¹Virginia Tech Carilion School of Medicine; Roanoke, VA, USA
² Section of Dermatology and Mohs Surgery, Department of Internal Medicine, Carilion Clinic; Roanoke, VA, USA

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

Abstract:
Human papillomavirus (HPV)-induced cutaneous disease is a common complaint for patients presenting for dermatology evaluation. Infection by HPV is the major etiologic factor in the development of cutaneous warts, epidermodysplasia verruciformis, and possibly a subset of cutaneous squamous cell carcinoma. Carcinoma of the genitourinary tract, most notably cervical carcinoma, is the most severe manifestation of infection with specific serotypes of HPV. For this reason, the HPV immunization (Gardasil) was developed in 2006 and upgraded in 2018 to a nonavalent formulation that includes serotypes 6, 11, 16, 18, 31, 33, 45, 52, 58. While immunization is highly effective at preventing infection with serotypes included in the formulation, it is less clear if the immunization can aid in managing active HPV infection. This review examines the available literature regarding the role of HPV immunization in managing common warts, genital warts, keratinocyte carcinoma, and epidermodysplasia verruciformis.

Key Words:
human papillomavirus, HPV, HPV immunization, Gardasil, Cervarix, common warts, verruca vulgaris, genital warts, condyloma acuminata, epidermodysplasia verruciformis, keratinocyte carcinoma, squamous cell carcinoma

Introduction

Human papilloma virus (HPV) is a non-enveloped, double-stranded circular DNA virus. Transmission usually occurs through skin-to-skin contact, but the virus can also be transmitted vertically and via fomites, such as transvaginal ultrasounds and colposcopes.¹ Over 100 HPV strains exist. HPV types 1, 2, 4, 7, 27, 57, and 65 frequently cause common, plantar, and flat warts,² while types 6 and 11 are the usual agents behind genital warts and recurrent respiratory papillomatosis.^3,4 The high-risk HPV types, 16 and 18, are responsible for the majority of HPV-induced carcinomas of the cervix, vagina, vulva, anus, rectum, penis, and oropharynx, with a minority caused by the less prevalent high-risk types (31, 33, 35, 45, 52, 58).^4-6 Other dermatologic conditions associated with HPV infection include keratinocyte carcinomas of the skin^7,8 and epidermodysplasia verruciformis (EV), which is caused by mutations that increase susceptibility to β-genus HPV strains.⁹

The first formulation of the HPV vaccine (quadrivalent Gardasil®), US FDA approved in 2006, covered types 6, 11, 16, and 18. The vaccine was designed mainly to aid in the prevention of cervical carcinomas, as reflected in its initial target population of female patients aged 9-26 years. Like other non-living vaccines, the immunization employed an adjuvant (aluminum hydroxide, 225 mg) that served to amplify the immune response. In 2009, a bivalent formulation (Cervarix®) that covered just serotypes 16 and 18 was approved by the FDA. Cervarix contains a proprietary adjuvant (3-O-desacyl-4 monophosphoryl lipid A [AS04]) that has increased potencycompared to aluminum hydroxide.¹⁰ Also in 2009, FDA approval was extended to include males between 9-26 years of age. Most recently, Gardasil upgraded to a nonavalent formulation that includes 9 serotypes (6, 11, 16, 18, 31, 33, 45, 52, 58) as well as an increase in adjuvant dose to 500 mg of aluminum hydroxide.¹¹ Additionally, approved coverage was expanded by the FDA in 2018 to include all individuals (from 9 years of age), male and female, up to 45 years old.

The effectiveness of HPV immunization in preventing HPV infection in naive individuals and subsequent cervical dysplasia and carcinoma is excellent and well-documented.^5,12 An interesting question that has arisen since widespread acceptance of the HPV immunization is what role does immunization play, if any, in the management of active HPV infection. Anecdotal reports and case series have described improvement or resolution of common and genital warts with administration of HPV vaccination, but conflicting reports documenting little to no benefit have also been published. This article provides a brief review of the literature exploring the potential utility of the HPV immunization in treating HPV-related dermatologic conditions.

Cutaneous Warts

Common, plantar, and flat warts are notoriously difficult to treat, many recurring or failing to regress with multiple treatment modalities.¹³ For this reason, additional treatments for recalcitrant warts would benefit patients and physicians. Nofal et al. published a study documenting their use of the bivalent HPV vaccine (Cervarix) in 44 patients with common warts who were randomly assigned to receive either standard Cervarix immunization (0, 1, and 6 months) or intralesional injection of Cervarix into the largest wart every 2 weeks until complete clearance or for a maximum of 6 sessions.¹³ Each participant had multiple, recalcitrant common warts that had been present for more than 2 years duration and failed to respond to at least 2 treatment modalities. Complete clearance was observed in 18 patients (81.8%) of the intralesional group and 14 patients (63.3%) of the intramuscular group; however, this was not statically significant. No recurrence was noted in the 6-month follow-up period. Additionally, a retrospective analysis of 30 patients documented complete clearance of common and plantar warts for 14 patients (46.67%) following administration of 3 doses of quadrivalent Gardasil.¹⁴ An additional 5 patients (16.67%) showed a partial response while 11 patients (36.67%) showed no response at all. Although the HPV strains most associated with common warts are not specifically targeted in the HPV vaccinations, the therapeutic effect is possibly due to antigenic similarity of the L1 capsid proteins across types or by nonspecific immune stimulation by the adjuvant contained within the formulation. The latter may partially explain the higher clearance rate observed with administration of Cervarix compared to Gardasil since a more potent adjuvant (AS04) is utilized in the Cervarix formulation.^5,13 Alternatively, the vaccine may alter the cytokine environment enhancing the native immune response.^4,13

Additional literature examining the role of HPV immunization in treating conventional warts is limited to case reports and small case series.^15-21 Abeck & Holst studied the effect of quadrivalent HPV immunization on 6 children with a 2-year history of recalcitrant extragenital warts.¹⁵ After the second dose, all but 1 child had complete resolution of warts, the sixth child was noted to respond after the third dose. A similarly designed study documented complete clearance of chronic verruca vulgaris in 4 patients following quadrivalent HPV administration intramuscularly.¹⁶ Moscato et al. described a single case of complete remission of plantar warts after 2 of 3 doses of the HPV quadrivalent vaccine. Interestingly, this patient also had genital condylomata, which did not regress following HPV vaccination.¹⁷ Kreuter et al. described an immunocompromised patient with disseminated cutaneous extragenital warts that significantly regressed starting 4 weeks after single dose of HPV quadrivalent vaccine with further regression noted 1 year after the third dose. This patient also had concurrent genital warts, which did not regress with treatment.¹⁸ Finally, a more recent case report described remarkable improvement of disseminated verruca vulgaris in an immunosuppressed patient after administration of the nonavalent formulation of Gardasil.¹⁹

Genital Warts

The quadrivalent and nonavalent formulations of the HPV immunization specifically cover serotypes 6 and 11, which are implicated in most genital warts. Large studies reporting significant efficacy of Gardasil or Cervarix for treatment of condyloma acuminatum are lacking. Lee at al. reported responses to quadrivalent Gardasil in a 44-year-old male with significant perianal condylomata recalcitrant to imiquimod therapy.²² Near complete resolution of perianal warts was observed 8 weeks after the first dose of quadrivalent Gardasil. Resolution was confirmed by biopsies and histologic analysis and there was no evidence of recurrence at his 3-month follow-up. In a more recent 2019 exploratory study, 10 patients with condyloma acuminata were treated with all 3 doses of quadrivalent Gardasil.²³ Of these 10 patients, 6 (60%) had a complete response, 1 (10%) had a partial response, and 3 (30%) did not respond at all.

Although few published case studies and small trials point to a possible benefit with administration of HPV immunization, larger trials with adequate control arms are necessary to better understand the extent of their effects.

Keratinocyte Carcinomas

Clinicians have long suspected HPV as having an etiologic role in the development of cutaneous squamous cell carcinoma (SCC). A meta-analysis by Wang et al. confirmed this association and suggested HPV may serve as a co-carcinogen in conjunction with other factors that increase the risk of cutaneous SCC.⁷ Nichols et al. examined the effect of quadrivalent Gardasil vaccination in 2 patients with a history of multiple keratinocyte carcinomas.⁸ Both patients were immunocompetent and received standard schedule HPV immunization with full skin examinations performed every 3 months during the study period. Each patient subsequently demonstrated a reduced rate in the development of new SCCs and basal cell carcinomas (BCC) compared to their baseline rates. Patient 1 experienced a decrease in SCC by 62.5% per year and a decrease in BCC incidence from 1 to 0 per year. Patient 2 experienced a decrease in SCC incidence by 66.5% per year and had a similar decrease in BCC incidence.⁸

Nichols et al. subsequently employed the 9-valent HPV vaccine in the treatment of an immunocompetent female in her 90s with numerous basaloid SCCs on her right leg.²⁴ The patient was treated with 2 intramuscular injections of nonavalent Gardasil (given 6 weeks apart) followed by intratumoral injection into 3 of the largest tumors. She subsequently received 3 additional intratumoral injections over the following 8 months. Clinical improvement in size and number of tumors was noted within 2 weeks of administration of the second intratumoral dose. Eleven months after the first intratumoral dose, the patient had no remaining SCCs and sustained clinical remission for at least 24 months.

Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare autosomal recessive condition caused by mutations in the EVER1 and EVER2 genes on chromosome 17q25. These mutations confer increased susceptibility to certain β-HPV types, resulting in persistent infections.²⁵ There is also an acquired form of EV, which is seen in immunocompromised patients with a predisposing condition.^9,25,26 Ninety percent of patients with EV are identified as having chronic infection with HPV 5 and/or 8, and persistent infection of these and other β-HPV strains can lead to nonmelanoma skin cancers.^9,25 Maor et al. described the efficacy of quadrivalent Gardasil in the treatment of acquired EV in a 50-year-old female with medical immunosuppression following renal transplant.²⁶ Her EV had progressed despite initial treatment with topical tretinoin and imiquimod, as well as oral acitretin. Twenty-seven months after initial presentation, 3 doses of quadrivalent Gardasil were administered over a 6-month period. During this time, the patient continued tretinoin, imiquimod, and acitretin therapy. One month following the final Gardasil dose, the patient’s clinical disease was significantly improved and HPV DNA was negative by PCR of a skin swab. Although there are several confounding factors, this is the only report examining the use of HPV immunization for treatment for EV.

Conclusion

In conclusion, HPV vaccines (Gardasil and Cervarix) may indeed have a therapeutic role in patients who suffer from dermatologic conditions that are associated with various strains of HPV. Anecdotal reports and case series have described improvement or resolution of cutaneous lesions with administration of HPV immunization, but conflicting reports documenting little to no benefit have also been published. An additional, ancillary question is whether the improvement in HPV-related disease is solely due to immune sensitization to viral antigen or if nonspecific stimulation of the immune system by the vaccine adjuvant plays a role. While the studies cited in this review are suggestive of potential benefit, larger, randomized trials with matched control groups are the necessary next steps to confirm the utility of HPV immunization in managing common cutaneous conditions associated with HPV.

Purchase Article PDF for $1.99

Skin Therapy Letter uses reasonable efforts to include accurate and up-to-date information, we make no warranties or representations as to the accuracy, completeness, timeliness or reliability of the content and assume no liability or responsibility for any error or omission. The content primarily focuses on approvals issued by US and Canadian drug regulatory agencies, and is sourced from both regulatory and industry news releases.

Purchase PDF for $1.99

Articles are indexed by drug names, trade names and disease terms. Bold entries refer to major references.

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.

Purchase Article PDF for $1.99

Updated December 9, 2020. Figure 2 data corrected. 

Maxwell B Sauder MD, FRCPC, DABD;¹ Mary Addona BSCN, RN;² Anneke Andriessen PhD;³ Marcus Butler MD;⁴ Joel Claveau MD, FRCPC;⁵ Nicholas Feugas RN, BN;⁶ Tarek Hijal MD, FRCPC;⁷ Lisa Iannattone MD, FRCPC;⁸ Sunil Kalia MD, MHSc, FRCP, FAAD;⁹ Laura Teague MN, NP-Adult PhD candidate;¹⁰ Charles W Lynde MD, FRCPC¹¹

PDF Download

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

Abstract:
Introduction: As more Canadians are living with or surviving from cancer, an increasing number have cutaneous sequalae of anti-cancer treatments. These cutaneous changes can severely impact quality of life and ultimately treatment outcomes.

Objectives: The consensus paper aims to identify the impact on patients of skin toxicities associated with radiation, chemotherapy, targeted therapy, immunotherapy, and hormonal treatment, as well as evidence-based best practices for skincare to minimize or prevent these changes.

Methods: A literature review explored clinical insights into the role of skin care in cancer- treatment-related skin toxicity. An expert panel of clinicians treating oncology patients convened for a one-day meeting to discuss the literature selected before the meeting, and adopt statements using the expert opinion and experience of the panel. The information is intended for health care providers caring for cancer patients.

Results: Patients frequently report skin toxicities to be unanticipated and much worse than their initial beliefs that may result in treatment reduction, interruption or discontinuation. Strategies to prevent or mitigate skin toxicity aim to reduce inflammation, promote skin healing, improve comfort and quality of life during cancer treatment. While evidence is lacking, a simple skin care regimen focused on a gentle cleanser, a moisturizer, and sunscreen may reduce skin toxicities.

Conclusions: Skin toxicities induced by cancer therapy negatively impact body image, physical, emotional and functional wellbeing, and cancer treatment satisfaction. Management of skin toxicities should focus on the quality of life, psychological wellbeing, improving treatment adherence, and treatment response.

Key Words:
cancer treatment-related cutaneous toxicities; skincare

Introduction

Excluding skin cancer, the most commonly diagnosed cancer in females is breast cancer, in males, prostate cancer, and lung cancer in both sexes.¹ In 2019, these four cancer-types accounted for over half of all cancer diagnoses (220,400) and cancer deaths (82,100) in Canada.¹ Survival rates are increasing due to a variety of factors, including earlier diagnoses and new classes of more efficacious therapies. With diagnosis and survivorship of cancers both increasing, more Canadians than ever will be living with or have survived cancer.

Cancer treatments may include surgery, radiation, transplantation, traditional chemotherapies, targeted therapies, immunotherapy, or hormonal therapies. The type of treatment is dependant on the specific cancer, stage, and other patients related factors. Despite improved agents used for cancer treatment, adverse cutaneous reactions are common.^2,3 If not managed effectively, these skin toxicities may cause significant discomfort, can be disfiguring, lead to serious morbidities that severely affect the quality of life, and may limit or discontinue anticancer treatment.^3,4 Skin toxicity as a result of cancer treatment is a largely neglected field.⁴ The prevention and timely treatment of adverse cutaneous reactions deserve more attention from dermatologists, who should be part of the multidisciplinary oncology treatment team. Skincare products are used widely for inflammatory skin diseases and reported to help restore the dysfunctional epidermal barrier. The application of a proper skincare regime can reduce symptoms associated with dry skin and pruritus.^5-7 The use of gentle cleansers, moisturizers, and sunscreen for cancer-treatment related toxicity have demonstrated a reduced incidence of skin toxicities.^6-12

Scope

The authors reviewed challenges in addressing skin toxicity issues in oncology patients and to what extent these factors attribute to the patients’ quality of life and cancer treatment outcomes. Clinical insights into the best approach for oncology skin care programs for all stakeholders in the Canadian healthcare setting were then further explored to develop expert opinion recommended practices.

Methods

An expert panel of clinicians treating oncology patients convened for a one-day meeting (October 2019; Toronto, ON). Statements, intended for health care providers caring for cancer patients, were developed based on the literature selected before the meeting and were discussed and adopted using evidence coupled with the expert opinion and experience of the panel.

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 August 2019.

Excluded were articles with no original data (unless a review article was deemed relevant), not dealing with the management of oncology treatment-related skin toxicity, publication language other than English.

A dermatologist and a physician/scientist conducted the searches on September 16 and 17, 2019 on PubMed and Google Scholar of the English-language literature using the terms:

Cutaneous toxicities associated with radiation treatment, chemotherapy, targeted therapy, immunotherapy, hormonal treatment, prevention, management, maintenance of cutaneous toxicities, health-related quality of life, skincare, dermocosmetics for skin toxicities.

The results of the searches were evaluated independently by two reviewers; discrepancies were resolved by discussion. The searches yielded two-hundred and thirty-six papers, and after exclusion of duplicates, we reviewed one-hundred and forty-two publications. After exclusion of articles that were deemed not to be relevant (other subjects, poor quality, a small number, case studies), forty-nine papers remained. Twenty-eight were review articles, including one guideline, two algorithms, and one systemic literature review. Additionally, eight clinical studies, one book, and thirteen other publications were selected.

Living With Cancer in Canada

The number of Canadians living with cancer has increased since death rates peaked in 1988; mortality has decreased by 35% in males and 20% in females.¹ Reduced mortality rates are likely due to a combination of early detection efforts, increased access to screening for some cancers (for example, breast cancer), and more effective treatments. Moreover, there is an overall decline in the incidence of certain types of cancer because of successful prevention efforts (for example, anti-smoking measures).

When ranking the 1995-2014 five-year survival rates for those with the main four types of cancer, Canada ranks among the highest in the world.¹³ More Canadians are living with or surviving from cancer and may have cutaneous changes or sequala of anticancer treatments, impacting their quality of life and/or treatment outcomes.^3,4

Anticancer Modalities and Associated Skin Toxicities

Radiation Treatment

Approximately 50% of cancer patients receive radiotherapy. Radiotherapy damages the DNA of cancerous cells via ionizing atoms that make up the DNA chain.¹⁴ The development of radiation-induced skin changes is a significant adverse effect of radiation therapy occurring in up to 95% of patients.¹⁵ Radiation dermatitis occurs in up to 87% of breast cancer patients and 90% of head and neck patients and may be aggravated by concurrent anti-cancer therapies.¹⁶ Dermatitis is limited to the area that received the beam and is dependent on the target, dose, and treatment schedule. Radiation dermatitis is categorized as acute, occurring within 1 to 4 weeks of treatment or chronic occurring after four weeks and can develop years after treatment.¹⁶ Cutaneous repercussions of radiotherapy vary considerably in severity, course, and prognosis and can have severe sequelae that impact the quality of life as well as a cancer treatment (Table 1).^15,16

Chemotherapy

Chemotherapy aims to disrupt specific phases of the cell cycle in actively dividing cancer cells. The adverse effects occur primarily while the patient is on treatment, and sequelae of therapy/metabolites can occur on uninvolved organs.^3,15-17

An observational study that evaluated cutaneous toxicities in a thousand cancer patients undergoing chemotherapy reported that three hundred and eighty-four (38.4%) patients presented with cutaneous adverse reactions.¹⁷ Frequently observed toxicities were anagen effluvium (78.6%), xerosis (4.4%), thrombophlebitis (3.1%), pruritus (2.9%), melanonychia (2.9%), hand-foot syndrome (2.6%), extravasation reactions (1.8%), flagellate dermatosis (1.3%), prurigo nodularis (0.8%), exfoliation (0.5%), ichthyosis (0.5%), papulopustular rash (0.3%), bullous photodermatitis (0.3%), and Sweet’s syndrome (0.3%) (Table 2).^17,18 The investigators noted that anagen effluvium was mostly caused by combinations of alkylating agents, handfoot syndrome was mostly due to taxanes (docetaxel), flagellate dermatoses resulted mostly from treatment with antitumor antibiotics (bleomycin), and exfoliation from antimetabolites (methotrexate) therapy.¹⁷

Targeted Therapy

Targeted therapies are theoretically more effective and less harmful to normal cells than traditional chemotherapy since they act at the molecular level rather than the cellular level of chemotherapy.^18-21 Targeted molecules in chemotherapy have revolutionized the treatment of hematological malignancies and solid tumors of head and neck, breast, lung, liver, kidney or colorectal origin, and melanoma.²¹ Examples of these targeted molecules include: BRAF inhibitors (dabrafenib and vemurafenib) and MEK inhibitors (trametinib and cobimetinib), Brc-abl inhibitors (imatinib, dasatinib, nilotinib) and, multikinase inhibitors (sorafenib, sunitinib, sorafenib, etc).^21-26 There are both common and target specific cutaneous reactions to these molecules (Table 3).

Multikinase inhibitors, such as sorafenib, sunitinib, and regorafenib, may cause Hand-Foot Skin Reaction (HFSR).^21-26 HFSR presents with tender hyperkeratotic lesions, with or without blisters, surrounded rim of erythema and thickened, painful lesions are more pronounced on areas with increased pressure and friction.²² The onset of the reaction is typically between 2 and 24 days with scaling, swelling, redness, then dryness and peeling.

EGFR inhibitors such as erlotinib, cetuximab, and panitumumab, as well as MEK inhibitors, can cause acneiform/papulopustular eruptions.^18,23 The eruption involves sebaceous areas such as the scalp, face, upper trunk, and occurs in 45-100% of patients.²³ Follicular based papules and pustules become crusted, with no comedones present. Onset is typically at 8-10 days, with a peak at two weeks followed by resolution 8-10 weeks after the end of treatment.^23,24 In past studies, approximately 32% of oncologists will stop the treatment due to rash alone,^23,24 whereas the appearance of the eruption may be a positive prognostic factor.²⁷

BRAF related keratinocyte proliferation (KA), neoplasms (SCC), and verrucous keratoses may occur as early as one week after treatment, but on average, it takes 6-12 weeks.^25-29 KA and SCC may occur within a median time of eight weeks (4-31%) when using vemurafenib and when using dabrafenib, it takes up to 16 weeks (6-11%) for adverse skin reactions to appear.^25-28 In general, adverse skin reactions develop in the first six months but may also take over a year to develop.^25-29 With the shift to combination BRAF plus MEK inhibition, there has been a decrease in most cutaneous adverse events.

Immunotherapy

Immunotherapy activates host immune mechanisms to treat cancer. These monoclonal antibodies (moAbs) cut the brakes on the immune system by inhibiting regulatory molecules that inhibit T cell activation.^30-34 Immunotherapy using monoclonal antibodies may be administered as a single agent (anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab, and avelumab)) or a combination (ipilimumab and nivolumab).^30-34

Skin toxicities can occur at any time throughout the treatment and may continue long after treatment discontinuation.^30-34 Most skin toxicities occur early within the first few weeks of treatment and can impact patient activities of daily living (ADLs), psychological health, and self-image.^4,30-34 The most commonly observed cutaneous immune-related adverse events (irAEs) are ‘rash’ (24% CTLA-4, 15% anti-PD-1, 40% combo), pruritus (25-35% CTLA-4, 13-22% anti-PD-1, 33% combinations) and vitiligo (~8% of melanoma patients treated with PD-1 and combinations) and is considered a good prognostic indicator of response.^35-39 The fact that most studies state “rash” as most common cutaneous irAE shows the need for dermatologic management. Less common irAEs are vasculitis, sarcoidosis, panniculitis, drug-reaction with eosinophils and systemic symptoms (DRESS), Stevens-Johnson Syndrome or toxic epidermal necrolysis (Table 4).³⁰

Hormonal Therapy

Hormonal therapy is frequently applied for breast cancer patients, such as with aromatase inhibitors (anastrozole, exemestane, and letrozole) and selective estrogen receptor modulators (SERMs) (Raloxifene, tamoxifen, and toremifene) (Table 5).³ These drugs cause reversible alopecia, flushing, and vulvovaginal dryness or atrophy.³⁰ Dyspareunia and secondary vaginismus are common adverse effects of selective estrogen receptor modulators and aromatase inhibitors.⁴⁰ Symptoms of vulvovaginal atrophy are more prevalent in patients taking aromatase inhibitors.⁴¹

Skin Toxicity and the Impact on the Quality of Life

Cutaneous adverse events are frequently unanticipated before therapy and severely impact patients’ health-related quality of life (HRQL).⁴² Almost 70% of patients reported that cutaneous AEs are worse than their initial beliefs before the start of their treatment.⁴²

A prospective study measuring the frequency and impact on the quality of life of skin toxicities in women receiving chemotherapy showed that 34% reported the skin AEs as most important during treatment, and they were the most common significant contributor to overall HRQL.⁴³ Of those who developed skin toxicities, 69% felt significantly limited in their daily activities.⁴³ Chemotherapy-induced alopecia was rated as the most traumatic side effect in 58% of patients, and 8% of patients would decline chemotherapy because of fear of hair loss.⁴³

A single center cross-sectional online survey among fifty-five cancer patients receiving dermatologic care evaluated patients quality of life (adapted questionnaire from the Dermatology Life Quality Index) and patient satisfaction.⁴⁴ Patient reported quality of life showed an improvement and dermatologic care resulted in overall satisfied patient outcomes.⁴⁴ The influence of dermatologic care on cancer treatment adherence was not clarified.⁴⁴

Prevention and Treatment of Skin Toxicities Using Skincare

For the prevention of skin toxicities, it is recommended to initiate a skincare regime prior to the anticancer treatment.^45-47 Patients should be educated on a daily skincare regime focusing on: hygiene, moisturization, sun protection, and, if applicable, camouflage products.^46-48 The skincare formulations for patients undergoing cancer-therapy should be safe, effective, free of additives, fragrances, perfumes, sensitizing agents, and should have a near physiologic (skin surface) pH.^46-48 Further, the skincare regime should be cosmetically pleasant and easy to use.

According to the panel, the choice of skin care needs to be tailored to the individual patient and may be dependent on the patients’ individual preferences. The use of moisturizers can be helpful to restore skin elasticity, sustain skin homeostasis, and control trans-epidermal water loss.^7,15,46-48

A review of topical agents for the treatment of radiation therapy-related skin toxicities reported no benefits from formulations containing aloe vera, chamomile, ascorbic acid, pantothenic acid, dexpanthenol, and trolamine.¹⁵ However, benefits were shown when using formulations containing hyaluronic acid (HA), epidermal growth factor EGF, granulocyte-macrophage colony-stimulating factor (GM-CSF), topical corticosteroids (TCS) or statins.¹⁵ Topical agents that have common ingredients known as soothing may be beneficial for the symptoms such as niacinamide, panthenol, squalene, glycerin, and allantoin.⁴⁷ Wound healing products and barrier films are widely used, as well, in oncology for cracked skin due to severe dryness.^49,50

An unpublished multicenter study evaluated the efficacy and tolerability of thermal water containing skincare regime La Roche-Posay (LRP), used for preventing skin toxicity in breast cancer patients undergoing radiotherapy. The regime consisted of two types of cleansers, a moisturizer, a healing baume, and an SPF50+ sunscreen. The two-hundred-fifty-three women with mostly stage I (International Union Against Cancer (UICC) /American Joint Committee on Cancer (AJCC) classification) breast cancer used mainly the cleansers, moisturizer, and healing baume (162 [67%]). Two categories of low and heavy users were defined based on the number of products used (0 to 5) and the frequency at which products were used (Never used = 0; From time to time = 0,5; Often =1; Every day= 2). Those who were heavy users of the skincare regime showed significantly less severe skin toxicities than those with lower use of the skincare regime (Figure 1). There was a statistically significant difference (p ≤ 0.0001) noted by the investigating physicians between low users and heavy users (Figure 2).

The patient benefit index scores (PBI) [Relevant treatment benefit score PBI ≥ 1, no relevant benefit score PBI ≤1] revealed a statistically significant difference between low users and heavy users (p = 0.095). For low users: PBI score N = 88) was a mean of 2.7 ( SD ± 1.2), and for the heavy users, the PBI score (N = 143) was a mean of 2.9 (SD ± 1.1) (Figure 3). The regime was well tolerated and easy to use.

A multicenter prospective observational open-label study evaluated the use of a 12-product kit for patients receiving chemotherapy.⁵⁰ Patients received skincare kits before the start of their cancer treatment with instructions to use the skincare throughout the treatment phase. The physicians evaluated the patients’ skin condition (edema, erythema, dryness, desquamation, pigmentation disorders, and cracks), and the patients scored the performance of the kit at the end of the study. The study indicated the benefits of skincare, helping to minimize the impact of cutaneous reactions.⁵⁰

Challenges to implementing a skin regimen include: complex regimens, application viewed as a “chore” especially when initiated prophylactically, “wait and see” attitude, socioeconomic status, and cost.

The Role of a Dermatologist as Part of the Multidisciplinary Team

Dermatologists are experts in skin and skin disease. They can improve the care of oncology patients with regards to improving patients’ quality of life, treatment outcomes through adherence to anticancer treatment, and rule out life-threatening cutaneous toxicity conditions.⁴⁸ The panel recommends that, ideally, dermatologic services be readily available for patients undergoing anticancer treatments. Urgent access is paramount to identify and assist in the management of dangerous or life-threatening cutaneous toxicity and symptoms that are, thankfully, rare. However, almost equally important, is a dermatologists’ ability to aid in the improvement of quality of life-related to cutaneous toxicities.⁴⁸

Important to oncologists, an onco-dermatologist or skin toxicities team may be able to preserve anticancer treatment through managing skin toxicities that historically were treated with treatment discontinuation. Chen et al. (2019) reviewed inpatient records from 2011-2018 and selected 33 cases with confirmed cutaneous irAE with similar grading of severity.⁴⁸ The use of systemic steroids to manage irAE has been shown to decrease the treatment effect of immunotherapy.⁵¹ In the Chen study, when a dermatologist was involved in the treatment of skin toxicities, patients were less likely to receive systemic steroids (18 versus 55%) and less likely to have the cancer drug discontinued (0 vs. 36%).⁴⁸ The multivariable logistic regression showed that a dermatological consult results in a lower risk of disruption of oncologic management.⁴⁸

Conclusion

Cutaneous anticancer toxicities occur at any time during treatment, including well after discontinuation of treatment in the case of radiation and immunotherapy. These toxicities can have a major impact on HRQL.

Patient education, therapeutic relationship, and frequent, open communication between patient and oncology team is essential to treat AEs as early as possible to ensure optimal outcomes. It is necessary to look at the patient holistically and acknowledge the factors involved in their access to resources and willingness to adhere to recommended practices.

A cancer patient’s dermatologists/cutaneous toxicities team may improve treatment outcomes, such as reducing the risk of disruption of cancer treatment. Proactively initiating a simple dermocosmetic regime involving hygiene, moisturization, and sun protection is the first step in the prevention or reduction of cutaneous toxicities.

Limitations

As there is a lack of clinical trials on the use of skincare for cancer-treatment related skin toxicities, the recommendations are mainly based on expert opinion.

¹McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Baylor College of Medicine, Houston, TX, USA
³Katta Dermatology, Bellaire, TX, USA
⁴Rice University, Houston, TX, USA

Conflict of interest:
Rajani Katta is the author of a book for the general public on diet and dermatology and has been an advisory board member for Vichy Laboratories. Ariadna Perez Sanchez and Evelyne Tantry have no conflicts to declare for this work.

Abstract:
There is growing awareness of the complex link between nutrition and skin. In the last few decades, our understanding of this link has grown significantly with research findings from multiple laboratory, animal, and human studies. From the impact of diet on clinical features of aging skin, to documentation of the biochemical and histologic changes that occur, our understanding of this link continues to expand and evolve. In this paper, we review the research on the impact of diet on skin aging. A number of long-term observational population studies have documented that healthier diets are linked to fewer signs of skin aging. Animal and laboratory studies have elucidated the biochemical processes that play a large role in the development of these clinical findings. A number of studies have also reported on the role of specific dietary compounds in impacting these processes, whether by combating or potentiating these forces. This body of research serves as guidance in recommending nutritional strategies that can combat the skin aging forces of oxidation, inflammation, and glycation.

Key Words:
antioxidants, anti-wrinkle diet, glycation, inflammation, nutrition, oxidation, skin aging

Introduction

The clinical features of skin aging are well documented and a common question in clinical practice is whether dietary choices have any impact on these features. Based on research ranging from long-term human population to intervention studies, laboratory investigations, and animal studies, a diverse body of data links diet to skin aging.

This research provides significant guidance when discussing nutritional strategies that can promote healthy skin aging. Skin aging is particularly impacted by the processes of oxidation, inflammation and glycation. For each, dietary choices can play a large role in modifying these forces. Specifically, certain dietary patterns, foods, nutrients, and compounds have the ability to either potentiate or combat these processes.

It is well documented that certain populations differ in the rate of development of skin aging. Multiple large scale studies have reported that in those with healthier dietary patterns, fewer fine lines and wrinkles are seen,^1,2 while other population studies have documented fewer pigmentary changes³ and less skin atrophy and dryness.⁴ In one study of over 500 non-diabetic subjects, it was found that as blood glucose levels increased, perceived age increased.⁵

In researching the role of nutrition, researchers have focused on different avenues of study. Population studies, human interventional studies (both long-term and short-term), animal studies, and laboratory studies have all been used to investigate the role of dietary patterns, foods, nutrients, and/or dietary compounds. Population research now focuses on the study of dietary patterns,⁶ due to the complexity of long-term dietary effects. Human interventional studies have detailed both the beneficial and harmful effects of specific foods, nutrients, or compounds. Animal and laboratory studies have provided data on the biochemical and histologic effects of dietary compounds. Taken together, this body of research supports a strong, complex relationship between diet and skin aging. Importantly, this research identifies a number of areas where dietary modification may promote an improvement in the parameters of skin aging.

The Pathophysiology of Skin Aging

Skin aging is a highly complex process. Our current understanding of this process, while not complete, has indicated that the intricate and intertwined processes of oxidation, inflammation, and glycation play major roles. Each of these is highly impacted by diet.

Ultraviolet radiation (UVR) is the major contributor to extrinsic skin aging, and the impact of UVR on the skin has been well described. UVR is responsible for multiple direct effects on the skin, as well as numerous downstream effects. UVR may produce direct DNA damage via induction of DNA photoproducts.⁷ It also results in oxidative stress, with a resultant increase in free radical production, especially reactive oxygen species (ROS).⁸ These cause additional DNA damage⁹ as well as damage to both structural (collagen and elastin) and enzymatic proteins. Effects on lipids include peroxidation of cell membrane lipids.¹⁰

Metabolic processes, pollution, smoking, and other factors also contribute to oxidative stress. Due to constant exposure, the body’s defense mechanisms are designed to withstand the damaging effects of free radicals. Endogenous enzyme systems include superoxide dismutase, glutathione peroxidase, catalase, and others. The epidermis and dermis also contain antioxidant defenses, including vitamin C, vitamin E, carotenoids, selenium, and others.^11,12 While these are important components of the body’s endogenous defense systems, they require constant replenishment from dietary sources. and others. The epidermis and dermis also contain antioxidant defenses, including vitamin C, vitamin E, carotenoids, selenium, and others.^11,12 While these are important components of the body’s endogenous defense systems, they require constant replenishment from dietary sources.

Photooxidative stress also activates several inflammatory pathways and contributes to chronic inflammation, which impacts the clinical and molecular features of aging^13,14 as well as the promotion of skin tumorigenesis.¹⁵ Activation of these pathways ultimately acts to increase the expression of several matrix metalloproteinases (MMPs).^13,14,16

MMPs encompass a number of different enzymes, including collagenases. Along with elastases, these act to remodel the extracellular matrix (ECM), with resulting fragmentation of the collagen and elastin fibers that provide structural support and elasticity to the skin. UVR also results in the reduced expression of tissue inhibitor of MMPs (TIMPs), which ordinarily would act to inhibit ECM destruction.¹⁷

Several other inflammatory pathways are activated by oxidative stress, including pathways which promote the release of a number of inflammatory cytokines and prostaglandins. The induction of pro-inflammatory genes leads to the release of inflammatory mediators from keratinocytes, fibroblasts, white blood cells, and others, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha. These further contribute to the effects of chronic inflammation.

Glycation is another factor that accelerates aging of the skin. Glycation is distinct from photoaging, but is closely intertwined. Glycation refers to the non-enzymatic process whereby sugar molecules covalently bond to proteins, lipids, or nucleic acids. The resulting products are known as advanced glycation end products (AGEs) or glycotoxins. AGEs are a heterogeneous group of molecules, with the prevalent AGE in the human body, including the skin, being carboxymethyl lysine (CML).

Glycation is an important factor in atherosclerosis,¹⁸ renal disease,¹⁹ diabetic complications, and other conditions. It plays an important role in skin aging as well. The accumulation of AGEs within the skin results in typical structural and functional changes that are colloquially known as sugar sag.²⁰

AGEs have a large impact on the collagen and elastin fibers that maintain the structural framework of the skin and provide resilience and elasticity. Glycation results in intermolecular collagen cross-linking, resulting in increased stiffness and vulnerability to mechanical stimuli.²¹ In addition, cross-linked collagen cannot be repaired as well. Collagen is highly susceptible to glycation, in part due to its long half-life, and may undergo up to a 50% increase in glycation over a lifetime.²² Glycation is closely related to oxidation and inflammation as well. Glycation increases reactive oxygen species (ROS), further accelerating oxidative damage. Additionally, AGEs may bind to specialized cellular surface receptors called receptor for AGEs (RAGEs). When activated, RAGE triggers several cellular signaling pathways.²³ These further promote inflammation and altered cytokine expression.

Nutritional Strategies to Target Key Processes in Skin Aging

Research has demonstrated that dietary components have the ability to impact each of these skin aging processes. The skin is commonly referred to as the largest organ of the body, and as such plays a substantial role in its defense. The skin barrier and its concomitant complex immune defenses play a significant role in protection against UVR, physical impact, temperature variations, irritants, allergens, microbes, and other factors. In fact, it can be said that our skin is under siege every minute of every day. Because of these constant threats, the skin barrier has many intricate built-in defense and repair mechanisms.

Dietary factors have the ability to either support these mechanisms or impair them. In other words, certain dietary patterns, foods, nutrients, and compounds have the potential to either accelerate or combat skin aging.

Oxidation

Antioxidants (AOs) are a key feature of the body’s defense against free radicals. They may act to neutralize ROS or may upregulate genes encoding for enzymes that neutralize ROS. The cutaneous impact of dietary AOs has been demonstrated in multiple studies. Several animal studies, for example, have documented that oral AOs including vitamin C,²⁴ vitamin E,²⁴ beta-carotene,²⁵ selenium,²⁶ and others play important roles in skin photoprotection.²⁷

Human interventional studies have documented these benefits as well. In one randomized controlled trial, daily tomato paste ingestion for 10 weeks resulted in improved minimal erythema doses,²⁸ while another study documented histologic improvement.²⁹ Other human intervention studies have reported benefits from dietary AOs including green tea polyphenols, cocoa flavanols, pomegranate, and others.³⁰ As detailed in an extensive review, the documented clinical, histologic, and biochemical benefits of dietary AOs have included reductions in erythema, DNA damage, markers of inflammation, extracellular matrix damage, and others.³⁰

While single nutrients (such as vitamins, minerals, and phytonutrients) may serve as AOs, a key point is that one food may provide multiple AOs. One research study evaluated the total AO capacity of over 3100 foods and found that the categories of “spices and herbs” and “herbal/traditional plant medicine” contained the most AO-rich products analyzed in the study.³¹ Berries, fruits, and vegetables also included many common foods and beverages with medium-to-high AO values.³¹

While dietary AOs may be beneficial, high-dose AO supplements have not shown benefit. In fact, some have demonstrated harm, as outlined in a later section.

Inflammation

Many research studies have delineated the role of diet in modifying the inflammatory process. For example, some phytochemicals may specifically interrupt the inflammatory pathway that activates nuclear factor-kappa beta (NF-KB), including turmeric, cloves, ginger, garlic, and others.³² This pathway impacts MMPs and collagen remodeling, and in fact researchers were able to demonstrate that compounds from garlic in a mouse model inhibited UVB-induced wrinkle formation. This was accomplished via the modulation of NF-KB, with a resulting decrease of MMPs and collagen fiber destruction.³³

Multiple studies have described the impact of dietary patterns, foods, nutrients, and compounds on inflammatory biomarkers. One review article³⁴ specifically examined research on dietary patterns affecting high sensitivity C-reactive protein (hsCRP), a marker of inflammation with demonstrated predictive value for coronary heart disease.³⁵ Multiple dietary patterns had some evidence of impact, including the Dietary Approaches to Stop Hypertension (DASH) and similar diets.³⁴

The effects of specific foods and nutrients were described in one summary analysis in which researchers looked at over 1900 studies. These evaluated the effects of foods and nutrients on six major biomarkers of inflammation. If a nutrient increased levels of IL-1B, IL-6, TNF-alpha, or CRP, or decreased levels of IL-4 or IL-10, it was considered pro-inflammatory.³⁶ Using these results, researchers developed a dietary inflammatory index that highlights anti-inflammatory foods. Some of the strongest effects were seen with foods including turmeric, green/black tea, ginger, garlic, and onion, as well as with macronutrients and micronutrients including fiber, magnesium, vitamin D, and omega-3 fatty acids.³⁶ Highly anti-inflammatory phytonutrients included flavones, isoflavones, beta-carotene, and flavonols.

The Gut Microbiome

The gut-skin axis is an area of intense research, due to the impact of the gut microbiome on inflammation and skin barrier function,^37-39 as well as features of skin aging.^40,41 While more research is needed to delineate these impacts, the gut microbiome is considered an important factor in inflammation. Diet serves as the foundation for healthy gut flora, particularly a focus on fiber-rich foods, which beneficially support the growth of good gut microbes.^42-44 Fermented and cultured foods, with beneficial live microbes, may also play a role,⁴⁵ while prebiotic and probiotic supplementation research is ongoing to determine potential efficacy as well as dosing strategies.

Foods that Impact MMPS

Collagenase and elastase play important roles in ECM remodeling, thereby contributing to loss of skin elasticity, wrinkling, and sagging. Some foods and nutrients are able to block the activity of collagenase, such as green tea, white tea, and pomegranate,⁴⁶ while inhibition of elastases was also seen with ginger⁴⁷ and spices such as turmeric, cinnamon, and nutmeg.⁴⁸ Foods with anti-inflammatory capabilities, by blocking inflammatory pathways, may also ultimately result in lower levels of MMPs, as with curcumin,⁴⁹ omega-3 fatty acids,⁵⁰ and garlic.³³

Glycation

The accumulation of AGEs within the body arises from two main sources. The first is via endogenous production in the presence of hyperglycemia. The second is via the ingestion of foods that contain preformed AGEs, also known as dietary AGEs.

Therefore, nutritional strategies to limit AGE-induced tissue damage focus on three main areas. The first is a focus on patterns, foods, and compounds that limit hyperglycemia. The second is a focus on foods and compounds that limit the biochemical processes of glycation. The third is limited ingestion of dietary AGEs. Additional strategies, as outlined previously, include a diet rich in antioxidants and anti-inflammatory foods, as these processes are closely intertwined with glycation.

Limiting Hyperglycemia

Improving glycemic control is a key strategy in limiting AGE production. In one experimental study, improved glycemic control in human volunteers over a 4-month period resulted in significantly decreased new collagen glycation.⁵⁰ In fact, a key tenet of an anti-wrinkle diet is diabetes prevention. A full review of dietary strategies to limit hyperglycemia is beyond the scope of this review, and readers are referred to comprehensive reviews on this subject.⁵¹

Strategies supported by research include a low glycemic load diet, which focuses on low glycemic index foods as well as portion sizes.^52,53 Food groups and components with demonstrated benefits include fiber, monounsaturated fatty acids, fruits, vegetables, and others.⁵¹ Eating order (with protein consumed earlier)⁵⁴ and vinegar consumption with a meal⁵⁵ have also demonstrated benefits. Specific foods that have shown promise include garlic, onions,⁵⁶ nuts,⁵⁷ turmeric,⁵⁸ cinnamon,⁴⁸ fenugreek,⁵⁹ and a number of other spices.⁶⁰

Foods and Compounds that Limit Glycation

A number of dietary compounds have demonstrated the ability to inhibit AGE biosynthesis.⁶¹ Some limit glycation via their antioxidant properties, while others act via other mechanisms, such as trapping reactive intermediate compounds.^61-63

In laboratory studies, anti-glycation properties have been demonstrated by foods such as cinnamon,⁶⁴ garlic,⁶⁵ rosemary,⁶⁶ yerba mate,⁶⁷ and tomato paste⁶⁸. One laboratory study evaluating multiple foods demonstrated significant anti-glycation activity by ginger, cumin, cinnamon, black pepper, and green tea.⁶⁹ Phytonutrients exhibiting beneficial effects include the flavonoids luteolin, quercetin, and rutin,⁷⁰ as well as the phenolic acids ferulic acid, chlorogenic acid, vanillic acid, and others⁷¹. In animal studies, curcumin has inhibited collagen cross-linking,⁷² while green tea extracts have reduced AGE formation⁷³ and inhibited collagen cross-linking⁷⁴.

In a laboratory study specifically evaluating the anti-glycation potential of polyphenols in herbs and spices, the most potent spices were cloves, allspice, and cinnamon, while potent herbs included sage, marjoram, tarragon, and rosemary.⁷⁵ The researchers noted that level of inhibition correlated with total phenolic content. Similar findings were seen in a study evaluating spices used in European cuisine, with strong activity by star anise, cinnamon, allspice, cloves, and oregano.⁷⁶

Strategies to Reduce Dietary AGEs

Dietary strategies to limit ingestion of preformed AGEs focus on three main areas. These include the type of food, cooking method, and use of ingredients that modify AGE production.

Meat products, high in fat and protein, contain some of the highest levels of dietary AGEs, and are particularly prone to developing new AGEs during cooking.⁷⁷ High-fat cheeses are also relatively high in AGEs. In contrast, carbohydrate-rich fruits, vegetables, and whole grains contain low levels.

Cooking methods have a marked impact on AGE production. Dry heat methods such as grilling, roasting, and frying can increase AGE levels by 10 to 100 times.⁷⁷ Reduction strategies include moist cooking methods such as steaming and boiling, as well as cooking for lower temperatures and for shorter times. It is noteworthy that even with cooking, foods such as fruits, vegetables, and whole grains remain relatively low in AGEs. The exception is for carbohydrate-rich foods that are also high in fat, such as biscuits.

An additional strategy is the use of ingredients such as lemon juice and vinegar prior to cooking, as these reduce the amount of AGEs ultimately produced.⁷⁷

The Role of Nutrient Supplementation

A common question in patient care centers on the use of dietary supplements, more specifically, given the link between dietary compounds and the biochemical processes that impact skin aging, is if there is a benefit to consuming supplementation either in addition to, or in place of, dietary consumption?

While a review of supplements is beyond the scope of this article, a few points must be emphasized. At this time, there is very limited evidence for benefit of nutrient supplementation beyond the treatment of deficiency states. Indeed, there is significant evidence of potential harm from some supplements.

The primary role of supplementation has always been, and continues to be, in the treatment of deficiency. Although research from deficient-state conditions is often used to justify supplementation in general, evidence is lacking for this approach.

As one example, biotin deficiency leading to hair loss may be improved with supplementation, but has not shown efficacy in hair loss overall.^78,79

In the case of AOs, supplements have not shown benefit and in some cases have shown harm. AO supplements were the subject of much research, given promising observational human studies of dietary intake as well as laboratory and animal studies. Unfortunately, multiple trials of high-dose (as opposed to dietary dose) vitamins C and E, beta-carotene, and selenium, indicated that they were not effective in non-melanoma skin cancer (NMSC) prevention.²⁷ In fact, some may even become pro-oxidant at high doses, as in a study of women exhibiting higher rates of skin cancer after use of a supplement containing vitamins C and E, beta-carotene, selenium, and zinc (with median follow-up of 7.5 years).⁸⁰ This emphasizes the point that nutrients must be at the right dose in order to provide benefits. In the case of AOs, the ideal dose appears to be physiologic doses, such as that supplied via whole foods.

This issue of short-term tolerability not necessarily equaling long-term safety is an important point to remember as researchers continue to study promising supplements. Nicotinamide has shown benefit in a sharply defined population, with a 23% reduction in new NMSC in those at high risk, and has been well-tolerated over a 1-year period.⁸¹ The herb Polypodium leucotomos has demonstrated photoprotective abilities in short-term studies, but also lacks long-term data.^82,83

In the case of other supplements, evidence is simply lacking. One review summarized published trials of collagen supplementation used for skin conditions ranging from aging skin, to wound healing, to cellulite.⁸⁴ In total, the authors found only 11 studies, some funded by the manufacturer and some lacking placebo, utilizing at least three different types of collagen at widely differing doses and duration.

Conclusion

A number of research studies have documented the link between diet and skin aging. These results may be used to develop dietary recommendations that combat the forces of oxidation, inflammation, and glycation. For those wishing to promote healthy skin aging, a diet that incorporates these strategies is recommended, with a focus on foods that are naturally rich in antioxidants, are anti-inflammatory, limit hyperglycemia, and inhibit glycation. When counseling patients, it is important to emphasize that a number of eating patterns focusing on these underlying principles (Table 1) may achieve this goal. Table 2 provides more details on dietary strategies that combat these aging processes.

Purchase Article PDF for $1.99

Related: Skin and Diet: An Update on the Role of Dietary Change as a Treatment Strategy for Skin Disease

Articles are indexed by drug names, trade names and disease terms. Bold entries refer to major references.

Purchase Article PDF for $1.99

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.

Purchase Article PDF for $1.99

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.

Purchase Article PDF for $1.99