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.

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

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

Introduction

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

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

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

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

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

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

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

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

Scope

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

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

Methods

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

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

Literature Review

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

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

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

Radiation Dermatitis, Prevention, and Treatment

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

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

Table 1: External beam radiation therapy

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

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

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

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

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

Box 1: Contributing factors to radiodermatitis (RD)

Table 2: Acute and chronic radiation dermatitis²⁰

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

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

Table 3: CTCAE and RTOG grading for acute RD

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

Algorithm for the Prevention and Management of Acute Rd

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

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

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

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

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

Figure 3: RD Treatment according to presentation

Grading according to CTCAE v5¹⁹

Education on Prevention and Treatment of RD

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

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

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

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

Box 2: Resources and information

Sun Avoidance and Sun Protection

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

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

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

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

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

Box 3: Information on photoprotection and sunscreen application

Assessment of Skin Condition

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

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

Skincare Using Cleansers and Moisturizers

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

Box 4: Criteria and application of cleansers and moisturizers

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

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

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

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

Table 5: Evidence levels of components of topical treatments

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

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

Topical Pharmaceuticals

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

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

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

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

Wound Healing Products

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

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

The Multidisciplinary Team

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

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

Limitations

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

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

Conclusions

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

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

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

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

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

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

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

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

Key Words:
cancer treatment-related cutaneous toxicities; skincare

Introduction

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

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

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

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

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

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

Scope

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

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

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

Methods

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

Literature Review

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

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

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

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

Cancer Treatment-Related Skin Toxicities

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

The CaSMO Algorithm

Features of a Medical Algorithm

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

A clinical algorithm’s function is to standardize and support medical decision-making, such as regulating the selection and use of treatment regimens, thereby improving adherence to evidence-based guidelines.²⁷ The best algorithms have inputs and outputs, precisely defined specific steps, and uniquely defined results that depend on the preceding steps.²⁷

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

Education on Cancer Treatment-Related Skin Toxicities

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

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

Strategies suggested by the panel include:

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

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

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

Box 1: Information and patient education

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

Prevention Measures Using Skincare

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

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

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

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

Box 2: Skincare using cleansers and moisturizers

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

Box 3: Criteria for moisturizers

A study on the efficacy and tolerability of thermal water containing skincare regime (La Roche-Posay) consisted of two types of cleansers, a moisturizer, a healing baume, and an SPF50+ sunscreen.²⁶ The skincare was used for preventing skin toxicity in two-hundred-fifty-three women with mostly stage I (International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC)) breast cancer undergoing radiotherapy. The heavy users who daily used the total skincare regime showed significantly (p ≤ 0.0001) less severe skin toxicities than those with lower skincare regime use who used parts of the regimen from time to time.²⁶

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

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

Box 4: Sun protection

Assess for Life-Threatening or Dangerous Reactions

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

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

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

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

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

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

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

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

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

Treatment Measures With a Focus on Skincare

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

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

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

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

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

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

Implementation of the Algorithm

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

Limitations

A few physicians developed the algorithm, representing a few centers, and did not include patients in the development. Although limited evidence was available to guide the development, the project will hopefully spur more skincare studies to prevent and manage cutaneous toxicities.

Conclusion

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

¹Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: All of the authors have no conflicts to declare for this work.

Abstract:
Nicotinamide (or niacinamide), a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin), is a low-cost, evidence-based oral treatment option for actinic keratosis, squamous cell carcinomas, basal cell carcinomas, and bullous pemphigoid. Despite its favorable safety profile and affordability, the integration of nicotinamide into clinical practice is an ongoing process, and like many over-the-counter supplements it has faced some barriers. The purpose of this article is to address some of those barriers by reviewing its efficacy, safety profile, and emphasizing the difference between nicotinamide and niacin. Lastly, we offer practical guidance around recommendations and the availability of nicotinamide, which can be hard to find for patients and providers alike.

Key Words:
nicotinamide, niacinamide, nonmelanoma skin cancer, squamous cell carcinoma, basal cell carcinoma, skin cancer, chemoprevention, bullous pemphigoid

Nicotinamide and How It Relates to Niacin

Nicotinamide is the amide version of its carboxylic acid precursor niacin (or nicotinic acid). Historically, niacin was identified as the first lipid-modifying drug when hypercholesteremia was beginning to be recognized as a risk factor for cardiovascular disease around the middle of the 20th century.¹ However, the use of niacin in the treatment of dyslipidemia was limited due to common cutaneous adverse effects, mainly flushing and telangiectasias.² Biochemically, nicotinamide and niacin are sequential precursors in the pathway converting the essential amino acid tryptophan into the ubiquitous electron acceptor cofactor nicotinamide adenine dinucleotide (NAD+) (Figure 1). Despite their structural and chemical similarity, nicotinamide and niacin differ significantly from a therapeutic standpoint, in that nicotinamide does not share either of the aforementioned lipid-modifying and vasodilatory effects of niacin.³ This dissimilarity is best explained by the release of prostaglandin D2 from the skin via an unknown mechanism causing cutaneous vasodilation and through specific nicotinic acid receptor binding interactions in adipose tissue^3,4 An overview of the differences between nicotinamide and niacin are summarized in Table 1.

Background

Niacin is synthesized from tryptophan, an essential amino acid obtained from dietary sources, including poultry, salmon, and red meat. In the body, niacin is converted to nicotinamide, and like most water-soluble vitamins, it functions as enzyme cofactors. Nicotinamide is the precursor of NAD+ and the reduced form NADP, which are implicated in oxidative phosphorylation and adenosine triphosphate (ATP) production, and function as enzyme cofactors in at least 200 different biochemical reactions.⁵

Actinic keratosis (AK) and nonmelanoma skin cancers (NMSC) are caused principally by ultraviolet (UV) radiation directly damaging DNA in keratinocytes and by immunosuppression. Nicotinamide works at multiple steps to counteract the carcinogenesis of squamous-cell carcinomas (SCC) and basal-cell carcinomas (BCC) (Figure 2). First, by preventing ATP depletion, nicotinamide boosts cellular energy which counteracts the “energy crisis” in photodamaged skin through an array of protective responses within keratinocytes, including DNA repair, anti-inflammatory effects, and by enhancing local cutaneous immunity.² Nicotinamide is also the exclusive substrate for poly-ADP-ribose-polymerase (PARP-1), a key enzyme involved in DNA repair.⁶ Moreover, nicotinamide reduces the level of immunosuppression that results from UVB irradiation of lymphocytes in the skin through similar mechanisms by enhancing cellular energy and DNA repair enzyme activity without altering baseline immunity.^7,8

Uses in Dermatology

Nicotinamide therapy has been studied in both the prevention of NMSC and in the treatment of bullous pemphigoid (BP). Both disease processes involve a degree of immune dysregulation and are on opposite ends of the spectrum of epidemiological significance. Together, AK, SCCs, and BCCs account for at least 14% of all dermatology office visits and the incidences of all three are currently rising.^9,10 On the other hand, BP is an autoimmune subepidermal bullous disorder affecting about 10 per million of the general population, however, it is associated with considerable mortality, especially among elderly patients. The mean age of disease incidence ranges between 60 and 80 years.¹¹

Actinic Keratosis and Nonmelanoma Skin Cancer

The Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study, a phase 3 double-blinded randomized clinical trial published in the NEJM in 2015, concluded that oral nicotinamide was safe and effective in reducing the rates of NMSC and AK in high-risk patients.¹² The study was conducted in Australia. High-risk patients included study participants who had at least two NMSC in the previous 5 years, and groups were randomly assigned to receive either 500 mg nicotinamide BID (n = 193) or placebo for 12 months (n = 193). At 12 months, the rate of new BCCs was 20% lower in the nicotinamide group and with respect to AK and SCCs, the incidences were 13% and 30% lower, respectively. Overall, the rate of new NMSC was 23% lower (p = 0.02) in the nicotinamide group versus the placebo group and there was no difference in safety between groups.¹²

The authors concluded that nicotinamide treatment was safe and effective, especially among patients with higher numbers of prior NMSC. Moreover, two earlier phase 2 studies showed that 500 mg of oral nicotinamide taken once or twice daily in individuals with sun-damaged skin (4 or more AK and with or without a history of skin cancer) significantly reduced AK counts and the incidence of new NMSC.¹³ In addition, the authors of the ONTRAC study performed a similar, albeit smaller study (n = 22) in immunosuppressed solid organ transplant recipients.¹⁴ Nicotinamide 500 mg BID was associated with a non-significant 35% relative reduction in the rate of NMSC (p = 0.36) compared to placebo and there were no safety differences between groups.¹⁴ Thus, it appears that oral nicotinamide is an effective chemoprotective agent for most patients with varying degrees of immunological status and sun-damaged skin, and the effects are observed as early as 2 months with 500 mg of nicotinamide either once or twice daily.^12-14

A recent systematic review looking at treatments for AK covered 18 topical treatments, 1 oral option, which was an oral retinoid, and 3 chemical interventions, including cryotherapy.¹⁵ The authors concluded that photodynamic therapy and some topical treatments, namely diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate all had similar efficacy, and thus the choice of treatment should be guided by the patient’s tolerances and preferences. However, some of the aforementioned agents can be cost prohibitive for some patients, whereas oral nicotinamide is a low-cost option that has proven clinical efficacy and a favorable safety profile. Additionally, as an oral agent it can be used as an adjuvant to an existing topical or office-based treatment regimen. Though its use in conjunction with existing treatment options, such as topical immunomodulators and office-based interventions including cryotherapy and photodynamic therapy, has not been directly studied, as an oral agent we believe it can be safely used as an adjuvant to a patient’s existing regimen or on its own for the chemoprevention of AKs and NMSC.

A recent systematic review looking at treatments for AK covered 18 topical treatments, 1 oral option, which was an oral retinoid, and 3 chemical interventions, including cryotherapy.¹⁵ The authors concluded that photodynamic therapy and some topical treatments, namely diclofenac, 5-fluorouracil, imiquimod, and ingenol mebutate all had similar efficacy, and thus the choice of treatment should be guided by the patient’s tolerances and preferences. However, some of the aforementioned agents can be cost prohibitive for some patients, whereas oral nicotinamide is a low-cost option that has proven clinical efficacy and a favorable safety profile. Additionally, as an oral agent it can be used as an adjuvant to an existing topical or office-based treatment regimen. Though its use in conjunction with existing treatment options, such as topical immunomodulators and office-based interventions including cryotherapy and photodynamic therapy, has not been directly studied, as an oral agent we believe it can be safely used as an adjuvant to a patient’s existing regimen or on its own for the chemoprevention of AKs and NMSC.

Bullous Pemphigoid

An alternative use in dermatology for nicotinamide is in combination with tetracycline antibiotics for the treatment of BP. A small (n = 20) unblinded randomized trial did not find significant differences in efficacy between traditional systemic steroid therapy versus tetracycline plus nicotinamide.¹⁶ The duration of treatment in the study was 8 weeks and the outcomes assessed were lesion counts and pruritis. Out of the 14 patients treated with tetracycline (500 mg QID) plus nicotinamide (500 mg TID), there were 5 each of complete and partial responses, and 1 each with no response and worsening BP. Among the 6 patients treated with systemic steroids (prednisone 40 to 80 mg/day), 1 had complete resolution while the other 5 responded partially. In summary, a larger blinded randomized trial is needed, but tetracycline plus nicotinamide is likely a useful alternative to systemic steroids, with similar efficacy and fewer side effects, especially among BP patients who tend to be older than 70 years of age and more prone to developing serious adverse effects from corticosteroid therapy. The side effects observed in the tetracycline plus nicotinamide arm included GI upset and acute tubular necrosis. Because of the potential of nephrotoxicity in patients with baseline severely decreased glomerular filtration rate (GFR), the authors of the study recommended exclusion of patients with a serum creatinine level >177 μmol/L or blood urea nitrogen (BUN) >14.3 mmol/L. However, more recently the BLISTER trial published in the Lancet comparing doxycycline (200 mg daily) alone to corticosteroids demonstrated non-inferiority in patients with BP, while showing long-term safety benefits in the doxycycline group.¹⁷ Assuming a class-effect for tetracycline antibiotics, a suitable regimen for the treatment of BP patients (in whom high-dose corticosteroid therapy should be avoided) that reduces the pill burden and eliminates the need for renal monitoring, would be doxycycline 200 mg daily plus nicotinamide 500 mg BID or TID.

Adverse Effects and Potential Drug Interactions

Unlike other oral agents used for prevention of NMSC, such as systemic retinoids or chemotherapeutic agents in organ transplant recipients, nicotinamide has a much more favorable safety profile. Furthermore, nicotinamide is not associated with the undesirable side effects of its biochemical precursor niacin, such as skin flushing, pruritis, and xerosis.^18,19 In the two largest phase 3 studies involving nicotinamide, the ONTRAC study (n = 386) outlined above and the ENDIT study (n = 552) involving patients at risk of developing Type 1 diabetes mellitus, both showed that there was no difference in patient tolerability and laboratory adverse events between nicotinamide (1-3 g/day) and placebo.^12,20 Other reported adverse events of nicotinamide include thrombocytopenia and hepatotoxicity, however, the ONTRAC study showed no difference in platelet counts between nicotinamide versus placebo groups, and evidence of liver toxicity has only been reported at extremely high dosages of nicotinamide in excess of 3 g/day.^12,18 Nicotinamide is renally cleared and 1 study in patients with ESRD on dialysis receiving nicotinamide reported thrombocytopenia, though reassuringly all cases resolved upon cessation of nicotinamide.²¹

In summary, 1g daily of nicotinamide is well tolerated as highlighted by multiple reports of minimal if any adverse events.^12,14,15,21 Unlike niacin, nicotinamide does not cause flushing, and thrombocytopenia and hepatotoxicity are rare, isolated effects in patients receiving hemodialysis or at extremely high dosages in excess of 3 g per day.

Regarding potential drug interactions, Lexicomp reports both niacin and nicotinamide as potentially increasing the adverse effects of statins, with a risk rating to monitor therapy. Clinical trials involving statin-niacin combination therapy have not reported myopathy, however, there have been case reports of niacin in combination with specific statins associated with rhabdomyolysis and transaminase elevations.²² Though, upon searching the Ovid MEDLINE database using the nicotinamide synonyms and medical subject heading for HMG-CoA reductase inhibitors, there were no adverse drug interactions cited between nicotinamide and statins. Thus, as with statin monotherapy, patients should be cautioned to report symptoms suggestive of myopathy and consideration should be given to monitoring creatinine kinase (CK) and transaminase levels.

Real World Experience

Despite nicotinamide’s potential benefit to a large cohort of patients as a safe and inexpensive over-the-counter vitamin supplement for NMSC prevention, its translation into clinic practice has been hindered, mainly due to difficulties of finding it in stores, confusion over labeling, and relation to niacin. Notably, both products may be labeled vitamin B3, with niacin being the acid form and nicotinamide the amide form. Also, the labeling of North American products is predominantly niacinamide rather than nicotinamide, but both are the same thing.

In our own experience, drug store chains and other retailers are more likely to sell niacin and vitamin B-50 and B-100 complexes, the latter two only contain 50 mg and 100 mg of nicotinamide (or niacinamide), respectively. However, most large naturel health product stores we’ve encountered sell nicotinamide/niacinamide 500 mg products in the vitamin aisle along with other B vitamins. In addition, nicotinamide/niacinamide is easily accessible online (Table 2) and from specialty vitamin stores. The authors have had some success writing this as a prescription and having the pharmacist order in or locate the niacinamide/nicotinamide for patients (Figures 3 and 4).

Conclusion

In summary, oral nicotinamide is an affordable over-the-counter supplement with demonstrated benefit in the treatment of a range of skin conditions, most notably AK and NMSC. Furthermore, it has a favorable safety profile with minimal if any adverse effects or potential drug interactions. The proven chemoprotective action of nicotinamide offers an opportunity for its use as an adjunctive treatment or on its own for patients at risk of NMSC, however, due to confusion around its naming and availability, its adoption into practice has been met with some resistance. Thus, we hope that this article is able to shed some light on the differences between nicotinamide and its precursor niacin and offer practical information around recommending nicotinamide to patients, including where to purchase it.

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¹Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
²Medical Sciences Program, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
³Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
⁴Department of Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada

Conflict of interest:
David Bulir, Steven Liang and Maureen O’Malley have no conflicts to report for this work.
Elaine McWhirter has served on advisory boards for Bristol-Myers Squibb, EMD Serono, Merck, Novartis and Roche

Abstract
Today, a number of treatment options are now available for metastatic melanoma. Within the last decade, the development of novel immunotherapies for cancer has significantly altered the course of the disease in patients with melanoma. With more patients receiving these potentially life-saving treatments, not only have we learned more about the interplay between the immune system and melanoma, but more importantly, which treatment options are most appropriate given the clinical picture.

Key Words:
immunotherapy, melanoma, update, checkpoint inhibitors, BRAF

Introduction

Today, malignant melanoma represents a significant disease affecting Canadians. In Canada alone, there were an estimated 7200 new cases of melanoma in 2017; of that, approximately 17% (1250 patients) will die from the disease.^1,2 Melanoma represents the 7th leading cause of all cancer-related deaths in Canada. In 2014, approximately 1050 Canadians died from melanoma (from 6500 cases), and 440 from non-melanoma skin cancers (from 76,100 cases). Although melanoma accounts for less than 1% of all skin cancers, the vast majority of deaths are caused by melanoma.^1,2 According to the Canadian Cancer Society, there has been increasing incidence of 2.1% per year for males and 2.0% per year for females over the last 25 years in Canada.^1,2 Despite this increase in incidence, limited therapies have existed for the treatment of metastatic melanoma until recently.³

Dual inhibition of MEK and BRAF

Approximately 50% of all melanomas are positive for BRAF mutations. BRAF encodes the B-Raf proto-oncogene; when mutated, it leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and unregulated cell growth.^4,5 Specific inhibitors of BRAFV600 mutations were first approved for use by Health Canada in 2012.^4,5 Confirmation of BRAF mutational status from testing either primary tumor samples or metastatic lesions is required before initiating therapy.⁴ Monotherapy with the BRAF inhibitors dabrafenib and vemurafenib have shown significant clinical benefit compared to standard chemotherapy.^6-8 Acquired resistance and paradoxical activation of the MAPK pathway in response to BRAF inhibition has been addressed through combination therapy of BRAF and MEK inhibitors.⁴ Combination MEK/ BRAF inhibition has been shown to provide a greater overall survival, response rate, and progression-free survival compared to monotherapy with BRAF inhibitors alone.^9-11 Recently, a phase II trial comparing dabrafenib to dabrafenib plus trametinib, a MEK inhibitor, demonstrated durable long-term overall survival. Patients receiving dabrafenib were allowed to cross over to the combination therapy group if disease progression occurred. In patients who received combination therapy from the start, or crossed over from monotherapy, the 4 year and 5 year overall survival rates were 30% and 28%, respectively. Overall survival rates were noted to be higher at 45% and 51% in patients with normal baseline serum lactate dehydrogenase (LDH) levels or with normal LDH with fewer than three metastases, respectively, in patients receiving both dabrafenib and trametinib.¹²

Inhibition of CTLA-4 and PD-1

Presently, two main classes of immunotherapeutics, also known as immunotherapy or checkpoint inhibitors, exist for metastatic melanoma: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptor antagonists.^13-16 CTLA-4, also known as CD152, is a receptor found on the surface of both regulatory T cells, and activated T cells.^13-16 Activation or inhibition of the T cell depends on a sequence of events involving antigen-presenting cells (APCs). The T cell receptor (TCR) interacts with the APC via an epitope in the major histocompatibility complex (MHC).^13-16 In addition to the MHC, co-receptors CD80 or CD86 interact with the T cell through CTLA-4 or CD28, providing an inhibitory or activating signal, respectively. CTLA-4 binds CD80 and CD86 with higher affinity and avidity compared to CD28, leading to inhibition of T cell activation, thereby reducing the chance of T cells spontaneously reacting to self-antigens.^13-16 The fine balance between activating and inhibitory signals provided by CD28 and CTLA-4, respectively, is exploited in melanoma immunotherapy to non-specifically activate the immune system in attempts to destroy cancerous cells.

Programmed cell death protein 1 (PD-1), known as CD279, like CTLA-4, is a surface receptor on immune cells that also plays an important role in down-regulating the adaptive immune system at the effector phase and promoting tolerance in tissues.^13-16 Endogenous ligands for PD-1 are programmed cell death protein ligand 1 and 2 (PD-L1 and PD-L2).^13-16 In the absence of PDL1 or PD-L2 binding to PD-1, the immune system remains activated, leading to CD4+ and CD8+ T cell proliferation, and subsequent effector function through cytokine production and direct cytotoxic effect, respectively.^13-16 Although tumor cells can present antigens on MHC, which can signal to the immune system to respond and clear the cancerous cell, these aberrant cells are capable of immune evasion through a number of mechanisms, including upregulation of PD-L1 and subsequent downregulation of T cell effector function.^13-16 Like CTLA-4 receptor antagonists, the development of immunotherapeutics blocking the inhibitory nature of PD-1 following activation has also revolutionized the treatment of metastatic melanoma by harnessing the natural ability of the immune system to clear these cancerous cells. See Figures 1 and 2 for a brief overview of CTLA-4 and PD-1 in T cell regulation.

Ipilimumab

The first immunotherapeutic for metastatic melanoma approved by Health Canada was ipilimumab in 2012, a monoclonal antibody targeting the CTLA-4 receptor.¹⁷ Approval for ipilimumab followed a trial demonstrating a significant overall survival of 10.1 months in the ipilimumab group compared to 6.4 months in the control arm of glycoprotein 100 (gp100) vaccine alone in patients who had previously treated, unresectable advanced melanoma.^17-19 Furthermore, 24-month overall survival rates were significantly higher in the ipilimumab group at 23.5%, compared to 13.7% in the gp100 vaccine group.^17-19 However, the unregulated proliferation and activity of immune cells induced by ipilimumab led to significant adverse reactions, including immune-mediated enterocolitis, dermatitis, hepatitis, endocrinopathies, and neuropathy among a significant number of patients.^17-19 It has been over a decade since the first clinical trial was conducted involving ipilimumab. In follow-up studies, patients who received ipilimumab and dacarbazine (DTIC) as part of a phase III trial have had an overall survival rate of 18.2%, compared to 8.8% among patients who received DTIC alone. The survival curve for patients receiving ipilimumab began to plateau 3 years after starting therapy, with minimal change thereafter.²⁰

Pembrolizumab

The first antibody targeting the PD-1 receptor was pembrolizumab, approved by Health Canada in June 2015 based on data from the KEYNOTE-001 trial.²¹ Patients with metastatic melanoma and disease progression after receiving at least two doses of ipilimumab were randomized to different doses of pembrolizumab. Patients receiving either 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks had a similar overall response rate at 26% and median follow-up of approximately 8 months.²¹ Follow-up of the phase Ib KEYNOTE-001 trial has demonstrated a 3-year overall survival rate of 40% in patients who received pembrolizumab, regardless of previous treatment.²² The randomized, phase III KEYNOTE-006 trial compared two doses of pembrolizumab to ipilimumab in patients with unresectable or metastatic melanoma. Interim analysis during the study shows significant improvements in progression-free survival (47.3% and 46.4% pembrolizumab vs. 26.5% ipilimumab), 1-year overall survival (74.1% and 68.4% pembrolizumab vs. 58.2% ipilimumab), and overall response rate (33.7% and 32.9% pembrolizumab vs. 11.9% ipilimumab).²³ Recent updated results demonstrate a median overall survival of 16 months on the ipilimumab arm, which was not reached in either of the pembrolizumab groups. The 24-month overall survival rate was identical on the pembrolizumab arms at 55%, compared to 43% for ipilimumab.²⁴

Nivolumab

Shortly after approval of pembrolizumab, nivolumab, also an anti-PD-1 antibody, was approved for the treatment of melanoma. Interim analysis of 120 patients who received nivolumab in the CheckMate-037 trial provided the basis for nivolumab’s approval. Patients whose disease progressed while on ipilimumab or a BRAF inhibitor were randomized to investigator’s choice chemotherapy (ICC) or nivolumab. Patients receiving nivolumab demonstrated an overall response rate of 32%.^25,26 Long-term data published this year from the original CheckMate-037 trial demonstrated more durable responses among patients receiving nivolumab than ICC, but no difference was noted in overall survival (15.7 vs. 14.4, respectively). However, the absence of a difference in overall survival may be accounted for by a higher incidence of brain metastases, elevated LDH, and lower incidence of crossover treatments among patients receiving nivolumab vs. ICC.²⁷ These two classes of immunotherapeutics have revolutionized the treatment of metastatic melanoma and led to a significant number of clinical trials, regulatory approvals, and basic science research around immunotherapeutics.

Combination Immunotherapy

Following the success of both CTLA-4 and PD-1 inhibitors, combination immunotherapy trials ensued. Phase I and II trials demonstrated better outcomes with combination nivolumab and ipilimumab in patients with advanced melanoma, regardless of BRAF mutation status or prior treatment, compared to monotherapy with ipilimumab. The randomized phase III CheckMate-067 trial, completed in 2015, demonstrated that patients with previously untreated malignant melanoma receiving combination ipilimumab plus nivolumab had a higher objective response rate, higher rates of complete response, and longer progression-free survival compared to monotherapy with either ipilimumab or nivolumab.²⁸ However, the incidence of severe (grade 3 or 4) adverse events was significantly higher among combination therapy (54%) as opposed to monotherapy with ipilimumab (24%).²⁸ Updated results from the CheckMate-067 trial were recently published.²⁹ While no change was noted in the safety profile during the 3-year period, there were significant differences in survival.²⁹ With a minimum of approximately 36 months of follow-up, median overall survival was 19.9 months among patients receiving ipilimumab, 37.6 months in patients receiving nivolumab, and was not reached on the combination arm.²⁹ Overall survival rate at 3 years had a similar pattern, with the combination group having a survival rate of 58%, and 52% and 34 % on the nivolumab and ipilimumab arms, respectively. Given the similar overall survival rate among patients receiving combination nivolumab plus ipilimumab vs. nivolumab alone, though the study was not powered for this comparison, further studies are needed to help elucidate predictors for treatment response and identify the patient population who would benefit from combination therapy vs. anti-PD-1 monotherapy. This is crucial given the significantly lower rate of toxicity with nivolumab compared to combination therapy (21% vs. 59% treatment-related grade 3-4 adverse events).²⁹ Recent data from a retrospective analysis of patients who discontinued combination nivolumab and ipilimumab due to adverse events during treatment induction had not reached a median overall survival, and demonstrated an objective response rate and progressionfree survival similar to patients who continued treatment.³⁰ Data from this study highlights the importance of identifying predictors of treatment response, and exploring treatment regimens that maximize clinical response but minimize adverse events. A recent phase Ib trial was completed in which standard dose pembrolizumab plus reduced dose ipilimumab (1 mg/ kg rather than the standard 3 mg/kg) every 3 weeks for four doses, followed by pembrolizumab every 3 weeks represented a promising modified dose combination therapy with a manageable toxicity profile and anti-tumor activity.³¹ Modified dose regimes are another area of clinical research needing to be explored, as few studies have looked to this area to help manage the adverse events associated with combination therapy.

Studies comparing first-line BRAF-targeted therapy to immunotherapy, with cross-over at progression, are pending results (NCT02224781). Thus, current first-line recommendations for advanced melanoma suggest either combination MEK/BRAF inhibition (in BRAF mutated patients) or immunotherapy with combination anti-PD-1/CTLA-4 or anti-PD-1 monotherapy.

Immunotherapeutics for Adjuvant Therapy

Checkpoint immunotherapy and MEK/BRAF inhibition have also shown significant benefits in overall survival and recurrence-free survival in the adjuvant setting. Prior to checkpoint immunotherapy and MEK/BRAF inhibition, interferon was the only approved adjuvant treatment, and provided only modest benefit with significant toxicities.³² A study comparing a higher dose of ipilimumab (10 mg/kg) to placebo for 3 years demonstrated significant benefits.³³ Three-year recurrence-free survival among patients receiving ipilimumab was 46.5% compared to 34.8% in the placebo group.³⁴ The median recurrence-free survival was significantly higher in the ipilimumab group compared to the placebo group, at 26.1 vs. 17.1 months, respectively. Of note, there were five deaths related to adverse events associated with ipilimumab and 46% of patients had grade 3 or higher adverse events leading to approximately 40% of patients discontinuing therapy before starting maintenance therapy.³³ Recently published updated results demonstrated a 5-year overall survival rate of 65.4% in the ipilimumab arm, compared to 54.4% for placebo (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001).³⁴ Due to the significant number of patients who discontinued ipilimumab after induction, there may be potential for greater benefit if patients continued with maintenance therapy.

In late 2017, the Food and Drug Administration in the United States approved nivolumab for adjuvant treatment in patients with melanoma and completely resected lymph nodes or metastases (stage IIIb/c or IV), based on the CheckMate-238 trial.³⁵ This randomized, phase III trial compared 1 year of treatment with nivolumab or ipilimumab in patients with resected melanoma.³⁵ The recurrence-free survival in patients who received nivolumab was 70.5%, compared to 60.8% in the ipilimumab arm. Six months after discontinuation of therapy (18 months after starting), recurrence-free survival in patients treated with nivolumab was 66.4% compared to 52.7% with ipilimumab.³⁵ Patients who received nivolumab had a considerably lower frequency of grade 3 or greater adverse events, 14.4% vs. 45.9% with ipilimumab. The discontinuation rate related to adverse events, regardless of severity, was only 9.7% with nivolumab compared to 42.6% with ipilimumab.³⁵ CheckMate-238 is presently ongoing and plans to assess longterm survival.

Combination MEK/BRAF inhibitors have also been studied in the adjuvant setting, with stage III BRAFV600E/V600K mutation positive melanoma. In the COMBI-AD trial, patients received dabrafenib and trametinib or placebo for 1 year.³⁶ With a median followup of 2.8 years, disease recurrence occurred in 37% of patients receiving dabrafenib and trametinib compared to 57% of patients in the placebo group, with a 3-year recurrence-free survival rate of 58% and 39%, respectively.³⁶ The 3-year overall survival among patients receiving active therapy was 86% vs. 77% in the placebo group.³⁶ Patients receiving combination treatment had a significantly reduced rate of distant metastases or deaths (25%) compared to those receiving placebo (35%).³⁶

Conclusion

The treatment of unresectable or metastatic melanoma has changed over the last 7 years. There has been remarkable progress after years of poor outcomes from treatments that have limited clinical efficacy. PD-1 and CTLA-4 are just two proteins in a complex network of immune regulation that have been exploited to help utilize the body’s natural ability to clear cancerous cells. Over the last decade, there has been an explosion of new immunotherapeutics that have been approved or are in clinical and pre-clinical trials, which will hopefully continue to expand our arsenal in the treatment of melanoma and other previously difficult to treat malignancies.

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¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Department of Dermatology, The George Washington Medical Faculty Associates, Washington, DC, USA

Conflict of interest: 
Adam Friedman is currently developing a nanoparticle encapsulated cannabinoid with Zylo Therapeutics – this work is not referenced in the manuscript. Dustin Marks has no conflicts of interest to report for this work.
Funding: The George Washington Department of Dermatology received no funding in support of this manuscript.

Abstract
Cannabinoids have demonstrated utility in the management of cancer, obesity, and neurologic disease. More recently, their immunosuppressive and anti-inflammatory properties have been identified for the treatment of several dermatologic conditions. This review thus assesses the therapeutic potential of phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids in the management of cutaneous disease. The PubMed^® and Scopus^® databases were subsequently reviewed in December 2017 using MeSH and keywords, such as cannabinoid, THC, dermatitis, pruritus, and skin cancer. The search yielded reports on the therapeutic role of cannabinoids in the management of skin cancer, acne vulgaris, pruritus, atopic and allergic contact dermatitis, and systemic sclerosis. While cannabinoids have exhibited efficacy in the treatment of inflammatory and neoplastic skin conditions, several reports suggest pro-inflammatory and pro-neoplastic properties. Further investigation is necessary to understand the complexities of cannabinoids and their therapeutic potential in dermatology.

Key Words:
acne, cannabinoid, cannabis, dermatitis, endocannabinoid, fibrosis, palmitoylethanolamide, inflammatory skin disease, pruritus, skin cancer, sclerosis, THC, tetrahydrocannabinol

Introduction

While the term “cannabis” often draws association to marijuana, cannabinoids represent a diverse class of hydrophobic compounds, deriving from plants (phytocannabinoids), animals (endocannabinoids), and chemical synthetics (Table 1).¹ In mammalian tissue, two G protein-coupled cannabinoid receptors have been identified: cannabinoid receptor 1 (CB1R) in brain and neural cell lines and cannabinoid receptor 2 (CB2R) in the immune system.^2,3 The cannabinoid receptors, transporters, and enzymes form the endocannabinoid system (ECS).⁴ Furthermore, phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids bind to the CB1R/CB2R and induce cannabimimetic responses via ECS activation as shown in Figure 1.⁵

The neuropathic properties of cannabinoids are well established and utilized in the treatment of obesity, cancer, spasticity, and tremor. More recently, the immunosuppressive and antiinflammatory effects of cannabinoids have been investigated in the treatment of inflammatory bowel disease, arthritis, vascular inflammation, and common dermatologic conditions.^5-9 Herein, we provide a literature review to assess the therapeutic potential of cannabinoids as it relates to their role in skin growth control and homeostasis, pruritus, inflammation, and fibrosis.

Cannabinoids in Skin Growth Control and Homeostasis

Cannabinoids influence the homeostasis of keratinocytes, melanocytes, and sebocytes through CB1R/CB2R-dependent and -independent mechanisms.^1,10,11 In the epidermis, CB1R activity in the stratum spinosum and stratum granulosum and CB2R in the basal layer may increase DNA methylation in human keratinocytes through a p38 MAP kinase to inhibit keratinocyte proliferation.⁸ In contrast, endocannabinoids inhibit keratinocyte proliferation independently of the CB1R/CB2R potentially through peroxisome proliferator-activated receptor gamma (PPAR-γ) and/or G-protein coupled receptor GPR55 activity.¹²

Non-Melanoma Skin Cancer (NMSC)

Given their role in keratinocyte homeostasis, cannabinoids influence basal and squamous cell carcinoma development.¹ Following long-term exposure to ultraviolet B (UVB) light, tumorigenesis was significantly increased in CB1R/CB2R+/+ mice in comparison to CB1R/CB2R–/– mice, suggesting a receptor-dependent role of UV-induced skin carcinogenesis.¹³ In contrast, Gegotek et al.¹⁴ defended the anti-neoplastic properties of cannabinoids. The authors found a significant reduction in endocannabinoid receptors, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) in keratinocytes and fibroblasts following UVA and UVB radiation. They determined that AEA exhibits nuclear factor kappa B (NFkB) inhibitory activity independently of CB1/CB2R, supporting pro-apoptotic properties of cannabinoids.¹⁴

Other reports, in comparison, have supported a CB1/CB2- dependent pathway as anti-neoplastic.^15,16 WIN-55,212-2 (a mixed CB1/CB2 agonist) and JWH-133 (a CB2 agonist) decreased the viability of the skin tumor cells in mice with PDV.C57 epidermal tumor cells. The antitumoral activity resulted from an induction of apoptosis and impaired tumor vascularization with decreased expression of vascular endothelial growth factor (VEGF), placental growth factor, and angiopoietin 2.¹⁵

The paradoxical findings (i.e., cannabinoids exhibit both pro- and anti-neoplastic properties) may be explained by concentration-dependent effects.¹ Nanomolar levels of endogenous cannabinoids associated with UVB and chemical carcinogens may stimulate NMSC tumorigenesis, while micromolar levels of exogenous cannabinoids may decrease NMSC growth. Data supports a similar concentration-dependent effect of cannabinoids on melanoma development.¹

Melanoma Skin Cancer

Human melanomas express CB1R/CB2R and activation of these receptors is associated with decreased growth and increased apoptosis in mice.¹⁰ In vitro and in vivo, tetrahydrocannabinol (THC) induced autophagy, loss of cell viability, and apoptosis in melanoma A375, SK-MEL-28, and CHL-1 cell lines. Compared to temozolomide, THC and cannabidiol inhibited melanoma viability, proliferation, and tumor growth in mice with BRAF wild-type melanoma xenografts.¹⁶

Nonetheless, CB1R activation may promote tumor growth in melanoma. Compared to control, melanoma cells without CB1R showed reduced p-Akt and p-ERK expression, reduced colonyforming ability and cell migration, and increased cell cycle arrest at G1/S.¹⁷ The influence of cannabinoids in the development of skin cancers is evidently complex. While most reports validate the anti-neoplastic properties of cannabinoids, the evidence remains equivocal.^1,10,14-16 Given the immunomodulation properties of cannabinoids, further investigation of its effects on immunosurveillance is imperative to appreciating the principal therapeutic effects.⁴

Acne Vulgaris

Similarly, the regulatory function of cannabinoids on sebocytes has been implicated in acne vulgaris treatment.^11,18,19 Sebocytes positively regulate sebaceous gland lipid homeostasis and negatively regulate sebocyte survival via CB2R.²⁰ Specifically, cannabidiol inhibited the lipogenic actions of arachidonic acid, linoleic acid, and testosterone, and thus decreased sebocyte proliferation and lipogenesis.11 The principal investigator reinforced the sebostatic properties of cannabichromene and THC but noted pro-sebaceous activity of cannabigerol and cannabigerovarin.¹⁸ In a single-blinded, split-face study, 3% cannabis seed extract cream decreased skin sebum and erythema content, demonstrating a potential treatment for acne vulgaris and seborrhea.¹⁹

Cannabinoids in Pruritus

Activation of CB1R/CB2R in cutaneous nerve fiber bundles may decrease excitation of these nerve fibers and thus attenuate axon reflex flare responsible for the sensation of pruritus.^21,22 Utilizing an acute allergic murine model, Schlosburg et al.²³ established that systemic THC reduced scratching response induced by compound 48/80. Additional mice were treated with an inhibitor of fatty acid amide hydrolase (FAAH), the principal enzyme responsible for degradation of anandamide, which displayed equivalent scratch-reduction to loratadine and dexamethasone administration. The authors concluded that neuronal FAAH suppression reduces pruritus via CB1R activation, establishing the therapeutic role of cannabinoids in pruritus.²³

WIN-55,212-2 has also exhibited anti-pruritic activity in murine models.²⁴ Following intradermal serotonin injection, WIN- 55,212-2 displayed a significant and dose-dependent reduction in pruritus. Notably, reduced levels of monoamines in spinal tissue, secondary to artificial neurotoxic destruction, showed no impact on the anti-pruritic activity of WIN-55,212-2. These findings suggest that cannabinoid’s anti-pruritic properties act distinctly and independently from descending serotonergic and noradrenergic pathways.²⁴

In human skin, peripheral administration of HU210, a cannabinoid receptor agonist, reduced histamine-induced itch in 18 participants.²¹ HU210 reduced vasodilation and neurogenic flare reaction with decline in neuropeptide (namely CGRP) release. However, co-administration of HU210 and histamine amplified protein extravasation significantly higher than histamine alone.²¹ Although cannabinoids exhibit predominant anti-pruritic properties, this additional finding indicates a more complex relationship between cannabinoid receptors and histamine.

The endocannabinoid palmitoylethanolamide (PEA) also exhibits anti-pruritic properties when applied topically. In an open-label application of a PEA-containing emollient (PEACE), 14 of 22 patients with prurigo nodularis, lichen simplex, and pruritus had an average itch reduction of 86.4%.²⁵ Similarly, in an observational, prospective cohort study of 2456 patients with atopic dermatitis, the average itch on standard visual analogue scale (VAS) was reduced from 4.89 to 1.97 after 39 days of treatment with PEACE (P < 0.001). While the tolerance was assessed by physicians as very good or good in 66.3% and 25.7% of participants, 3.4% displayed poor tolerance with significant pruritus, burning, erythema, and/or miscellaneous events.²⁶

Hemodialysis patients, likewise, demonstrated improved uremic pruritus following use of topical AEA and PEACE. After twicedaily application, 8 of 21 (38.1%) participants had resolved uremic pruritus as validated by both VAS and questionnaire method.²⁷ Overall, these findings indicate a therapeutic role for cannabinoids in the management of itch but double-blinded, placebo-controlled studies are necessary to further determine their efficacy.⁸

Cannabinoids in Inflammation and Fibrosis

While pro-inflammatory properties have been identified, cannabinoids exert a largely anti-inflammatory effect by cannabinoid receptor-dependent and -independent mechanisms.^5,6 In mice modules, WIN-55,212,2 decreased tumor necrosis factor (TNF), interleukin (IL)-12, IL-1β and CXCL8 (IL-8), while THC decreased TNF and IL-6 when coadministered with lipopolysaccharides, but increased these cytokines when co-administered with Legionella pneumophila. Furthermore, cannabinoids suppress T helper type 1 (TH1)-cell immunity and promote TH2-cell immunity through cannabinoid type 2 receptor (CB2R) on B, T, and antigen-presenting cells.⁶ These potential anti-inflammatory properties have been indicated in the treatment of atopic dermatitis (AD), allergic contact dermatitis (ACD), and systemic sclerosis.

Atopic Dermatitis

Related to their anti-inflammatory and anti-pruritic effects, cannabinoids may function to treat AD.⁹ CB1R– mice displayed an increased response to fluorescein isothiocyanate-induced atopic-like dermatitis and decreased epidermal barrier repair. Specifically, IL-4, thymic stromal lymphopoietin (TSLP), and CCL8 cytokine were elevated in these mice, suggesting that CB1R maintains epidermal barrier homeostasis and attenuates type 2 CD4+ T helper cell response.²⁸

Clinically, PEACE has demonstrated efficacy in the treatment of AD.^26,29,30 In the aforementioned cohort study discussed in the section on pruritus, PEACE not only reduced pruritus but improved dryness, excoriation, lichenification, scaling, and erythema in 70% of patients with AD, as determined by physician assessment. Globally, AD symptoms improved substantially in 56.3% of participants and reduced weekly topical steroid use by 62%.²⁶

In an investigator-blinded, split-body trial of 25 children and 18 adults with AD, Del Rosso²⁹ similarly demonstrated the therapeutic value of PEACE. The combination of PEACE and topical corticosteroid resulted in faster AD clearance when compared to moisturizer and topical corticosteroid. Additionally, PEACE prolonged the mean time to flare by 28 days compared to moisturizer.²⁹ A similar split-body trial of 74 participants found that PEACE versus emollient alone prolonged time to AD flare by a median of 43 days and 29 days respectively. Mild stinging and burning was reported by 9 (12.2%) participants.³⁰

In addition to topical application, dietary hempseed oil may improve AD. In a randomized, crossover study, daily consumption of 30 ml hempseed oil decreased skin dryness, itchiness, and use of dermal medications compared to consumption of olive oil. Symptomatic improvement may have resulted from the high concentration of polyunsaturated fatty acids in hempseed oil.³¹

As evidenced by several clinical studies, PEACE is efficacious in the treatment and further management of AD.^26,29,30 Its therapeutic role has been suggested not to replace topical corticosteroids but rather to complement and reduce their use.^26,29 Further research is necessary to understand the potentially synergistic mechanism of combination PEACE and topical steroids.

Allergic Contact Dermatitis

The anti-inflammatory properties of cannabinoids may also serve to treat ACD.⁹ Specifically, CB1R/CB2R–/– mice had increased cutaneous contact hypersensitivity induced by 2,4-dintirofluorobenzene (DNFB). Additionally, THC decreased ear swelling and reduced Gr-1+ granulocytes following DNFB administration. Mice deficient in FAAH, furthermore, displayed decreased allergic response. These findings support that CB1R/ CB2R activation reduces inflammation in ACD. A notable exception, acute administration of a CB2R antagonist initially diminished inflammatory response, suggesting that CB2R antagonism may initially reduce acute inflammation but later propagate it.³²

Further studies have similarly suggested a pro-inflammatory role of CB2R activation.^33,34 Following DNFB-induced ACD, mice deficient in CRB2 exhibited decreased ear swelling after 24 hours. Additionally, 2-AG activation of CB2R was associated with increase in ear weight in murine models and elevation of IL-8 and MCP-1 gene expression in human leukemia cell line HL-6.³³ Ueda et al.³⁴ further supported the pro-inflammatory activity of CB2R in mice.

Systemic Sclerosis

The therapeutic role of ECS has also been proposed for the management of systemic sclerosis.^35,36 Ajulemic acid (AjA), a synthetic analogue of THC, significantly prevented bleomycininduced dermal fibrosis and modestly reduced its progression in three independent murine models. Moreover, co-treatment of AjA and a selective PPAR-γ antagonist entirely reversed the antifibrotic effects, illustrating that AjA activates PPAR-γ to reduce and further prevent fibrosis. Given its tolerated therapeutic dose, AjA offers a potential treatment for systemic sclerosis.³⁷

In a randomized, placebo-controlled, double-blinded phase 2 clinical trial (NCT02465437) of 42 participants with diffuse cutaneous systemic sclerosis, lenabasum (AjA, JBT-101) significantly improved Combined Response Index Systemic Sclerosis (CRISS) scores by 33% in addition to the Modified Rodnan Skin Score, Systemic Sclerosis Skin Symptoms Questionnaire, and Health Assessment Questionnaire Disability Index.^38,39 While one participant withdrew from the study due to dizziness, lenabasum established an acceptable safety profile without severe adverse events secondary to the study drug.³⁹

Conclusion

These reports demonstrate the evident but complex role of cannabinoids and the endocannabinoid system in skin homeostasis and pathology. Clinical trials have supported the therapeutic role of cannabinoids in the management of acne vulgaris, pruritus, atopic dermatitis, and systemic sclerosis, as highlighted in Table 2.^{19,25,26,27,29,30,31,38,39} In vitro and in vivo studies have further indicated the potential therapeutic use of cannabinoids in skin cancer and allergic contact dermatitis.^10,14,32 While the majority of evidence emphasizes the anti-inflammatory, anti-neoplastic activity of ECS, pro-inflammatory and proneoplastic properties have been documented.^{13,17,21,32,33,34,36} Further investigation is imperative to understand the influence of the cannabinoid type, delivery method, and concentration on pro- and anti-inflammatory mediators in skin homeostasis to ultimately define the therapeutic role of cannabinoids in clinical dermatology.

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¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Pacific Derm, Vancouver, BC, Canada
³Department of Dermatology, New York University Medical Center, New York, NY, USA

Conflict of interest:
Jason Rivers has been an advisory board member, investigator, speaker, consultant, or received honoraria from Allergan, DermTech, Galderma, Janssen, Leo, MetaOptima, Regeneron, Sanofi, Valeant. Michael Copely has no conflicts to disclose. Ryan Svoboda participated in a fellowship program partly funded by Castle Biosciences and received and participated in an focus group for Castle Biosciences, for which he received an honorarium. Darrell Rigel is a consultant for DermTech.

Abstract
The Pigmented Lesion Assay (PLA) is a gene expression test that helps rule out melanoma and has the potential to reduce the need for surgical biopsies of atypical pigmented skin lesions. Utilizing a new technological platform for the non-invasive profiling of skin, the assay analyzes samples collected from adhesive patches for expression of two key genes (PRAME and LINC00518) known to be overexpressed in melanoma. The test result is binary (positive/negative) based on the detection of one or both genes. PLA positive cases are generally biopsied to establish the histopathologic diagosis, while PLA negative cases are considered for ongoing monitoring. The combination of visual inspection with histopathology, the current gold standard for melanoma diagnosis, has a relatively low negative predictive value (NPV) of approximately 83%, meaning that 17% of melanomas will be interpreted as benign lesions. In contrast, the PLA has a very high NPV (>99%). Further, with its high specificity (69-91%), use of the PLA can reduce the number of false positive samples subjected to histopathology review. By adding the PLA to the current care pathway, the number of surgical biopsies needed to find a melanoma (number needed to biopsy) is markedly reduced from 20-25 biopsies for dermatologists and 39 biopsies for physician assistants, to an average of 2.7. To date, unnecessary surgical procedures of benign lesions have been reduced by 88% based on a sample of more than 20,000 analyzed cases. This has resulted in fewer missed melanomas and significant cost savings to health care systems.

Key Words:
Pigmented Lesion Assay, non-invasive, melanoma, gene expression, test

Introduction and Current Care Pathway

Management of atypical pigmented lesions involves ruling out melanoma via visual and/or dermoscopic assessment followed by surgical biopsy and histopathologic examination (Figure 1A).^1,2 Ideally, when melanomas are identified, they are found at the earliest stages (melanoma in situ [MIS]/Stage 1a) when a high cure rate is possible by wide excision.^3,4 While the purpose of the visual assessment/surgical biopsy paradigm is to rule out melanoma, this approach has relatively poor performance metrics with an estimated 3-10% specificity for visual examination alone.⁵ This, coupled with the low sensitivity of 64-84% for histologic assessment^6,7 and the estimated in-office prevalence of around 5-10%, leads to a low NPV for early stage disease (83%, Figure 1). Thus, during histopathologic assessment, a small number of melanomas are identified from a large pool of biopsied pigmented lesions. Perhaps even more concerning is the risk of false negative histologic diagnoses resulting from a significant overlap in the histopathologic criteria between atypical nevi and early stage melanoma^6-8 Elmore et al. concluded the diagnosis of early stage melanoma was not accurate after finding 187 pathologists misinterpreted 35% of slide interpretations for MIS/Stage 1a melanomas.⁶ Given the prevalence of early stage melanoma in biopsied lesions is approximately 5-10%, the NPV can be approximated as between 75-89%.^5-7,9,10

The number of surgical biopsies needed to identify one melanoma (NNB, number needed to biopsy) averages around 20-25 and ranges from 8 to >30 depending on the clinical setting.^5,9,11-13 Further complicating the issue is that the histopathologic assessment of routinely biopsied lesions, without serial sectioning, is limited. With routine step sectioning of the tissue block providing less than 2% of the material for evaluation, there remains uncertainty as to what is present in the rest of the specimen. With the current diagnostic approach, it is estimated that, in the United States, 3 million pigmented lesion surgical biopsies were performed in the year 2017 alone, yielding <200,000 melanoma diagnoses.^14,15

Pigmented Lesion Assay Overview

The PLA is a gene expression test that helps clinicians rule out melanoma and avoid the need for a surgical biopsy of concerning pigmented lesions (Figure 1B).^16-22 The PLA is based on a new technology for non-invasive skin testing that permits gene expression analysis of skin samples collected with adhesive patches.¹⁹ In order to retrieve enough genetic material, the lesion is sampled consecutively four times, each time with a different patch. For each patch, the clinical margin of the lesion is delineated in pen and then the outlined tissue is dissected from the surrounding sample at the processing lab. Finally, the recovered RNA is extracted and analyzed for two indicator genes. The indicator genes used are PRAME (Preferentially Expressed Antigen in Melanoma) and LINC00518 (Long Intergenic Non- Coding RNA 518), both of which are overexpressed in melanoma. These genes were categorized as the key factors driving test performance in a microarray-based gene expression screen that identified a group of 312 genes differentially expressed in melanoma versus non-melanoma pigmented lesion samples.^16,21 Sampling of the most superficial skin layers contains information from deeper epidermal cells as a result of normal skin physiology in which basal cells migrate to the surface of the skin as they differentiate into squamous cells. During this process, keratinocytes acquire melanosomes from melanocytes through a phagocytic process of the melanocyte dendrite. In addition, some melanocytes migrate to the skin surface by a process known as pagetoid spread. Consequently, epidermal sampling with an adhesive patch yields molecular material from a variety of cells, including melanocytes, keratinocytes, and immune cells.¹⁹ In contrast to histopathologic sectioning, this method of genetic tissue sampling allows for the collection of material from the entire lesion. The PLA is intended for use in patients 18 years of age or older with pigmented lesions measuring 5 mm or larger and suspicious for, but without obvious clinical features of melanoma. It is not intended for use on non-melanocytic lesions (e.g., seborrheic keratoses), non-melanoma skin cancers (e.g., basal cell carcinomas) and bleeding or ulcerated lesions. Further, at present, the PLA cannot be used on palms, soles, nails, or mucous membranes.

Importantly, the PLA is intended to aid clinicians in surgical biopsy decisions but not to be used as a diagnostic test for melanoma. Positive PLA tests should be followed with a surgical biopsy, while patients with a negative test can have the lesion monitored per standard of care.

PLA Versus Current Standard of Care

Table 1 compares the key performance metrics of the PLA against the current standard of care (visual assessment and surgical biopsy/histopathology) for pigmented lesion management. In contrast to the current standard of care, the PLA has a very high NPV (>99%) coupled with a high sensitivity (91-95%), ensuring a very low probability of missing a melanoma.^16,17 The relatively high specificity of the PLA (69-91%) also helps to effectively reduce the number of lesions that would require subsequent histopathology review.¹⁶ Consequently, using the PLA, the number of lesions needed to be biopsied to find one melanoma is reduced from 20-25 to 2.7 (Table 1, Figure 2).^5,9,11-13,17

By utilizing the PLA, unnecessary surgical procedures may be reduced by as much as 88%.¹⁸ The findings of this internal data set is consistent with a recently published review of 18,715 biopsied pigmented lesions where 83% of those lesions were either benign or mildly atypical nevi and did not require additional treatment.¹⁰ Thus, about 90% of surgical biopsies performed on pigmented lesions in the general community may be avoidable.

Conclusion

In the current diagnostic pathway for pigmented lesions, the relatively low specificity of the clinical examination has resulted in a large number of biopsies to ensure the detection of melanoma. The addition of PLA to this diagnostic pathway, can lead to fewer surgical procedures and would provide signficiant benefits to patients such as reduced pain, infections and scarring. In addition, significant benefits accrue to the healthcare system because the PLA can reduce the costs associated with unnecessary surgical procedures.²² Most important, however, is the lower probability of missing a melanoma compared with the current standard of care. The PLA provides a unique and disruptive technology for the assessment of pigmented lesions that may soon transform the current diagnostic pathway to one that is less often invasive, highly reproducible, and a cost savings to the health care system.^16-20

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Introduction

Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy.  The aim of this document is to summarize current Canadian guidelines on NMSC management to provide guidance for primary care physicians. Based on a literature review conducted by the NMSC Guidelines Committee, the 2015 recommendations (five chapters) for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas and actinic keratoses were condensed for a family physician audience. This practical summary includes a brief review on epidemiology and pathophysiology of NMSCs, recommendations on primary prevention of NMSCs, and management of actinic keratoses, basal cell carcinomas, and squamous cell carcinomas. The importance of education in primary prevention is highlighted, and an overview of treatment options including topical, cryotherapy, photodynamic, surgical, and radiation therapies are discussed.

NMSC Chapter 1: Introduction to the Guidelines

Introduction

• Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer among Canadians,¹ with basal cell carcinomas (BCC) and squamous cell carcinoma (SCC) accounting for approximately 95% of these cancers.²
• Actinic keratoses (AKs) are precancerous lesions that have the potential to develop into SCCs³ and are therefore regarded as a marker of chronic skin photodamage.⁴

Epidemiology

• 1 in 6 Canadians will develop some form of skin cancer in their lifetime. In 2013, 81,700 Canadians were diagnosed with NMSCs.⁵

Risk Factors

• UV radiation
  • The major environmental risk factor^6-8
  • Proximity to equator and increase in altitude are associated with greater UV exposure and accordingly higher rates of NMSCs.^9,10
• Age
  • 70-80% of cases occur in people aged ≥60^2,11
• Male sex
  • Male to female ratio of 1.7:1 for SCC and 1.2:1 for BCC⁵
• Personal history
  • Personal history of NMSC increases risk¹²
• Ethnicity
  • Caucasians are at greatest risk, followed by Asians and Hispanics; risk is lower in African Canadians.¹³
• Special patient populations
  • Organ transplant recipients, patients with albinism, xeroderma pigmentosum, HIV/AIDS.^14-17

Pathophysiology

• UV radiation (including short wavelength UVB and long wavelength UVA) is the primary causative agent in NMSCs, via three main mechanisms:
  1. Direct mutagenic effects in the tumour suppressor genes P53^18,19 and CDKN2A^20-22, as well as the Hedgehog signalling pathway, specifically in the PTCH1 and SMO genes. The first molecularly targeted therapy in NMSC, vismodegib, is an inhibitor of SMO.²³
  2. Proliferation of malignant and premalignant cells by stimulating production of cytokines.¹⁹
  3. Alteration of cutaneous immune responses. The immunomodulator imiquimod helps target this.²⁴

Diagnosis

• Basal cell carcinomas (BCC)
  • BCCs are found predominantly on the head and neck (80%), followed by the trunk (15%), arms, and legs.⁸
  • Histologic subtypes (figure 1)
    • Nodular (most common) – translucent or waxy nodule with raised telangiectatic edges, with or without central ulceration/crusting.
    • Superficial – frequently occur on the trunk, presenting as scaly erythematous patches. Can be difficult to distinguish from psoriasis, eczema or SCC in situ (Bowen’s disease).⁶
    • Morpheaform – sclerosing or fibrosing
    • Pigmented
    • Infiltrative
  • 40% of patients present with mixed patterns of 2 or more of these subtypes.²⁵

• Squamous cell carcinoma (SCC) (figure 2)
  • Unlike BCCs, which are thought to develop de novo, invasive SCCs have known precursor lesions e.g. AKs and SCC in situ.⁴
  • AKs – 80% occur on face, bald scalp, ears, neck and dorsal arms/hands.⁴
    • Typically red, scaly macules and patches.
  • SCC in situ – slowly growing scaly erythematous macule or patch, similar to superficial BCC.
    • 3-5% risk for progressing to invasive SCC.²⁷
  • SCC – typically thicker than AK, with an erythematous, raised base and irregular borders prone to bleeding. Indurated with or without central ulceration. The edges have a fleshy, rather than clear, appearance.²⁸
  • Keratoacanthomas (KAs) – develop primarily on face, neck, hands.
    • Etiology unclear but lesions believed to originate from hair follicles. Rapid onset, growth and spontaneous regression (usually lasting 4-6 months in total).^29-31
    • Difficult to distinguish from SCC on clinical and histological basis, thus management is essentially similar.⁶

Prognosis and Staging

• Prognosis depends strongly on the lesion’s histologic grade, tumour location, size, thickness and perineural or perivascular invasion, as well as host immune function and prior treatment history.
• SCC metastasis occurs in 2-6% of cases,³² with a much lower rate for BCC (0.0028-0.55%).⁸ Metastatic NMSC has about 44% survival within 5 years.³³

Prevention and Management

• Photoprotection should be started in childhood.
• Biopsies should always be considered for lesions suspicious for skin cancer.²⁸
  • Suspicion of melanoma – complete excision.
  • Raised lesions – superficial shave biopsy.
  • Small lesions with distinct borders can be completely excised with a 2-10mm punch biopsy
  • Small lesions in areas where tissue loss is acceptable can be excised with 3-4mm margin.
  • Large lesions can be sampled by 1 to 2 small-punch biopsies (2-3mm) of the most suspicious areas; incision or shave biopsies are also appropriate.
• Modalities of treatment (Chapters 3, 4, 5) include:
  • Nonsurgical (topical, photodynamic therapy, radiation).
  • Surgical (excision, electrodessication with curettage, cryosurgery, laser ablation).
• Frequent re-evaluation is paramount as the risk for subsequent SCCs or BCCs among patients with previous diagnosis is increased 10-fold.³⁴

Chapter 2: Primary Prevention of Non-Melanoma Skin Cancer

Introduction

• UV radiation, as described previously, is the major modifiable risk factor for NMSC.
• In Canada and elsewhere, much effort has gone into educating the public on the hazards of unprotected exposure. However, various myths and misunderstandings about skin cancer risk continue to impede public education efforts.

Some Misguided Notions

• “I rarely bother with sunscreen”
  • Skin damage from UV exposure accumulates in a roughly linear fashion over time, underscoring the importance of early and lifelong sun protection.³⁵
  • Only 56% of Caucasian North Americans report moderate or frequent use of sunscreen when outside on a sunny day.³⁶
  • In organ transplant recipients, who experience long term immunosuppression and are particularly susceptible to NMSCs, regular sunscreen use was associated with significant reductions in new SCC and AK occurrences.³⁷

• “A tan will protect me from skin cancer”
  • The protective effect tanning (facultative pigmentation) yields only modest protection, the equivalent of using a sunscreen with a sun protection factor (SPF) of 2-3.³⁸
  • UVB (but not UVA) does induce a small amount of melanin biosynthesis, but the dose of UV radiation required to achieve this is mutagenic in itself³⁹ (as previously described in Chapter 1 – Pathophysiology).

• “Indoor tanning is safer than the sun”
  • UVA emissions from tanning beds can exceed that from the sun by as much as 10-fold.⁴⁰
  • Tanning devices increase the risk of BCC and SCC by 1.5 and 2.5-fold, respectively.⁴¹
• “With sunscreen, I can stay out all day”
  • In one study, use of sunscreen was associated with sun exposure that was 13-39% longer than if no sunscreen was applied.⁴²
  • Over-reliance on sunscreen can offset or eliminate the benefits of this protective measure.
  • The most basic photoprotective tools are avoidance of midday sun (when UV index, based on intensity of UVB radiation, is highest) and wearing UV-blocking clothing.
• “I choose a sunscreen by its SPF”

• • SPF is a measure of how much longer it takes sunscreen-protected skin (applied at 2 mg/cm²) to produce a minimal erythema (redness) response to UVB exposure, compared with unprotected skin.
  • The relationship with UVB deflection is not linear. A product with an SPF of 15, under laboratory-controlled conditions, blocks 93% of UVB rays, while another with an SPF of 30 will block 97% of UVB rays.
  • SPF provides only a crude estimate of how much protection a sunscreen product can provide against UVB-induced damage, since the strength of UV rays can alter with environmental changes.
  • SPF does not indicate efficacy in blocking UVA, which can also be damaging and carcinogenic to the skin.

  Figure 3. An explanation of Sun Protection Factor (SPF)⁴³

  • SPF value has traditionally been synonymous with the efficacy of a sunscreen product; however, SPF measures only UVB protection.
  • Newer UV absorbers cover the entire UV spectrum and can be divided into two groups: organic filters and inorganic blockers.
  • Organic filters are chromophores that absorb UV radiation.⁴⁴
  • Inorganic blockers (zinc oxide and titanium dioxide) can both absorb and reflect or scatter UV radiation.⁴⁵
  • The implication of reactive oxygen species in UV-induced lesions has also inspired the inclusion of antioxidants such as vitamin C and E.⁴⁶
  • Sunscreen products are labelled “broad spectrum” if they protect against both UVA and UVB.
  • Only broad-spectrum products with an SPF of ≥15 can claim to retard/reduce the incidence of skin aging and skin cancer.⁴⁷
• “Everyone knows how to use sunscreen”
• • Manufacturers recommend that sunscreens be applied at an even thickness of 2mg/cm², because SPF values are determined under those laboratory conditions.
  • However, the amount of sunscreen used is typically less than half that recommended,⁴⁸ decreasing UV protection by 2-4 fold.⁴⁹
  • Sunscreen application is also not homogenous, with some commonly neglected areas (e.g. ears, neck, back of hands, temples).^50,51 With normal bathing, physical activity and towelling, the SPF of a single application of sunscreen is also reduced by 40% and 55% after 4 and 8 hours, respectively.⁵²

Recommendations⁴³

• Physicians should regularly counsel patients that:
  • They should protect their skin from the sun by wearing appropriate clothing, avoiding exposure to midday sun, and using sunscreen.
  • They should use broad-spectrum sunscreen products with a SPF ≥30 or equivalent.
  • They should apply sunscreen liberally and evenly (2mg/cm²; about 35mL or 2 tablespoons for an average-sized adult), ideally at least 15 minutes before going outside.
  • They should reapply sunscreen, ideally, at least once during the day and more frequently if swimming or sweating and after towelling.
  • Use of sunscreen should not be a reason for extending the duration of sun exposure.
  • Indoor tanning should be avoided at all times.

Chapter 3: Management of Actinic Keratoses

Introduction

• These lesions are keratinocyte intra-epidermal neoplasias,⁵³ and are by definition confined to the epidermal layer of the skin.
• They are typically small (3-6mm), flat, pink or nonpigmented, and painless.⁵⁴
• However, hyperkeratotic/thickened and pigmented AKs can also occur.
• Sometimes better detected by palpation as a result of their sandpaper-like texture.
• Precursors in the evolution of SCC.⁵⁵

Occurrence and Natural History

• AKs are common in older, fair-skinned individuals.⁵⁶
• AKs often present in clusters on sun-exposed areas of the arms, head and neck.^57,58
• In one study, 0.6% of lesions progressed to in situ or invasive SCC over 1 year, whereas 55% spontaneously regressed clinically.⁵⁹ However, unless the areas has been surgically excised, there are high rates of recurrence.^60,61

Treatment Options

• Surgical Removal
  • AKs are not routinely surgically excised, and a biopsy is generally unnecessary unless lesions are recurrent or diagnosis is unclear.
  • Shave excision is commonly used for removal of hypertrophic AKs.
  • Curettage may be used alone or in conjunction with shave excision, electrodessication, or cryosurgery.
• Cryosurgery
  • Local treatment with liquid nitrogen (LN2/cryosurgery) is the most common approach to AK management.
  • Outcomes are operator-dependent and vary depending on freeze time, number of LN2 applications, and other parameters.⁶²
  • Because of these variables, as well as the fact that cryosurgery only targets clinically evident lesions, only 4% of patients remained free of AKs in the treated area.⁶³
• 5% 5-FU (Fluorouracil) Cream
  • 5% 5-FU cream was first used as treatment for discrete AKs, but may be also used as field therapy.^63-65
  • Generally applied twice daily for up to 4 weeks.
  • Leads to local inflammation, erosion and pain, which may be tolerated poorly and reduce compliance.⁶⁶
  • About half of patients achieve complete clearance, and >90% experience some reduction in lesion number.⁶⁵
• 5% Imiquimod Cream
  • Used primarily as field therapy
  • The most commonly used regimen is three-times-weekly dosing, applied in 4-week treatment cycles
  • Transient increase in the number of visible AKs in the treated field, thought to arise from subclinical lesions. These eventually regress and should be regarded as evidence of efficacy^67,68
  • With the above regimen, 73% of patients maintained clearance in the treated field for at least a year, which is significantly greater than that of patients using 5% 5-FU (33%) or receiving 2 sessions of cryosurgery (4%)⁶³

• 75% Imiquimod Cream
  • Used as field therapy, applied daily to face or scalp for two 2-week cycles, separated by a 2-week rest period.
  • Trials reported fewer withdrawals due to adverse effects, compared to 5% imiquimod.⁵⁴
  • Eight weeks after treatment, complete clearance occurred in about 36% of patients;⁶⁹ however, within one year further AKs developed in half of these patients.⁷⁰
• Ingenol Mebutate Gel
  • Available in two concentrations – one (0.015%) for the face and scalp, and the other (0.05%) for the trunk and extremities.
  • Dosing is once daily for 3 days for the facial and scalp areas, and 2 days for the trunk and extremities – shorter than the other topical agents and potentially advantageous in terms of compliance.⁷¹
  • After 12 months about half of the patients remained clear and overall lesion count was reduced >85% in the treated area.⁷²
• 5% 5-Fluorouracil +10.0% Salicylic Acid Solution
  • A dual-action topical indicated to treat hyperkeratotic AKs.
  • Salicylic Acid (SA) is a keratolytic, and the theory behind its use is to improve penetration in hyperkeratotic AKs.⁷³
  • Dosing is once daily to affected lesions, until lesions have cleared or for a maximum of 12 weeks.
  • At 8 weeks post-treatment, complete histological clearance of a single pre-defined AK lesion was achieved in 70% of patients. 50% of lesions were cleared at end of treatment.⁷³
• PDT and Daylight PDT
  • Two PDT systems available for AK treatment.
    • Blue light + photosensitizer 5-aminolevulinic acid (ALA)
    • Red light + methyl aminolevulinate (MAL)
  • Reasonable option for AKs disseminated over large areas.
  • In hyperkeratotic AKs, curettage is generally required before PDT.
  • PDT causes a burning sensation while the treated area is being illuminated.⁷⁴
  • Daylight PDT is currently being explored, in which MAL cream is applied to the photodamaged skin and patients sit in bright sunlight for 2 hours, wearing sunscreen as usual for UV protection. Pain is reported to be significantly reduced.^75,76
• Combined Treatment Modalities
  • One option is the combination of cryosurgery followed with an adjunctive field-directed therapy (e.g. imiquimod, 5-FU) 1-2 weeks after.^77,78
• Treatment Options for Actinic Cheilits (AC)
  • An AK occurring on photodamaged lips, or AC, presents as a white lesion with interspersed red areas.
  • Histologic analysis of the vermillion surrounding ACs commonly identifies foci of SCC;⁷⁹ because SCCs in this area have an elevated rate of metastasis,⁸⁰ field-directed therapy may be preferred over cryosurgery.
  • Surgical vermilionectomy allows for long-term clearance but poses risk of cosmetic damage or functional impairment.⁸¹
  • Less invasive approaches include field therapy with 5% FU, ALA-PDT, and MAL-PDT. Imiquimod is also commonly used, although Canadian labelling restricts use on the lips.⁸²

AKs in Organ Transplant Recipients

• Rate of SCC development increased by ~100-fold.^83,84
• AKs may be morphologically different from typical AKs, appearing more prominent (wartlike) and hyperkeratotic, and their SCCs are at elevated risk of local recurrence and metastasis.⁸²
• Field treatment with topical therapy or PDT is recommended.⁸⁵

Treatment Recommendations Summary⁸⁶

1. AKs with atypical morphology or presentation or resistant to treatment should be biopsied/excised.
2. Isolated AKs should generally be treated with cryosurgery or a surgical procedure. Curettage or direct surgical excision are preferred options, if the lesions are hyperkeratotic.
3. Areas with clustered AKs and those with histologic evidence of field cancerization should be treated with field-directed therapies.
4. If cryosurgery or surgery is used in patients with solar elastosis or other evidence of extensive photodamage, field-directed therapy may be applied once healing is complete.
5. Patients with evidence of photodamage or history of AKs should be regularly monitored for new lesions, with increased monitoring with any of the following – history of NMSC, history of nonresponsive AKs, ongoing systemic immunosuppression.
6. Actinic cheilitis may be treated with any of the following modalities: cryosurgery, field-directed therapy, PDT, complete or partial vermillionectomy, laser resurfacing, ED&C.
7. Organ transplant recipients and others with long-term systemic immunosuppression and clinical evidence of AKs may receive field-directed therapies to prevent the emergence of AKs and NMSC in areas of photodamage.
8. In organ transplant recipients, a high level of suspicion for malignant transformation should be noted. Lesions that do not respond to treatment should be biopsied/excised.

Chapter 4: Management of Basal Cell Carcinoma (BCC)

Introduction

• BCC is the most commonly diagnosed skin cancer in Canada.²
• It is a slow-growing malignant tumour originating in the basal layer of the epidermis.
• It rarely metastasizes, but growth leads to local destruction of neighbouring skin and underlying tissue.^8,87
• It most commonly affects sun-exposed surfaces – head and neck predominantly, followed by trunk and extremities.
• Subtypes:
  • Nodular (60%) – most common on face. Nodular/popular appearance, with pearly quality, and often surface telangiectasias and ulceration.
  • Superficial (30%) – most common on trunk. Red, scaly macule or patch.
  • Morpheaform/scleorsing (5%) – atrophic plaques or papules with ill-defined margins. Aggressive growth pattern
  • Less common, aggressive
    • Infiltrative
    • Micronodular
    • Mixed

• Risk associated with age (incidences increase ≥60 years of age) and sex (male).⁸⁸
• UV radiation is the most significant risk factor. Additional risk factors – fair skin, immunosuppression, environmental exposure to ionizing radiation, arsenic, UV radiation, psoralen plus UVA (PUVA), and a past history of BCC.^89-99
• Basal cell nevus syndrome (BCNS) is an autosomal dominant condition characterized by a mutation in the PTCH gene (important in the Hedgehog signalling pathway), leading to development of multiple BCCs.¹⁰⁰
• With timely detection and treatment, prognosis of BCC is usually excellent.
• Features used to stratify risk include site, size, histologic subtype, tumour margins, perineural or perivascular invasion, prior treatments, and immune status (table 2).
• Metastasis is rare (0.028% to 0.5%), usually to regional lymph nodes, lung, bone.⁸

Treatment Overview

• Goal of treatment – complete removal with optimal preservation of function and cosmesis.
• Surgical
  • Surgical excision with postoperative margin assessment, Mohs micrographic surgery (MMS), cryosurgery, and electrodessication and curettage (ED&C).
• Nonsurgical
  • Photodynamic therapy (PDT), radiotherapy (RT), and topical therapy.

Surgical Treatment

• Surgical Excision with Predetermined Margins
  • For well-defined, low-risk BCC <2cm, excising a 3-4mm peripheral margin results in a 95% tumour clearance rate.^102,103
  • For high-risk subtypes and large BCCs, 6-10mm margin recommended.¹⁰²
• Mohs Micrographic Surgery
  • MMS is a technique used on high-risk skin cancers to maximize tissue sparing and maximize cure rates.
  • MMS begins with narrow margin (0.5-1mm) excision, then the tissue is immediately processed using horizontal frozen sections. The physician examines the sections, and accordingly removes more tissue where any residual tumour is located. This process is continued until the tissue section(s) show no histologic evidence of residual tumour.¹⁰⁴
  • Cure rates as high as 99% and 96% for primary and recurrent tumours, respectively.^105-107
• Electrodessication and Curettage (ED&C)
  • Higher cure rates for smaller lesions.^108,109
  • Advantages – inexpensive, tissue-sparing, generally well tolerated.
  • Disadvantaged – potential hypopigmented scars, need for specialized training, lack of histologic confirmation of clearance.
• Cryosurgery
  • Most effective for treating low-risk BCC on trunk and limbs.^110,111
  • Not generally indicated for head and neck lesions or high-risk BCC due to poorer outcomes.^112,113
  • Curettage often combined with cryosurgery, which may improve cure rates.¹¹⁴

Nonsurgical Treatment

• Photodynamic therapy (PDT)
  • A topical photosensitizing agent (generally methyl aminolevulinate [MAL]) is applied to the lesion and irradiated with light, causing tumour cell death.
  • Adverse reactions – local pain, pruritus, erythema, edema.¹¹⁵
  • A systematic review reported a 1 year clearance rate of 84%.¹¹⁶
  • Good evidence for use of PDT in treatment of small lesions for patients contraindicated for surgery who can tolerate higher risk of recurrence and for whom cosmetic outcome is important, or possibly for patients with multiple small, low-risk BCCs.
• Radiation therapy (RT)
  • Primary surgical alternative for high-risk BCC, with long-term cure rates ≥90% for both primary and recurrent high-risk lesions.⁸
  • RCTs have compared RT with surgically alternatives; for primary facial BCC <4cm, 4-year tumour clearance rates were 99.3% and 92.5% for surgical excision and RT, respectively.¹¹⁷
  • Main advantages – tissue-sparing, non-invasive.¹¹⁸
  • Risks – local erythema, edema, ulceration, infection.
  • Potential long-term sequelae – chronic dermatitis, radio-necrosis, radiation-induced malignancies.¹¹⁹
• Topical therapy
  • Imiquimod, an immune response modifier, is the main topical therapy used in treating superficial BCCs.^120,121
  • Approved for treatment of superficial BCCs on trunk, extremities, neck
  • Clearance rates over 80%.^122,123
  • Nodular BCC does not appear to respond as well to topical imiquimod.¹²⁴

Locally Advanced or Metastatic BCC

• No standard therapy exists, in large part due to the rarity of such progression.
• Combination of surgery, radiation, chemotherapy.
• Newer research examines genetic targets of BCC.
• The oral agent vismodegib (inhibitor of Smoothened gene) is approved in Canada for treatment of metastatic BCC or locally advanced BCC that is inappropriate for surgery or radiotherapy.^124,125
• Disadvantages – high cost and toxicity (hair loss, muscle cramps, taste disturbance).¹²⁶

Follow-up

• A meta-analysis assessing the risk of developing a second BCC reported a 3-year risk ranging from 33-70%, with a mean of around 44%.³⁴
• Patients who received surgical treatment of low-risk tumours and confirmed histological clearance of high-risk tumours are at very low risk of recurrence and could safely be followed annually.¹¹⁹
• For patients at higher risk of recurrence (no histological confirmation of clearance, or nonsurgical treatment), biannual skin checks are recommended for the first 3 years, then yearly thereafter.

Recommendations

Chapter 5: Management of Squamous Cell Carcinoma

Introduction

• Second to BCC, squamous cell carcinoma (SCC) is the most common form of non-melanoma skin cancer, accounting for ~20% of all cases in Canada.²
• Although less common than BCC, SCC has a great potential for metastasis and is associated with a higher risk of mortality.^32,33
• Chronic exposure to UV radiation is the most important risk factor.^6-8
• SCCs arise from the superficial layers of keratinocytes and commonly appear on sun-exposed surfaces, such as the head and neck.
• SCC has varied presentations – it can be scaly, centrally ulcerated, or erythematous, and may have irregular borders prone to bleeding. It may arise from actinic keratosis.
• It is sometimes confined to epidermis (SCC in situ or Bowen disease), but can also invade nearby tissues and metastasize to regional lymph nodes and more distant sites.¹³⁶

Staging And Prognosis

Sentinel Lymph Node Biopsies

• Although SCC metastasis is rare, region lymph nodes (usually head and neck) are the most common site of disease spread.¹³⁸
• Prognosis of metastatic SCC is poor – 34.4% survival rate beyond 5 years.³⁸
• Thus, early detection of nodal involvement is important.
• Sentinel lymph node biopsy is commonly used in breast cancer and cutaneous melanoma but its value in high risk SCC is not well established.

Surgical Treatments with Margin Control: The cornerstone of SCC management

• Fixed-Margin Surgical Excision
  • Widely regarded as the treatment of choice for most cutaneous SCCs.¹³⁹
  • Advantages – histologic verification of tumour margins, rapid healing, good cosmesis.¹⁴⁰
  • SCC recurrence rates following surgical excision of primary invasive cutaneous SCC tumours: 5.7% for short term (follow up <5 years) and 8.1% for long term (follow up >5 years).³⁸
  • Higher recurrence rates for recurrent tumours: 17.3% and 23.3% for short- and long-term, respectively.³⁸
  • No consensus for acceptable surgical margin.¹⁴¹
    • 4-5mm for low-risk SCCs
    • 6-13mm for high-risk SCCs

• Mohs Micrographic Surgery
  • Highest clearance rates, and allows normal tissue to be spared by offering complete control of the surgical margin.^142-150
  • Thus, MMS should always be considered for SCC lesions with poorly defined borders, especially for cosmetically sensitive areas such as the face, hands, feet.

Destructive Treatments Without Margin Control

• Electrodessication and Curettage (ED&C)
  • Generally, 1-3 cycles of ED&C are performed during a single visit.¹⁴⁰
  • Cure rates for SCC in situ are 93-98%.^151,152
  • Since reliable margin control is not achieved, the effectiveness is highly dependent on the skill and experience of the physician.
  • Because the tumour margin is lost, ED&C should not be used for recurrent or high-risk tumours, or for deeper lesions that extend to soft, subcutaneous fat.^139,142
• Cryosurgery
  • In low-risk SCC lesions, including SCC in situ and KAs, high short-term clearance (follow up <5 years; 96.8-100%) and 5 year cure rates (96.1%) have been reported following cryosurgery.^63,113,114
  • May be inferior to ED&C in terms of patient pain, speed of healing, recurrent rate.¹⁵³
  • Disadvantages – scarring, hypopigmentation,¹⁵⁴ no established standards for optimal temperature, duration of treatment.

Radiation Therapy

• Can be used to treat inoperable primary cutaneous SCC lesions.
• High rates of short-term clearance (93.3%) and long-term cure (90-92.5%) are comparable to those achieved with surgical excision.^38,155
• Often suggested as an adjuvant to surgical management of high-risk SCC lesions, especially those with perineural involvement and positive surgical margins.^141,142

Photodynamic Therapy

• Currently, use of PDT in Canada is restricted to treatment of superficial BCCs and AKs.
• May be effective for SCC in situ, especially in the lower leg (which generally has poorer healing in response to other therapies).¹⁵⁶

Topical Regimens

• No topical therapies approved by Health Canada for treating SCC.
• Topical agents, such as 5-FU and imiquimod, have shown efficacy in the treatment of SCC in situ;¹⁵⁷ short-term cure rates of 27-85% with 5FU and 73-88% with imiquimod.¹⁵⁸
• Adverse effects of 5FU – erythema, pain, dermatitis, pruritus.¹⁵⁷
• Adverse effects of imiquimod – erythema, edema, weeping, pruritus, hypopigmentation, erosion, burning, pain.¹⁵⁷
• 5-year cure rates are unknown so cannot be recommended, but anecdotal evidence suggests they may be used off-label to manage low-risk SCC.

Other Approaches

• Laser
  • Argon, CO2 and Nd:YAG lasers have been studied in the treatment of SCC in situ in case reports and small series.
  • Mostly focusing on anogenital lesions, as well as SCC in situ of the digits.¹⁵⁹
  • High cost and need for specialized equipment.

• Intralesional therapy
  • Intralesional therapy with alpha-interferon or chemotherapeutics such as methotrexate, 5-FU, and bleomycin has produced cure rates of 91-100% for keratoacanthomas.¹⁵¹
  • Currently rarely used in practice.¹⁶⁰

Treatment Recommendations¹³⁷

1. Suspected SCCs should be biopsied according to the criteria outlined in Chapter 1.
2. Risk of recurrence should be established using the criteria in Table 4.
3. Selected patients with high-risk SCCs may be considered for sentinel lymph node biopsy in consultation with a multidisciplinary skin cancer clinic.
4. Primary low-risk SCC lesions of the skin, including SCC in situ and keratoacanthomas, may be treated with the following options:
   1. Surgical excision with 4-5mm margin (first line)
   2. ED&C
   3. Cryosurgery
   4. Radiation therapy
5. The following off-label modalities can be also considered in the treatment of SCC in situ:
   1. Photodynamic therapy
   2. 5-FU
   3. Imiquimod
6. Treatment options for recurrent or otherwise high-risk SCC lesions include the following:
   1. MMS
   2. Surgical excision with 6-13mm margin
   3. Radiation therapy
7. Adjuvant radiation therapy may be added to the surgical treatment of high-risk SCCs, such as those with perineural invasion.
8. Patients with select, high-risk SCCs may be considered for a referral to a multidisciplinary clinic.

Conclusion

• Complete removal of SCC along with preservation of function and cosmesis is best achieved through surgical methods allowing tumour margin assessment.
  • Fixed-margin surgical excision and MMS are the cornerstone treatments.
• Treatment options for high-risk lesions are limited to MMS, fixed-margin surgical excision, and radiation therapy.
• There are a number of second-line options for management of low-risk SCCs; while not currently approved, PDT and topical therapy may be especially useful for lesions in lower leg.

University of Alberta, Faculty of Medicine and Dentistry, Edmonton, AB, Canada

Conflicts of Interest:
The authors have no conflicts to disclose.

ABSTRACT
Nicotinamide, an amide form of vitamin B3, has shown the potential to treat a variety of dermatological conditions, including acne, rosacea, and atopic dermatitis. Recent studies have demonstrated the role of nicotinamide, in both topical and oral forms, as a chemopreventive agent against skin cancer. Its anti-carcinogenic role may be due to its ability to enhance DNA repair and prevent ultraviolet (UV)-induced immunosuppression, which is known to contribute to the progression of pre-malignant lesions. Furthermore, nicotinamide is a precursor of essential coenzymes for many important reactions in the body, including the production of nicotinamide adenine dinucleotide (NAD). NAD is a key coenzyme in the synthesis of adenosine triphosphate (ATP), which transports chemical energy within cells. Therefore, nicotinamide plays a significant role in supporting energy-dependent cellular processes, including DNA repair.

Key Words:
vitamin B, nicotinamide, skin cancer, chemoprevention

Introduction

Nicotinamide is an amide form of vitamin B3. The other main form of vitamin B3 is niacin (Figure 1). Vitamin B3 is an essential water-soluble vitamin. It is not stored in the body, and is maintained by dietary intake of both vitamin B3 and tryptophan. Tryptophan is an essential amino acid found in most forms of protein.¹ Vitamin B3 is found in foods such as legumes, nuts, grain products, mushrooms, chicken, pork, beef and fish.² The recommended daily intake of niacin for men and women is 16 mg and 14 mg, respectively; this dose increases to 18 mg during pregnancy and 17 mg for lactating women.³ Diets deficient in vitamin B3 can result in a condition known as pellagra, which is characterized by diarrhea, dermatitis, dementia and death (the 4 D’s).⁴

Both vitamin B3 derivatives, niacin and nicotinamide, are precursors for the production of nicotinamide adenine dinucleotide (NAD), which is a key coenzyme in the synthesis of adenosine triphosphate (ATP).⁵ Since ATP is responsible for transporting chemical energy within cells, nicotinamide and niacin play a significant role in boosting cellular energy and supporting many energy-dependent cellular processes, such as DNA repair.¹ Nicotinamide has been shown to prevent the depletion of cellular NAD levels, which occurs as a result of ultraviolet (UV) exposure.⁶ Decreased NAD levels are associated with increased susceptibility to cell genotoxicity, indicating that there is an inverse relationship between cellular NAD concentration and susceptibility to DNA damage.⁵ A study conducted by Gensler et al. (1999) demonstrated that in mice there is an inverse relationship between niacin supplementation and UV-induced skin cancer susceptibility due to niacin’s role in increasing cellular NAD levels.⁷ The findings of the study showed that dietary supplementation with 0.1%, 0.5% or 1.0% niacin reduced the incidence of skin cancer from 68% to 60%, 48% and 28%, respectively. These results demonstrate a dose-dependent reduction in skin cancer risk with the use of niacin supplementation.

Cellular Mechanisms

Nicotinamide and PARP-1

One mechanism by which cellular NAD levels influence responses to DNA damage involves the consumption of NAD for the synthesis of adenosine diphosphate (ADP)-ribose polymers and cyclic ADP-ribose, both of which are critical for apoptosis and necrosis.⁵ In addition, NAD is the single known substrate and inhibitor of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1).5 PARP-1, shown to be activated by UV radiation, plays a significant role in DNA repair and genomic stability.⁵ It does so by regulating transcription factors that are associated with the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators.⁸ Both PARP-1 and NAD influence cellular responses to genotoxicity and, as a result, may prevent mutagenesis and cancer formation.

Nicotinamide and Sirtuins

Sirtuins, NAD-dependent enzymes, play a key role in cellular responses to environmental stressors.⁹ Their effect on various transcription factors, including the tumor suppressor protein p53, contributes to their role in modulating cell metabolism and regulating cell survival.⁹ Sirtuin gene expression is triggered by UV irradiation. Actinic keratosis (AK) and squamous cell carcinoma (SCC) lesions show an upregulation of sirtuin gene expression, indicating that sirtuin may be associated with early stages of skin cancer formation.⁹ Nicotinamide inhibits sirtuin activity, which likely contributes to its protective effect against UV mutagenesis.⁹

Nicotinamide and DNA Repair

Nicotinamide plays an important role in DNA repair due to its function as an NAD precursor and as a substrate for PARP-1.¹⁰ PARP-1 is involved in several DNA damage responses, including DNA repair, maintenance of genomic stability, transcriptional regulation, signaling pathways involved in apoptosis, and telomere functions.¹⁰ As can be seen in Figure 2, nicotinamide and niacin are key components of NAD synthesis. This, in turn, is essential for ATP production and the activation of PARP-1. DNA strand breaks result in the activation of PARP-1, cleaving NAD into nicotinamide and ADP-ribose.⁵

The activation of PARP-1 by DNA strand breaks can activate 3 different cellular pathways, depending on the severity of DNA damage. When DNA damage is mild, PARP-1 activation enhances DNA repair by interacting with p53, signaling cell cycle arrest and facilitating DNA repair enzymes.5 Irreparable DNA damage causes PARP-1 activation to lead to apoptotic cell death by preventing ATP depletion and DNA repair through caspase-mediated PARP-1 cleavage. Finally, severe DNA damage leads to the overactivation of PARP-1. This causes NAD depletion and a cellular energy crisis as cells consume ATP in an attempt to replenish depleted NAD stores. The result is necrotic cell death.

UV radiation (from both UVA and UVB exposure) is the primary cause of skin cancer. UVB exposure damages DNA, which results in the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs).¹¹ CPDs lead to signature C to T and CC to TT transition mutations. UVA exposure also induces CPDs, but causes singlet oxygen photosensitization-induced DNA photolesions including 8-oxo- 7,8-dihydro-2′-deoxyguanosine (8oxoG).¹¹ In 2013, Surjana et al. conducted a study to observe nicotinamide’s effect on DNA repair following UV irradiation. The results showed that nicotinamide increases DNA excision repair activity in immortalized human keratinocytes (HaCaT cells) and enhances the repair of CPDs and 8oxoG following the exposure of human keratinocytes and ex vivo human skin to solar-stimulated UV.¹¹ This may contribute to nicotinamide’s apparent chemoprotective effects against skin cancer. Further evidence to support nicotinamide’s chemoprotective effects is that, under conditions of NAD depletion, human HaCaT keratinocytes showed increased DNA damage, even if genotoxic stressors were not present.¹² The addition of nicotinamide to the NAD-depleted cell cultures reversed this effect.

Nicotinamide and Immunosuppression

UV radiation, even in small doses, can cause immunosuppression, which contributes to the development of skin cancer by impairing the immunosurveillance of DNA damage.¹³ Sivapirabu et al. (2009) conducted a randomized, double-blinded study involving 70 healthy participants to show that topical nicotinamide (5%) prevents UV-induced immunosuppression.¹⁴ Skin immunity was determined by the Mantoux reaction, which measures the erythemal component of the delayed-type hypersensitivity response. The results showed a reduction of immunosuppression by approximately 50% after both single and multiple UV exposures. Similar results were found when the study was repeated using a much lower dose of topical nicotinamide (0.2%). Another study conducted by Damian et al. (2008) showed that applying 5% topical nicotinamide 3 days before solar-simulated UV exposure significantly suppressed Mantoux reactions.¹⁵ Based on this evidence, topical nicotinamide is effective at preventing UV-induced immunosuppression, whether it is applied prior to or after UV exposure.

Oral nicotinamide has also been shown to be effective in protecting against UV-induced immunosuppression. A randomized, placebo-controlled study using 30 healthy Mantouxpositive participants showed that 500 mg of oral nicotinamide taken 3 times daily for 7 days significantly reduced UVinduced immunosuppression.¹³ The study was repeated with 31 participants using a once daily dose of 500 mg oral nicotinamide. The results showed that the lower dose was equally as effective in reducing UV-induced immunosuppression.¹³

Clinical Evidence

Numerous studies have demonstrated the ability of nicotinamide to decrease the incidence of new nonmelanoma skin cancers (NMSCs) and AKs in susceptible individuals. Kim et al. (2015) combined the results of 2 randomized, double-blinded phase 2 trials that examined the effect of oral nicotinamide on AK counts in individuals with photo-damaged skin.¹⁶ Seventy-four patients were enrolled in the 2 trials (37 in the placebo group and 37 in the nicotinamide group). Approximately 81% of participants in the placebo group and 79% of participants in the nicotinamide group had previous skin cancers; 11 patients developed a total of 20 new skin cancers at 4 months in the placebo group, while 2 patients developed a total of 4 new skin cancers at 4 months in the nicotinamide group. The results demonstrated a significant reduction in the odds of developing at least 1 skin cancer with the use of nicotinamide in comparison to placebo (p=0.019).

A recent phase 3 randomized, double-blind, controlled trial conducted by Chen et al. (2015) recruited 386 patients who had been diagnosed with at least 2 NMSCs, specifically basal cell carcinomas (BCCs) plus SCCs, in the previous 5 years.¹⁷ The participants were randomized in a 1:1 ratio to receive either 500 mg nicotinamide twice daily or placebo for 12 months. Dermatologists evaluated participants at 3-month intervals for the 12-month trial period, as well as for 6 months after the intervention period. The primary endpoint of the trial was the number of new NMSCs during the 12-month intervention period. Secondary endpoints included the number of new BCCs, SCCs, and AKs during the 12-month period, the number of NMSCs in the 6-month post intervention period and the safety of nicotinamide. The results of the trial showed a 23% reduction in the rate of NMSCs in the nicotinamide group compared to the placebo group at 12 months (p=0.02). Similar results were found for the rate of BCCs and SCCs (20% and 30% lower in the nicotinamide group than in the placebo group, respectively). The number of AKs was also found to be lower in the nicotinamide group than in the placebo group at 3 months, 6 months, 9 months, and 12 months. The trial reinforced the safety profile of nicotinamide by showing no between-group differences with regards to the number or types of adverse events during the intervention period.

Other Skin Conditions

Nicotinamide has also shown to be beneficial in treating various dermatological skin conditions, including acne and rosacea. In addition, used together with corticosteroids, it is commonly prescribed for inflammatory autoimmune conditions like bullous pemphigoid and pemphigus.¹⁸

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions for which patients seek dermatologic care.¹⁹ Factors contributing to acne vulgaris include sebum production, bacterial growth, and associated inflammation.¹⁹ Nicotinamide has anti-inflammatory, sebo-suppressive, and healing properties, which have shown benefit for acne vulgaris when used topically. A study of 50 Japanese participants treated with 2% topical nicotinamide showed significantly lowered sebum excretion rates after 2 and 4 weeks of application.¹⁹ An earlier double-blind trial by Shalita et al. (1995) involved 76 participants with moderate inflammatory acne.²⁰ The results demonstrated that 4% topical nicotinamide gel and 1% clindamycin gel were statistically similar in decreasing acne symptoms over an 8-week period. From the participants treated, 82% showed improvement in acne symptoms.

Rosacea

Rosacea is a chronic facial dermatosis, characterized by the presence of erythema, papules, pustules, telangiectasias and sebaceous gland hyperplasia.²¹ Wozniacka et al. (2005) treated 34 patients with rosacea using a gel containing 0.25% N-methylnicotinamide (a metabolite of nicotinamide) for 4 weeks.²¹ The results indicated a good to moderate improvement in rosacea in 76% of participants. After 2 weeks of use, the majority of patients experienced a 50-75% reduction in the appearance of erythema and papules.²¹

Aging Skin

Nicotinamide also improves the appearance of aging skin.²² A double-blind randomized controlled trial with 50 Caucasian female participants observed the effect of topical nicotinamide on the appearance of photo-aged skin.²² Participants used 5% nicotinamide cream on their faces for 12 weeks. The results showed a significant improvement in skin appearance, including reductions of fine lines and wrinkles, hyperpigmented spots, red blotchiness and skin sallowness, as well as improved elasticity.

Inflammatory Autoimmune Conditions

Nicotinamide has shown to be an effective treatment for a variety of autoimmune conditions, particularly autoimmune blistering disorders. Nicotinamide, in combination with tetracycline, inhibits neutrophil and eosinophil chemotaxis, resulting in inhibition of the humoral immune response.²³ Thus, the combination of these two drugs has been shown to be an effective treatment in patients with bullous pemphigoid.²³ Nicotinamide has also been demonstrated to be a beneficial adjunctive therapy for patients with pemphigus vulgaris. A study conducted by Iraji and Banan (2010) showed that nicotinamide gel, applied topically, is an effective alternative to corticosteroids for treating pemphigus vulgaris lesions.²⁴

Conclusion

Nicotinamide is a widely available, inexpensive and welltolerated agent. It has been reported in a small number of studies to be of benefit in a range of skin conditions, including acne, rosacea, immunobullous disease and photoaging. Recent studies show that it may also be an effective chemopreventive agent against skin cancer, possibly due to its ability to both augment cellular DNA-repair mechanisms and counteract UVinduced immunosuppression. Due to its favorable safety profile and demonstrated effectiveness, nicotinamide supplementation should be considered as an adjunctive chemopreventative treatment for patients at high risk of developing NMSC or AKs.

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