after which 116 were excluded for duplication or poor quality. After a review of the articles in full, 297 remained (Figure 1).

General Management Principles for Skin Toxicities of Anti-cancer Treatment (Stats), Including Caes Induced by Targeted Therapy

A recently published article by the CaSMO working group reviewed in details general skincare measures to prevent STATs, including CAEs induced by targeted therapies.¹⁴ Their preventive algorithm is mainly based on three major behaviors: cleanse, moisturize, and protect. (Tables from the previous publication).

Papulopustular Eruption

EGFR inhibitors and mTOR inhibitors can induce a papulopustular eruption. MEK inhibitor monotherapy is also a common cause whereas BRAF inhibitors rarely induce this toxicity. Combining a BRAF inhibitor to MEK inhibitors significantly decreases the incidence and severity of MEK inhibitor induced papulopustular eruption.²¹ Papulopustular eruption is the most common toxicity of EGFR inhibitors, affecting 50-100% of patients, depending on the agent.²² Cancer response and survival have a positive correlation with the incidence and severity of the papulopustular eruption in patients receiving EGFR inhibitors.⁴

Papulopustular eruption, also sometimes referred as acneiform eruption or folliculitis, classically occurs early after the initiation of targeted therapy, in the first 7 to 10 days of treatment. It peaks after two to four weeks, then stabilizes and decreases in intensity after six to eight weeks. A mild papulopustular eruption often persists over months or the eruption may sometimes self-relieve despite continuing targeted therapy. It affects seborrheic and UV-exposed areas, mainly the scalp, face, neck, upper chest, and back. The eruption is characterized by monomorphous inflammatory papules and pustules. Pruritus is a common associated symptom. As opposed to classic acne, it lacks typical comedones and cysts. Papulopustular eruption is dose dependent.

Atypical acneiform eruption warrants bacterial culture and viral swab to exclude bacterial and herpetic infection. It can either be a primary cutaneous infection or a superinfection developing on a pre-existing papulopustular eruption. Infection should be considered when papulopustular eruption is widespread and involves non-seborrheic areas such as upper extremities, lower extremities, abdomen, and buttocks, does not involve the face, lasts longer than eight weeks, appears late after more than 12 weeks of targeted therapy, or is recalcitrant to appropriate treatment.^{23, 24} Other signs of infection include the presence of vesicles, yellow crusts, discharge, or painful lesions.^{23, 24}

Some trials have studied preventive tools to decrease the incidence and severity of papulopustular eruption (Table 2). A phase II randomized controlled trial (STEPP trial) evaluated a pre-emptive regimen in patients receiving panitumumab, an EGFR inhibitor, for metastatic adenocarcinoma of the colon or rectum.²⁵ Patients were randomized into two groups. One group received a pre-emptive treatment beginning day -1 of panitumumab and continued through weeks 1 to 6 and it consisted of a combination of skin moisturizer daily in the morning, sunscreen before going outdoors, hydrocortisone 1% cream at night, and oral doxycycline 100 mg twice a day. The other group received only reactive treatment deemed necessary by the investigator to manage emergent skin toxicity. The incidence of protocol-specified grade 2 or higher skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. These protocol-specified skin toxicities included pruritus, acneiform dermatitis, skin desquamation, exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritus, rash, pustular rash, skin infection, skin ulceration, and local infections. Papulopustular eruption was reported less frequently with pre-emptive treatment (77%) comparing to reactive treatment (85%). This preventive regimen should be initiated in patient receiving EGFR inhibitors and MEK inhibitors which are targeted therapies with a higher risk of papulopustular eruption. Another randomized controlled trial evaluated the preventive use of doxycycline to prevent erlotinib-induced acneiform eruption.²⁶ Incidence was comparable between patients receiving doxycycline and the ones receiving the placebo, but doxycycline decreased the eruption severity.

Photoprotection is likely an important preventive tool even though some studies did not show any benefits.²⁷ Patients must avoid using tanning bed. A physical/inorganic sunscreen should be favored instead of chemical/organic sunscreen that can irritate the skin²⁸.

Treatment lines are detailed in Table 2. Typical over the counter and prescribed topical acne treatments such as benzoyl peroxide, retinoid, azelaic acid, and alpha-hydroxy acid should be avoided. These therapies are typically drying and irritating, which may worsen the papulopustular eruption. Topical tazarotene was studied in a cohort of patients on cetuximab.²⁹ Patients applied it on one side of the face and the other side was used as control. Most patients did not experience any improvement with the use of topical tazarotene. Furthermore, the rash was assessed as more severe on the tazarotene side for some patients.

Phototoxicity induced by tetracycline class antibiotics must be taken into consideration in patients receiving targeted therapy. Doxycycline has an overall better tolerance and safety profile than minocycline but comes with a risk of phototoxicity which could potentially worsen the papulopustular eruption. Photoprotection must be reinforced in this setting. Minocycline is another option that does not lead to phototoxicity but has potential serious side effects including autoimmune hepatitis and drug-induced systemic lupus. In patients who cannot commit to strong photoprotective measures or who are living in areas with high ultraviolet index, minocycline may be a better option, but should be given for less than a year to decrease the risk of autoimmune side effects. For all other patients, doxycycline is a better option because of its safety profile. Especially for patients with renal insufficiency, doxycycline is the drug of choice.

Topical dapsone has been studied in patients receiving cetuximab.³⁰ They were randomized to apply dapsone 5% gel to one side of the face and chest twice daily, and a moisturizer to the contralateral side, used as control. All patients were also receiving oral minocycline. A statistically significant reduction in lesion count was observed on the dapsone-treated sides. Dapsone has anti-inflammatory and anti-bacterial properties without the risk of skin atrophy or microbial resistance potentially induced by the prolonged application of topical steroids and antibiotics, respectively.³⁰

Isotretinoin is an effective treatment if tetracyclines or topical treatments fail. A low dose of 0.15-0.35 mg/kg is recommended.³¹ Tetracyclines should be stopped before starting isotretinoin. Concomitant use of isotretinoin and tetracycline increases the risk of pseudotumor cerebri (idiopathic intracranial hypertension). Isotretinoin has overlapping side effects with targeted therapy such as xerosis and excessive granulation tissue. Isotretinoin-induced xerosis may exacerbate the papulopustular eruption, so the regular application of an emollient should be reinforced. Isotretinoin can also induce photosensitivity, which can worsen the acneiform eruption. Photoprotective measures must be reinforced in patients receiving isotretinoin.

Targeted therapy dosage sometimes needs to be reduced or the medication even needs to be temporarily stopped. If targeted therapy is stopped, it should be restarted when papulopustular eruption is back to a CTCAE severity grades 0 or 1 (papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness).³² Some recommend restarting targeted therapy at 50% of the initial dosage.³³

Table 2: Prevention and treatment recommendations for targeted therapy-induced papulopustular eruption

Xerosis

All targeted therapies can induce xerosis. This ttCAE is progressive and appears usually one to three months after the initiation of cancer treatment. Xerosis can potentially worsen papulopustular eruptions. It can also lead to pruritus, asteatotic eczema, and painful fissures, especially on the hands and feet.

Emollient containing humectant such as urea and lactic acid can be effective to manage xerosis. Fissures are challenging to treat. They can be symptomatic with a burning sensation and significant pain. Emollient and barrier cream are essential. Cyanoacrylate glue, more commonly known as liquid skin glue or liquid bandage, can be applied directly in the fissures to decrease the healing time. Hydrocolloid dressing is another treatment option.

Pruritus induced by targeted therapy is challenging to manage and can be multifactorial. A detailed discussion about pruritus is beyond the scope of this article.

Table 3: Prevention and treatment recommendations for targeted therapy-induced xerosis

Paronychia

Paronychia is a late CAE that can be induced by EGFR inhibitors, MEK inhibitors, mTOR inhibitors, multikinase inhibitors, and VEGF inhibitors. It usually appears after one to two months of targeted therapy with painful periungual inflammation characterized by erythema and swelling. The first digit and first toe are most affected. Paronychia is highly morbid with severe pain and functional limitation. It can lead to the formation of excessive friable granulation tissue, onychocryptosis/ingrown nail, and periungual abscess. It is a common cause of targeted therapy dose reduction or discontinuation. Bacterial and fungal superinfections represent a common complication. If a superinfection is suspected, a bacterial and fungal culture must be done, and the infection treated accordingly.

A few trials have evaluated paronychia treatment. In a retrospective cohort study evaluating the topical use of timolol 0.5% gel twice daily under occlusion to treat targeted therapy-induced paronychia and/or periungueal pyogenic granuloma, 15% of patients were considered in complete response (2/13 patients), 46% in partial response (6/13) and 39% in failure (5/13).³⁵

Surgical interventions may be needed for severe or refractory cases. In a retrospective case series, partial matricectomy, nail avulsion, debridement/clipping, and incision and drainage were performed with resolution rates of 100% (11/11), 38.5% (5/13), 12.5% (1/8), and 0% (0/4), respectively.³⁶

Table 4: Prevention and treatment recommendations for targeted therapy-induced paronychia and periungual hypergranulation

Hand Foot Skin Reaction

HFSR can be induced by multikinase inhibitors, VEGF inhibitors, BRAF inhibitors, and one specific EGFR inhibitor (lapatinib). It usually appears after one-to-six weeks of treatment and has three overlapping clinical phases. It first presents with an inflammatory phase described as symmetrical well-defined erythema over palms and soles with occasional painful tense blisters. Then, it evolves to painful yellowish plaques with surrounding erythema. This is followed by hyperkeratotic plaques more pronounced over pressure points and friction-prone areas on both hands and feet. Soles are more commonly involved than palms. HFSR is most severe with first cycles of treatment and tends to decrease in severity and incidence with subsequent cycles.³⁷ HFSR is another highly morbid toxicity with significant tenderness and functional impairment. It may lead to dose reduction, temporary interruption, or even permanent discontinuation of targeted therapy, compromising cancer outcomes.

HFSR, also referred as acquired palmoplantar keratoderma in few articles, must be differentiated from hand foot syndrome and periarticular thenar erythema with onycholysis (PATEO) that are also STATs involving hands and feet, but with different clinical presentations and causal medications (Table 5).

Table 5: Description of hand foot skin reaction (HFSR), hand foot syndrome, and periarticular thenar erythema with onycholysis (PATEO)

HFSR preventive and management tools are described in Table 6. One multicenter randomized controlled trial evaluated the preventive application of 10% urea three times a day on hands and feet in patients receiving sorafenib for advanced hepatocellular carcinoma.⁴⁰ Incidence of any grade HFSR within twelve weeks of starting sorafenib was significantly lower in the urea group compared to the group with best supportive care alone excluding the use of any cream. Incidence of grades 2 and 3 HFSR was also lower in the urea group. Pre-emptive visits to a podiatrist should be considered, especially for patients starting a targeted therapy associated with a high risk of HFSR (vemurafenib for example).

HFSR has two main components, hyperkeratosis and inflammation, and they guide treatments. Hyperkeratosis is treated with topical keratolytics or retinoids. Inflammation is treated with high potency topical steroids. Oral acitretin has been described in a retrospective study for the treatment of refractory HFSR induced by multikinase inhibitors.⁴¹ It was effective in seven out of eight patients.

Combining a BRAF inhibitor with a MEK inhibitor decreases the incidence and severity HFSR induced by BRAF inhibitor.⁴² Approved combinations of BRAF inhibitors and MEK inhibitors are dabrafenib with trametinib, vemurafenib with cobimetinib, and encorafenib and binimetinib. These combinations are used in the adjuvant or active settings for stage III and stage IV melanoma harboring a BRAF V600 mutation.

Table 6: Prevention and treatment recommendations for targeted therapy-induced hand foot skin reaction

Conclusion

Cancer treatments are constantly evolving, and targeted molecular therapy indications are increasing. Targeted therapies are safer than conventional chemotherapies, but they come with a high risk of CAEs that can lead to poor quality-of-life and cancer treatment dose reduction or even discontinuation, compromising cancer outcomes. This article aims to provide physicians information on frequent skin toxicities associated with targeted cancer therapies, including preventing and treating these CAEs. With this knowledge, dermatologists, medical oncologists, and other physicians can manage ttCAEs with confidence, thereby improving quality of life, treatment adherence, and cancer outcomes.

Disclosures: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

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

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

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

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

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Introduction

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

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

Methods

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

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

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

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

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

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

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

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

Results

Procedures Included in the Review

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

Surgical Excision

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

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

Curettage and Electrodesiccation

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

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

Cryosurgery

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

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

Facial Laser treatment

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

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

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

Pre-procedural Measures

All Discussed Procedures

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

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

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

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

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

Measures During the Procedure

Surgical Excision

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

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

Cryosurgery, Electrodesiccation, Curettage, ED&C

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

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

Laser Treatment

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

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

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

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

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

Table 1: Types of wound dressings and moisturizers

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

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

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

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

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

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

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

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

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

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

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

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

Table 2: Complications from laser treatment

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

Wound Healing After Laser Procedures

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

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

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

Limitation

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

Conclusion

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

Abstract

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

Acknowledgments and Disclosure: None

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

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Introduction

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

Scope of the Canadian Skin Management in Oncology Project

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

Methods

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

Literature Review

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

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

Hormonal Therapy

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

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

Table 1. Hormonal Therapies and Associated Cutaneous Adverse Effects

Type of Skin Reactions Associated with Hormonal Therapy

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

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

Patient and Caregiver Education

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

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

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

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

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

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

Table 2. General Skin Care Recommendations

Menopause/Andropause Symptoms

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

Table 3. Treatments for Menopause/Andropause Symptoms

General symptoms of menopause/andropause:

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

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

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

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

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

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

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

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

Skin-specific symptoms of menopause/andropause:

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

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

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

Androgenic Alopecia:

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

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

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

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

Rosacea

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

Table 4. Treatment for Rosacea

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

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

Hirsutism

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

Table 5. Treatment for Hirsutism

Other Eruptions

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

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

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

Combination Treatment:

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

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

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

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

Corticosteroid-related cAEs:

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

Conclusion

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

¹Center for Clinical Studies, Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
Stephen Tyring received grant support, paid to the Center for Clinical Studies, from Athenex. The other authors have no conflicts of interest.

Abstract:
Actinic keratosis (AK) is a common precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs. Early and effective treatment of AKs is important to prevent progression to squamous cell carcinoma. Many topical treatments for AKs are often limited because of poor tolerability, prolonged treatment duration, and reduced adherence. Tirbanibulin 1% ointment, a new topical field therapy for AKs, reduces these issues. It requires a consecutive 5-day application period and is effective, demonstrating complete (100%) clearance of AK lesions in 49% of patients, partial (>75%) clearance in 72%, and a median reduction in lesion count of 87.5% while exhibiting a favorable safety profile, mild adverse events, improved tolerability, and long-term results.

Key Words:
tirbanibulin; actinic keratosis, field therapy, 5-fluorouracil, diclofenac, imiquimod, face, scalp

Introduction

Actinic keratosis (AK) is a common, recurrent precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs.¹ Clinically AKs appear as macules, papules, or hyperkeratotic plaques with an erythematous background.² Its prevalence steadily increases with age and prolonged sun-exposure. The American Academy of Dermatology (AAD) notes that approximately 60% of predisposed individuals over the age of 40 are diagnosed with at least one AK.³ Other risk factors include male gender, fair skin (Fitzpatrick type I-II), ultraviolet (UV) exposure, immunosuppression, previous history of AKs or skin cancer, human papillomavirus (HPV) infection, and genetic diseases.³

Cumulative UV exposure is considered a major risk factor for AK development because of the resultant modification of cellular repair mechanisms in keratinocytes.⁴ UVB irradiation causes the formation of thymidine dimers in DNA and mutations of the telomerase gene, whereas UVA indirectly induces DNA mutation through photo-oxidative stress.³ The clinical significance of AKs is secondary to the associated discomfort, cosmetic burden, and the possibility of progression to invasive squamous cell carcinoma (SCC).⁵ Rates of malignant transformation vary from 0.025% to 16%, and the risk of progression increases in patients with multiple AKs (more than five).³ While AKs are a risk factor for the development of SCC, it is impossible to predict which lesions will transform, therefore treatment of all AKs is recommended.³

Many treatments exist for AKs. Single or few discrete AKs are typically treated with cryosurgery.¹ Treatment of multiple lesions and surrounding photo-damaged skin (field cancerization) includes topical agents and photodynamic therapy (Table 1).¹ These treatments may be associated with local skin reactions of pain, irritation, redness, flaking, erosions, ulcerations, and irreversible skin changes of pigmentation and scarring.¹ Furthermore, some treatments have to be administered over periods of weeks or months, which may reduce adherence and undermine treatment success.¹

Table 1

More recently, the role of the Src kinase in carcinogenesis has shed light on an alternative therapeutic option. In UV damaged skin, a cascade of events activates peroxisome proliferator activated receptor (PPAR) beta/delta which stimulates the Src oncogene expression, increases Src kinase activity and enhances the EGFR/Erk1/2 signaling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression.⁶ Elevated levels of Src have been linked to AKs and SCCs, and play a role in both primary tumor growth and metastases.⁷ Therefore, Src inhibitors were viewed as a plausible therapeutic option and many have since been developed. Tirbanibulin is a novel compound that inhibits Src kinase signaling and tubulin polymerization in rapidly dividing cells. It has shown promise as a new therapeutic agent for the treatment of AKs on the face or scalp.

Background

Mechanism of Action

The chemical name of tirbanibulin is N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yal) acetamide (Figure 1).⁴ It is a synthetic, first-in-class, anti-proliferative agent that disrupts Src kinase signaling and inhibits tubulin polymerization (Figure 2).⁸ Through these mechanisms, it also promotes the induction of p53, G2/M arrest of proliferating cell populations, and subsequent apoptosis.⁸

Clinical Trials

Phase I⁸

The Phase I trial was an open-label, single-center study in subjects aged ≥18 years with clinically typical AKs on the forearm. Thirty participants were enrolled into 4 sequential cohorts (n=4, 10, 8, and 8 in each cohort, respectively): Cohort 1 received tirbanibulin ointment 1% 50 mg/day once daily for 3 days over 25 cm² treatment area with 4-8 AK lesions; Cohort 2 received 200 mg/day once daily for 3 days over 100 cm² treatment area with 8-16 AK lesions; Cohort 3 and Cohort 4 were similar to Cohort 1 and Cohort 2, respectively, but treatment was for 5 days. The follow-up period was through day 45.

To assess tirbanibulin activity, AK lesion numbers at baseline (day 1), days 10, 17, 31, and 45 were collected. Complete (100%) and partial (≥75%) AK clearance rates (defined by the reduction in AK lesions in the treatment area at day 45 compared with baseline) were evaluated for each cohort.

Twenty-nine participants completed the study with one participant withdrawing consent on day 2. Reductions in lesion counts from day 1 to 45 were observed in all cohorts. On day 45, Cohorts 1-4 demonstrated 25%, 0%, 50%, and 12.5% of complete AK clearance in the treatment area, respectively.

Dermal safety clinical studies in healthy subjects demonstrated that tirbanibulin 1% ointment did not cause contact sensitization, phototoxic skin reactions, or photoallergic skin reactions.⁴

Phase II⁸

The Phase II trial was an open-label, uncontrolled, dose-regimen- finding, multicenter study in subjects aged ≥18 years with clinically typical AKs on the face or scalp. One hundred and sixty-eight participants were enrolled into 2 sequential cohorts (n=84 in each cohort): Cohort 1 received 50 mg/day tirbanibulin ointment 1% once daily for 3 days over 25 cm² treatment area with 4–8 AK lesions; Cohort 2 received the same treatment for 5 days.

AK lesion counts at baseline (day 1), 8, 15, 29, and 57 were collected, with a 12-month follow-up period for participants that achieved complete AK clearance to monitor for recurrence. All 168 participants completed the trial. Extensive overall AK clearance on the face or scalp was demonstrated in both cohorts. More participants had 100% clearance at day 57 in the 5-day (43% [95% Confidence Interval (CI) = 32, 54]) vs. the 3-day cohort (32% [95% CI = 22, 43]). Partial clearance rates were also slightly higher in the 5-day (56% [95% CI = 45, 67]) vs. the 3-day cohort (52% [95% CI = 41, 63]). There was a consistent decrease in lesion counts across all visits from baseline to day 57 for both cohorts.

All 63 participants who had 100% clearance at day 57 in the Phase 2 study were included in the Recurrence Follow-up Set. At 12 months post-day 57, recurrence rates for the 5-day cohort (57% [95% CI = 41, 73]) were lower than the 3-day cohort (70% [95% CI = 51, 87]). Most recurrence occurred within 6 months post-day 57.

Phase III¹

The Phase III trial was a randomized, double-blind, parallel-group, vehicle-controlled, multicenter (62 US centers) trial in subjects aged >18 years with 4-8 clinically typical AKs on the face or scalp within a contiguous area measuring 25 cm². A total of 702 participants, divided among two identical trials (n=351 at each site), were randomly assigned in a 1:1 ratio to receive either tirbanibulin 1% ointment for 5 days self-administered to a 25 cm² contiguous area or vehicle ointment (placebo). Enrollment across patients was controlled to achieve a 2:1 ratio of facial: scalp treatment areas. The primary outcome was the percentage of patients with a complete reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year.

Tirbanibulin demonstrated higher complete clearance levels in trial 1 (44% [95% CI = 32, 47]; P<0.001) and trial 2 (54% [95% CI = 33, 51]; P<0.001) compared to the vehicle groups (5% and 13% in trials 1 and 2, respectively). Pooled data from both trials demonstrated complete clearance in 49% ([95% CI = 35, 47]; P<0.001) of patients in the tirbanibulin groups and in 9% of the vehicle groups.

Partial clearance was significantly higher in both tirbanibulin groups at 68% (trial 1) and 76% (trial 2) than in the vehicle groups. Pooled data revealed partial clearance in 72% ([95% CI = 48, 60]; P<0.001) of patients in the tirbanibulin groups and in 18% of the vehicle groups. At 1 year, 47% of patients with complete clearance experienced recurrence of AKs.

Median reduction in AK lesion count in patients received tirbanibulin was 87.5% vs. 20% for vehicle (P<0.0001).¹

Safety and Tolerability

Throughout all phases, no serious adverse events (AEs) were reported secondary to tirbanibulin.^1,8 Local skin reactions (LSRs) consisted mostly of mild-moderate erythema, flaking or scaling, application-site pruritus, and application-site pain.¹ Erythema (93%) and flaking (82%) were most common.¹ Severe LSRs (all types) were observed in <10% of patients, with severe erythema in 6% of patients.¹ Other LSRs included crusting, swelling, scaling, vesiculation or pustulation, and ulcerations or erosions.⁴ LSRs typically appeared on treatment day 2 and peaked on treatment day 8, before spontaneously resolving in ~2 weeks-1 month.^1,8 No participants were withdrawn from the clinical trials due to AEs or LSRs.

Laboratory evaluation of blood chemistry, hematology, urine analysis, vital signs, electrocardiograms, and physical examinations in association with the phase III trials were not indicative of any systemic side effects.¹ Tirbanibulin produces adverse ophthalmic reactions, and therefore, patients must be careful not to transfer the drug into the periocular area or eyes.

There has been no data on possible birth defects and/or adverse fetal/maternal outcomes during pregnancy with the use of tirbanibulin.⁴ However, extremely high doses were noted to cause birth defects in rats and rabbits (more than 70 and 159 times the recommended human dose, respectively).⁴

Regulatory Approval

The topical 1% ointment formulation of tirbanibulin was approved by the US FDA in December 2020 for the treatment of AKs on the face and scalp.⁷ One packet of ointment (250 mg) contains 2.5 mg (1%) of tirabanibulin.⁴ The medication is applied on the affected area of the face or scalp once a day for 5 consecutive days.⁴ Each packet will cover up to 25 cm² on the face or scalp and is disposed of after its one-time use.⁴

There are no contraindications listed in the FDA-approved prescribing information.⁴

Discussion

Compared to other older topical treatments for AKs, tirbanibulin demonstrates several advantages. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application while demonstrating a favorable safety profile and long-term results. The most common AEs for tirbanibulin were mild and included erythema, flaking, pruritus and pain at the application site. Unlike most other topical treatments for AKs, severe local
reactions, including vesiculation or pustulation and erosion or ulceration, were infrequent.¹ The favorable tolerability is attributed to tirbanibulin mechanism of action in which it induces apoptosis rather than necrosis. Apoptosis is associated with little or no inflammation.¹⁰

Treatment adherence and patient satisfaction has shown to be significantly better with shorter duration topical treatments for AK.¹¹ Current first-line topical field therapies for AKs include 5-fluorouracil (5-FU), imiquimod, and diclofenac gel, all of which have unfavorable aspects undermining compliance and thus successful treatment (Table 1).¹² These therapies more frequently result in AEs, severe LSRs, and prolonged patient discomfort, at times necessitating a pause in treatment until the healthy skin has healed.¹² In addition, each requires an extended period of application ranging from 3-4 weeks to 8-12 weeks with more than one application daily and/or a second cycle.¹² Ingenol mebutate, a promising short duration (3-day) AK treatment, recently lost its first-line status after being discontinued in 2020 secondary to increased risk of skin malignancy.

A combination of 5% 5-FU cream plus 0.005% calcipotriol ointment has been used off-label to treat AKs with variable results.¹³ The evidence was based on a single center study using the combination topical treatment twice daily for 4 days applied to 25 cm² area.¹³ Twenty-seven percent of patients achieved complete clearance of AK lesions on the face, and <20% on the scalp at week 8.¹³ Severe erythema on the face was observed in 80% of patients.¹³

The incidence of recurrence with conventional treatments has ranged from 20% to 96%.¹ However, owing to the chronic nature of AKs, recurrence of lesions in sun-damaged areas is expected.¹ With tirbanibulin, 47% of patients with complete clearance experienced a recurrence at 1 year in the phase III trials. Despite the apparent benefits of tirbanibulin, no direct comparisons have been made with other AK treatments.¹ Ultimately, head-to-head studies will be needed to determine true superiority/inferiority.

Other uses of tirbanibulin are being explored. Phase I trials are underway in Taiwan to investigate its potential as a treatment for psoriasis.⁷ Tirbanibulin was noted to successfully eradicate periungual SCC in a patient that failed to clear with imiquimod 5% in combination with monthly cryotherapy, suggesting its potential as a nonsurgical therapeutic option for SCC.¹⁴

Conclusion

Early and effective treatment of AKs is important to prevent progression to SCC.⁴ Many topical treatments for AKs are often limited because of patient tolerability, treatment duration, and adherence. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application period while demonstrating a favorable safety profile, mild AEs, improved tolerability, and long-term results, making it a promising field therapy for AKs.

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¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
³Department of Dermatology, McMaster University, Hamilton, ON, Canada
⁴Dermatrials Research Inc. & Venderm Innovations in Psoriasis, Hamilton, ON, Canada
⁵Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁶Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁷Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁸Probity Medical Research, Waterloo, ON, Canada
⁹Dermatology Research Institute, Calgary, AB, Canada
¹⁰Skin Health & Wellness Centre, Calgary, AB, Canada
¹¹Probity Medical Research, Calgary, AB, Canada
¹²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
¹³Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁴Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula and Brian D. Rankin have no relevant disclosures. Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Astellas, Celgene, Dermira, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, and Takeda. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Funding sources: None.

Abstract:
A novel topical corticosteroid, halobetasol propionate (HP) 0.01% lotion (Bryhali™), has recently been introduced for the treatment of plaque psoriasis and corticosteroid-responsive dermatoses in adults. Once daily application of HP 0.01% lotion is indicated for use up to 8 weeks. Treatment success for plaque psoriasis in the pivotal phase 3 clinical trials (defined as an Investigator Global Assessment [IGA] of clear/almost clear [IGA 0/1] with ≥2-grade improvement from baseline) occurred in over one-third of patients by week 8. Treatment-emergent adverse events were typically mild-to-moderate in intensity and usually limited to the application site(s). No treatment-related cases of skin atrophy have been reported from the studies. Counselling should be considered to optimize treatment outcomes.

Key Words:
Bryhali™; halobetasol; topical; therapeutics; corticosteroid; psoriasis; clinical trial

Introduction

Topical corticosteroids are a mainstay in the management of plaque psoriasis and other corticosteroid-responsive dermatoses. Bryhali™ is a super-potent topical corticosteroid lotion with halobetasol propionate (HP) 0.01% as the active ingredient. It was approved by the US FDA in 2018 for plaque psoriasis and by Health Canada in 2021 for both plaque psoriasis and corticosteroid-responsive dermatoses. Available in 45 g, 60 g, and 100 g tubes containing 0.1 mg of HP 0.01% per gram, HP 0.01% lotion is applied once daily to affected areas (maximum dose of 50 g per week).^1,2 It has a safety profile allowing for extended use up to 8 weeks without physician re-evaluation (provided there are observed improvements in the condition being treated).³ Non-medicinal ingredients of this product include carbomer copolymer type b, carbomer homopolymer type a, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate, and sorbitol solution 70%. No data is currently available for its use in pediatric or pregnant patients; therefore, HP 0.01% lotion has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant women.¹

Background

Plaque psoriasis and certain corticosteroid-responsive dermatoses, such as atopic dermatitis, are chronic, immunemediated, inflammatory skin diseases that vary in severity. Topical corticosteroids are used across all severities, although moderate-to-severe disease often requires the addition of phototherapy or systemic therapies.⁴ Despite their efficacy, these conditions can quickly recur if treatment is discontinued; however, extended use of topical corticosteroids can also result in adverse events (AEs) that are either local (e.g., skin atrophy, folliculitis, striae, and telangiectasia) or systemic (e.g., hypothalamic-pituitary-adrenal [HPA] axis suppression).⁵

HP 0.05% cream or ointment (Ultravate^®) is a commonly prescribed topical corticosteroid applied once or twice daily per physician direction (maximum dose of 50 g per week).⁶ According to the product monograph, patients should limit use to a maximum of 2 weeks unless re-evaluated by a physician. However, considering the chronic nature of plaque psoriasis and many other corticosteroid-responsive dermatoses, such as atopic dermatitis, this limited treatment duration can become an issue for long-term utilization and compliance.⁶ Studies on HP 0.01% lotion have shown that despite demonstrating comparable efficacy to HP 0.05% cream, the safety profile allows it to be used for intervals longer than 2 weeks without the need for physician re-evaluation at 2 weeks.⁷

HP is a water-insoluble synthetic corticosteroid thought to act via the induction of lipocortins, a group of phospholipase A2 inhibitory proteins. It is theorized that these proteins act on pro-inflammatory mediators, such as prostaglandins and leukotrienes, via inhibition of the precursor arachidonic acid.⁸ HP has anti-inflammatory, anti-proliferative, antipruritic, and vasoconstrictive effects.^1,7

The once daily HP 0.01% lotion is formulated with proprietary PRISMATREX™ technology, a novel polymeric emulsification system that features oil droplets containing the active ingredient and other hydrating/moisturizing excipients dispersed evenly in an oil-in-water emulsion and separated by a 3-dimensional mesh matrix.^1,9 This allows for uniform distribution and enhanced penetration when applied onto the skin surface. The latter may provide rationale for the comparable efficacy of HP 0.01% lotion and HP 0.05% cream despite a 5-fold difference in the concentration of HP.⁷

Supporting Evidence from Clinical Trials (Table 1)

Table 1

Plaque Psoriasis

In a phase 2 multicenter, randomized, double-blind, vehicle-controlled clinical trial (n=150), the efficacy and safety of HP 0.01% lotion (n=60) versus HP 0.05% cream (n=57) was evaluated in adult patients with moderate-to-severe plaque psoriasis (Investigator Global Assessment [IGA] score: moderate [3] or severe [4]; affected body surface area [BSA]: 3% to 12%).⁷ At week 2: the primary endpoint of an IGA score of clear or almost clear (IGA 0/1) with ≥2-grade improvement from baseline (treatment success) was achieved by 30.0% and 31.6% of patients treated with HP 0.01% lotion and HP 0.05% cream, respectively (p=0.854); a 2-grade improvement from baseline in the 3 key signs of plaque psoriasis—erythema, elevation, and scaling—at the target lesion site (treatment success for specific psoriasis signs) was achieved by 38.3%, 40.0%, and 43.3% of patients treated with HP 0.01% lotion versus 31.6%, 36.8%, and 47.4% of patients treated with HP 0.05% cream, respectively (p=0.446, p=0.727, and p=0.663, respectively); and BSA improved by 22.3% with HP 0.01% lotion versus 20.9% with HP 0.05% cream (p=0.787). Both HP 0.01% lotion and HP 0.05% cream were more effective than vehicle at all time points, with HP 0.01% lotion demonstrating greater efficacy than HP 0.05% cream for patients with more severe disease (IGA=4) at baseline. Safety evaluation revealed AEs of treatment-related dermatitis (n=1) and severe itching (n=1) with HP 0.01% lotion as well as treatment-related severe itching (n=2) and severe burning/ stinging (n=1) with HP 0.05% cream. No treatment-related cases of skin atrophy, folliculitis, striae, or telangiectasia were observed in either treatment group.⁷ In summary, HP 0.01% lotion was comparable to HP 0.05% cream in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, and reduction in BSA, with both treatments demonstrating a favorable safety profile.

In a pooled analysis of 2 phase 3 multicenter, double-blind, randomized, parallel-group clinical trials (n=430), the efficacy and safety of HP 0.01% lotion (n=285) versus vehicle (n=145) was evaluated in adult patients with moderate-to-severe plaque psoriasis (IGA score: 3 or 4; affected BSA: 3% to 12%).⁹ At week 8: the primary endpoint of treatment success was achieved by 36.5% (Study 1) and 38.4% (Study 2) of patients treated with HP 0.01% lotion versus 8.1% (Study 1) and 12.0% (Study 2) of patients treated with vehicle (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (Study 1) and week 4 (Study 2); HP 0.01% lotion achieved treatment success for specific psoriasis signs at the target lesion site in 46.7% (Study 1) and 56.3% (Study 2) of patients for erythema, 52.5% (Study 1) and 62.7% (Study 2) of patients for elevation, as well as 54.9% (Study 1) and 63.1% (Study 2) of patients for scaling (p<0.001 for all comparisons versus vehicle); BSA improved by 34.2% (Study 1) and 36.2% (Study 2) with HP 0.01% lotion (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (both Study 1 and Study 2); mean Dermatology Life Quality Index (DLQI) score was reduced by 57.7% (Study 1) and 58.7% (Study 2) with HP 0.01% lotion (p=0.001 and p=0.004, respectively, versus vehicle); mean IGAxBSA composite score (calculated by multiplying the IGA by the BSA; range: 9-48) was reduced by 49.5% with HP 0.01% lotion versus 13.4% with vehicle (p<0.001), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2; and the proportion of patients achieving ≥50%, ≥75%, and ≥90% reduction in IGAxBSA composite score from baseline (IGAxBSA-50, IGAxBSA-75, and IGAxBSA-90, respectively) was 56.8%, 39.3%, and 19.3% with HP 0.01% lotion versus 17.2%, 9.7%, and 2.8% with vehicle (p<0.001 for all comparisons versus vehicle).^3,9 Safety evaluation revealed similar rates of AEs between the treatment groups: 21.5% with HP 0.01% lotion and 23.9% with vehicle. Most AEs (90.2%) were mild-to-moderate in intensity. No cases of treatment-related skin atrophy, folliculitis, or striae were reported.¹⁰ There was one AE of telangiectasia with HP 0.01% lotion, not deemed to be treatment-related. In summary, HP 0.01% lotion was superior to vehicle in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, reduction in BSA, as well as improvements in mean DLQI and mean IGAxBSA composite scores, with HP 0.01% lotion demonstrating a favorable safety profile.

Corticosteroid-Response Dermatoses

There are no clinical trials investigating the efficacy and safety of HP 0.01% lotion for corticosteroid-responsive dermatoses.

Dosage and Administration

The on-label recommendation is to apply a thin layer of Bryhali™ once daily to areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses until disease control is achieved.¹ The total amount used should not exceed 50 g per week due to the concern for HPA axis suppression. Uninterrupted treatment beyond 8 weeks is not recommended.¹

Counselling: Practical Tips to Optimize Use

A thin layer of HP 0.01% lotion should be applied, just enough to cover the areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses. It is essential to rub in gently and inform patients that applying excessive amounts will not improve treatment efficacy. If HP 0.01% lotion is applied after bathing, the treatment site(s) should be dry before application.

It is also important to allow sufficient time for the medication to dry before putting clothes on to prevent inadvertent spread onto unaffected skin. HP 0.01% lotion should not be used with occlusive dressings unless recommended by a physician. It is for external use only and must be kept away from the eyes, nose, mouth, and other mucosal sites. HP 0.01% lotion should not be applied to the scalp or sensitive sites, such as the face, groin, and axillae, nor on ulcers or wounds.¹ It is also advised to avoid application on areas affected by untreated bacterial, tubercular, fungal and viral infections involving the skin.¹

Conclusion

Once daily application of HP 0.01% lotion (Bryhali™) is a convenient topical therapy with comparable efficacy to HP 0.05% cream (Ultravate^®), despite a 5-fold difference in concentration of HP. One of the main advantages is its ability to be used safely for up to 8 weeks without concern for AEs (especially skin atrophy) and the requirement for physician re-evaluation (provided there are observed improvements in the condition being treated). Counselling with application tips should be considered for all patients.

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

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

Introduction

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

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

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

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

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

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

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

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

Scope

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

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

Methods

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

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

Literature Review

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

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

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

Radiation Dermatitis, Prevention, and Treatment

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

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

Table 1: External beam radiation therapy

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

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

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

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

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

Box 1: Contributing factors to radiodermatitis (RD)

Table 2: Acute and chronic radiation dermatitis²⁰

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

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

Table 3: CTCAE and RTOG grading for acute RD

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

Algorithm for the Prevention and Management of Acute Rd

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

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

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

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

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

Figure 3: RD Treatment according to presentation

Grading according to CTCAE v5¹⁹

Education on Prevention and Treatment of RD

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

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

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

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

Box 2: Resources and information

Sun Avoidance and Sun Protection

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

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

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

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

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

Box 3: Information on photoprotection and sunscreen application

Assessment of Skin Condition

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

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

Skincare Using Cleansers and Moisturizers

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

Box 4: Criteria and application of cleansers and moisturizers

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

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

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

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

Table 5: Evidence levels of components of topical treatments

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

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

Topical Pharmaceuticals

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

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

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

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

Wound Healing Products

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

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

The Multidisciplinary Team

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

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

Limitations

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

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

Conclusions

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

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

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¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Windsor Clinical Research, Windsor, ON, Canada
³Western University, Schulich School of Medicine, Windsor, ON, Canada

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Jerry Tan has been a consultant, investigator and/or speaker for Almirall, Bausch, Boots/Walgreens, Cipher, Galderma, L’Oréal, Promius, Sun and Vichy. Disclaimers: This manuscript is an original submission. Views expressed in the submitted article are our own and not official positions of our institutions.

Abstract:
The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Key Words:
alpha-adrenergic agonist, anti-parasitic, antibiotic, diagnosis, dicarboxylic acid, erythema, laser therapy, management, phenotype approach, phyma, retinoids, rosacea, telangiectasia

Table of Content:

1. Introduction
2. Quality of Evidence
3. Diagnosis
4. Evaluation and Differential Diagnosis
5. Associated Comorbidities
6. Management
7. Conclusion

Introduction

Rosacea is a chronic inflammatory dermatosis affecting the centrofacial region (cheeks, chin, nose, and central forehead), with a prevalence of 5.5% of the adult population.¹ While rosacea has been considered to primarily affect fair-skinned individuals, this may be due to difficulty in detecting facial redness in darker skin types. Nevertheless, rosacea patients of Asian, Hispanic, or African ancestry have been described in literature.² Women are more likely to develop rosacea, however, when present in men, the disease tends to be more severe.³ The typical age of onset is after 30 years old;^4,5 however, ocular rosacea can occur as early as 22 months of age.⁶ Pediatric rosacea is rare and is usually associated with a family history of the condition.^6,7 Ocular manifestations of rosacea occur in more than 50% of rosacea patients.⁸

There are several flare triggers in patients with rosacea including temperature changes, heat, cold, exercise, ultraviolet radiation, spicy food, and alcoholic beverages.⁹ Microbes have also been implicated in the pathophysiology of rosacea, including Demodex species, Bacillus oleronius, Staphylococcus epidermidis, Helicobacter pylori, and Bartonella quintana.¹⁰ The immune system, neurogenic inflammation, and vascular hyperreactivity are central to the pathophysiology of rosacea. Specifically, innate immune system activation via toll-like receptor 2 (TLR2), transient receptor potential (TRP) ion channels, and proinflammatory cytokines contribute to clinical manifestations of rosacea.¹¹

Rosacea has a significant impact on the emotional, social, and occupational wellbeing of affected individuals. Due to the altered facial features characterising this disease, patients with rosacea frequently experience stigmatization. Consequently, they can suffer from depression and anxiety and tend to avoid social situations.¹²

The phenotype approach establishes diagnosis and management based on the presenting features of the individual.¹³ While previously classified according to subtypes, each potentially comprising multiple signs and symptoms, this nomenclature should be abandoned as it limits the ability to study, evaluate, and treat individual features.¹³ The phenotype approach more accurately addresses patient features and can facilitate focused treatment on those of greatest severity and impact.¹³ Thus, this review provides an overview of the updated phenotype approach in the diagnosis and management of rosacea.

Quality of Evidence

The PubMed database was searched for systematic reviews, meta-analyses, and guidelines on the diagnosis, classification, and management of rosacea, with a focus on phenotypes. Key words included “rosacea” and “diagnosis” or “classification” or “management” or “guidelines” or “treatment”. There were no limits on age, sex, or nationality or year of publication. Only studies published in English on human subjects were included.

Diagnosis

The diagnosis of rosacea is clinical and based on specific features according to the ROSacea COnsensus expert panel (ROSCO)¹³ and the National Rosacea Society (NRS).¹⁴ On clinical exclusion of other conditions with similar presenting features, the diagnosis of rosacea is established with either: (1) phymatous changes, or (2) centrofacial persistent erythema (Table 1).^13,15 In their absence, diagnosis can be established by the presence of any two of the following major features: flushing/transient erythema, papules and pustules, telangiectases (Table 1), or ocular rosacea (Table 2).^13,15 Minor features, such as burning, stinging, dry sensation of the skin, or edema are not diagnostic of rosacea (Table 1).¹⁵ The diagnosis of rosacea in darker skin types (Fitzpatrick phototypes V and VI) is difficult as erythema and telangiectasia may not be readily visible, and a high level of suspicion based on minor features is required. A less common variant of rosacea is granulomatous rosacea, with multiple brown, yellow, or red cutaneous papules of uniform size. Occasionally, skin biopsy may be useful for diagnostic support.¹³

Table 1: Descriptions of cutaneous rosacea features by consensus

Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1273.¹⁵

Table 2: Descriptions of ocular rosacea features

Note that these are recommendations rather than consensus due to n = 2. Both ophthalmologists voted ‘Agree’ or ‘Strongly agree’ to the descriptions.
Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1274.¹⁵

Evaluation and Differential Diagnosis

Differential diagnoses of rosacea depend on the clinical feature(s) present (Table 3). Examples include contact dermatitis, photodermatitis, seborrheic dermatitis, and systemic lupus erythromatous for facial erythema; perimenopausal flushing, emotional flushing, carcinoid syndrome, and mastocytosis for flushing; and acne vulgaris and folliculitis for papules and pustules.¹⁶ Exclusion of mimics can be established by taking an adequate history, performing a directed physical evaluation for distinguishing features, and further testing as required.

Table 3: Differential diagnoses of rosacea

Information from Asai et al., 2016,¹⁶ Ogé et al., 2015,¹⁹ Scheinfeld et al., 2010,⁵⁵ and Izikson et al., 2006.⁵⁶

Associated Comorbidities

Associations between rosacea and metabolic, cardiovascular, gastrointestinal (GI), neurologic, and psychiatric diseases have been established (Table 4).¹⁷ Some of these share common innate inflammatory elements with rosacea, such as macrophage and macrophage-derived mediators, reactive oxygen species, matrix metalloproteinases, interleukin-1b (IL-1b), and tumor-necrosis-factor (TNF).¹⁸

Table 4: Rosacea and associated comorbidities

CI = confidence interval, N/A = not available, OR = odds ratio, P = probability

Management

The goals of rosacea treatment are to reduce the severity of features and the frequency and intensity of flares.¹³ General management includes routine skin care: gentle cleansers, moisturizers, sun protection, and avoidance of triggers.^16,19 Specific treatments should be targeted at clinical features (Table 5 on pages 7-8). If multiple features are present, combination treatment should be considered.¹⁶ The phenotype approach allows for such feature-based treatment according to the severity and impact of the presentation.²⁰ An updated systematic review of rosacea treatment based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, is outlined below (Table 5).²¹

Table 5: Treatment recommendations and certainty of evidence

CI = confidence interval, Er:YAG = erbium-doped yttrium aluminium garnet, I2 = heterogeneity, IPL = intense pulsed light, MD = mean difference, MR = modified release, N/A = not available, Nd:YAG = neodymium-doped yttrium aluminum garnet, NNTB = number needed to benefit, NNTH = number needed to harm, PDL = pulsed dye laser, P = probability, RCT = randomized controlled trial, RR = relative risk
Information from van Zuuren et al., 2019.²¹

Flushing/Transient Erythema

No randomized controlled trials available.

Persistent Erythema

Evidence to support the efficacy and safety in transient reduction of persistent erythema was derived from two randomized vehicle-controlled trials for topical brimonidine 0.33% gel²² and topical oxymetazoline 1% cream.^23,24 Quality of evidence for efficacy was reported as high-certainty for brimonidine 0.33% gel and moderate-certainty for oxymetazoline 1% cream.²¹ Adverse event frequency was similar to vehicle for both brimonidine²² (moderate-certainty evidence)²¹ and for oxymetazoline^23,24 (moderate-certainty evidence).²¹ In both, there is ongoing concern about the potential risk of worsening erythema with repeated use.^25,26

Papules and Pustules

Dicarboxylic Acids

Topical azelaic acid 15% foam twice daily is a safe and effective treatment for papules and pustules^27,28 (high-certainty evidence)²¹ with an adverse event frequency similar to vehicle^27,28 (moderate-certainty evidence)²¹ according to two randomized vehicle-controlled trials.^27,28

Another randomized controlled trial showed that azelaic acid 15% gel may be more effective in reducing mean nominal lesion count than metronidazole 0.75% gel²⁹ (moderate-certainty evidence).²¹ These differences, however, were not reproducible and were considered to be unimportant.^30,31

Antiparasitics

Topical ivermectin 1% cream once daily is more effective in the treatment of papules and pustules compared to vehicle³² (high-certainty evidence),²¹ and compared to metronidazole 0.75% cream twice daily³³ (moderate-certainty evidence).²¹ Adverse event rates for topical ivermectin were similar compared to vehicle³² (moderate-certainty evidence)²¹ and topical metronidazole.³³

Retinoids

In two randomized controlled trials, low-dose oral isotretinoin 0.25 mg/kg and low-dose oral isotretinoin 0.30 mg/kg were more effective than placebo³⁴ (high-certainty evidence)²¹ and oral doxycycline (100 mg for 14 days, then tapered to 50 mg)³⁵ (moderate-certainty evidence),²¹ respectively. The frequency of adverse events was higher for isotretinoin compared to placebo³⁴ (moderate-certainty evidence),²¹ but similar to oral doxycycline³⁵ (moderate-certainty evidence).²¹

Antibiotics

Several randomized vehicle- or placebo-controlled trials demonstrated the efficacy of topical metronidazole 1% cream,^36-38 topical minocycline 1.5% and 3% foam,³⁹ oral doxycycline 40 mg modified-release (MR),⁴⁰ and oral tetracycline 250 mg twice daily^41,42 in the treatment of papules and pustules. The quality of evidence for efficacy was moderate-certainty for the first three treatments, but low-certainty for oral tetracycline.²¹ Adverse event frequency was similar to vehicle/placebo for topical metronidazole^36-38 (moderate-certainty evidence),²¹ oral doxycycline,⁴⁰ and oral tetracycline,^41,42 but higher than vehicle for topical minocycline39 (moderate-certainty evidence).²¹ Topical clindamycin 1% cream or gel was found to be no more effective than vehicle for any outcome⁴³ (low-to-moderate certainty evidence).²¹ Compared to oral doxycycline 40 mg MR, oral minocycline 100 mg is similarly effective⁴⁴ (moderate-certainty evidence)²¹ with no differences in the rate of adverse events⁴⁴ (low-certainty evidence).²¹ Compared to oral doxycycline 100 mg, oral azithromycin 500 mg three times a week then tapered is similarly effective in reducing lesion counts⁴⁵ (very low-certainty evidence).²¹ Finally, 40 mg MR doxycycline is as effective as 100 mg with fewer side effects.⁴⁶

Telangiectases

There is low-to-moderate certainty evidence that long pulsed dye laser (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and intense pulsed light (IPL) therapy reduce telangiectasia.²¹

Clinically Non-inflamed Phyma

Physical modalities, such as ablative laser surgery using carbon dioxide or erbium-doped yttrium aluminium garnet (Er:YAG) modalities, electrosurgery, or cryosurgery, may improve clinically noninflamed phyma.¹⁶ However, it is difficult to determine their effectiveness due to the lack of evaluation by randomized controlled trials.^16,21

Clinically Inflamed Phyma

While there are no randomized controlled trials evaluating the efficacy of treatments for clinically inflamed phyma, oral doxycycline or oral isotretinoin are still recommended.^16,21

Ocular Rosacea

One randomized placebo-controlled trial supported omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) one capsule twice daily⁴⁷ (moderate-certainty evidence)²¹ in the treatment of ocular rosacea. Another randomized controlled trial supported cyclosporine ophthalmic emulsion 0.05% twice daily versus artificial tears⁴⁸ (low-certainty evidence)²¹ and versus oral doxycycline 100 mg twice daily for the first month followed by 2 months once daily⁴⁹ (low-certainty evidence).²¹ For the cyclosporine ophthalmic emulsion, there were no differences in the rate of adverse events compared to artificial tears (low-certainty evidence).²¹ For severe ocular rosacea or when there is diagnostic uncertainty, referral to an ophthalmologist should be arranged.²¹

Combination Therapies

Treatment combinations may address several different clinical features of rosacea. For example, compared to vehicle, topical brimonidine 0.33% gel with topical ivermectin 1% cream can effectively reduce both erythema and papules and pustules.⁵⁰ Compared to metronidazole 1% gel alone, metronidazole 1% gel with oral doxycycline 40 mg MR can reduce lesion counts to a greater extent.⁵¹

Finally, randomized controlled trials reported no difference in efficacy between oral minocycline 45 mg with or without topical azelaic acid 15% gel⁵² (moderate-certainty evidence)²¹ or between topical clindamycin phosphate 1.2% with tretinoin 0.025% gel compared to placebo⁵³ (moderate-certainty evidence).²¹ However, in the latter, there was a higher rate of adverse events in the topical clindamycin/tretinoin group compared to placebo (moderate-certainty evidence).²¹

Maintenance Therapies

Topical metronidazole 0.75% gel, ivermectin 1% cream, and azelaic acid 15% gel are reported as effective and safe for maintenance therapy of papules and pustules.^21,54

Conclusion

The diagnosis and classification of rosacea has evolved to a phenotype approach to accurately address the clinical features presenting in an individual and to advance epidemiological and clinical trials research.¹³ This review details the rosacea phenotype approach to diagnosis and classification, and summarizes current evidence-based treatment recommendations for individual features. There is no singularly effective treatment for all features of rosacea. There is an unmet need for high quality investigations for treatment of inflamed phyma, flushing/transient erythema, and ocular rosacea.

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