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

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

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

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

Introduction

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

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

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

Table 1

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

Background

Mechanism of Action

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

Clinical Trials

Phase I⁸

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

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

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

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

Phase II⁸

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

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

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

Phase III¹

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

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

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

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

Safety and Tolerability

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

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

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

Regulatory Approval

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

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

Discussion

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

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

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

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

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

Conclusion

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

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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.

¹MD/MBA/MPH Candidate at Yale University, New Haven, CT, USA
²Baylor College of Medicine, Houston, TX, USA
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Pacific Dermaesthetics, Vancouver, BC, Canada

Conflict of interest:
Jason Rivers has been a consultant for Almirall; Harrison Nguyen has no conflicts to report.

Introduction

Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AK. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm2, which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most commonly reported side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patient-applied therapeutic option for the treatment of both overt and subclinical AK.

Background

• Actinic keratosis (AK) is a lesion considered to be on a continuum with squamous cell carcinoma (SCC).^1-6
• Invasive disease occurs in up to 10% of cases over time, which highlights the need for early recognition and adequate treatment of all AK, including subclinical lesions.⁷
• Although many AK never progress to SCC, their treatment has been recommended to preempt this eventuality.
• Treatment options can generally be stratified based on whether only discrete lesions are treated, or whether subclinical lesions are also targeted, which is referred to as field-directed therapy.
• Lesion-directed therapy has historically consisted of ablative and/or surgical procedures. However, several topical agents have emerged as attractive alternatives in the treatment of AK.
• Examples of topical agents available in Canada include 5-fluorouracil (5-FU), imiquimod (2.5%, 3.75%, and 5% formulations), diclofenac 3%, methylaminolevulinate/aminolevulinic acid (for photodynamic therapy), and ingenol mebutate.⁸
• In one controlled clinical trial, topical 5-FU applied to AK resulted in a 96% clearance after 4 weeks of twice daily application.9 However, high rates of severe localized tissue reactions with 5-FU have led to reduced patient compliance, and this, in part, may explain why the long-term clearance of AK in clinical practice is around 50%.⁸
• This problem has resulted in a search for therapeutic agents less likely to induce skin irritation.¹⁰
• In 2011, a topical formulation combining 0.5% 5-FU with 10% salicylic acid (5-FU-SA) was introduced to the European market under the trade name Actikerall™ for the topical treatment of grade 1/2 AK (slightly palpable and/or moderately thick hyperkeratotic lesions) in immunocompetent adult patients.^11,12 This preparation is not novel as the same agent has been used in Europe for more than 30 years in the treatment of plantar warts (Verrumal®).

In this brief review, we present some of the clinical data to support the use of 5-FU-SA in patient-directed* management of AK and we summarize the salient information that the provider should be aware of when prescribing this product.

*Health Canada has elected to classify Actikerall™ as neither lesion-directed nor field-directed. This was done to support the individual needs of patients; the locational distribution of a patient’s lesions will dictate whether a lesion-directed versus a field-directed approach is preferred.

Evidence from Clinical Trials

• The primary evidence used to support the efficacy of 5-FU-SA in the treatment of AK comes from a single randomized, multi-center, phase 3 trial.¹³ The study included 470 patients with histologically diagnosed AK on the face, forehead, or bald scalp. Subjects were randomly assigned to 5-FU-SA, diclofenac 3% gel in hyaluronic acid (diclofenac HA), or placebo (5-FU-SA vehicle). Treatment was continued until either complete resolution of the lesions was evident, or for a maximum of 12 weeks.
• Subjects were instructed to apply their assigned intervention directly to their lesions – once daily for the 5-FU-SA and vehicle groups and twice daily for the diclofenac group.
• The primary outcome – histological clearance of one defined lesion within 8 weeks of treatment cessation – was achieved in 72.0%, 59.1%, and 44.8% of patients treated with low-dose 5-FU-SA, diclofenac and placebo, respectively.
• In addition to the histological data, the rate of complete clinical clearance was also highest in the study group (55.4% vs. 32.0% and 15.1% for 5-FU-SA, diclofenac HA, and vehicle groups, respectively).¹³ Similar to the temporary lesion increase associated with other topical therapies, an ephemeral increase in mean lesion area was observed only in patients treated with 5-FU-SA at week 2.
• However, by the end of the treatment period, reduction in mean lesion area was more evident in the study medication group compared to the comparator and placebo groups.
• In a more recent non-interventional study, a reduction in number and size of AK after 0.5% 5-FU-SA therapy was observed even after a short period of use: target results were achieved in approximately half of patients within 6 weeks of treatment commencement.¹⁵
• Another study assessed the efficacy of low-dose 5-FU-SA versus cryosurgery in patients with grade II/III hyperkeratotic AK.¹⁶ In this open labelled, randomized trial, patients with histologically confirmed AK received either a 6-week course of once daily topical 5-FU-SA applied directly to lesions or up to two cryosurgical treatments spaced 3 weeks apart.
• 5-FU-SA achieved greater histological clearance as measured by mean lesion area and lower recurrence of lesions compared to cryosurgery at the 6-month follow-up.

Adverse Effects

• In the phase 3 mentioned above¹³, about 95% of patients in the study medication group reported treatment-emergent adverse effects (TEAEs), with local inflammation and pruritus at the application site being the most common.
• Approximately 60% of patients in the vehicle group also reported application site burning, suggesting the etiology of this sensation was likely related to dimethyl sulfoxide, which facilitates tissue absorption and is a known irritant present in the 5-FU-SA excipients.
• For patients who have difficulty tolerating the side effects, dosing can be reduced from daily applications to treatment three times a week.
• In spite of the relatively high rate of TEAEs, patients have reported a high level of satisfaction with the use of low-dose 5-FU-SA.¹⁵
• No serious adverse effects directly related to 5-FU-SA treatment, including usage as Verrumal® for warts, have been reported in either clinical studies or post-marketing surveillance.

Dosing and Administration

• Actikerall™ is a transparent, colorless to slightly orange-white solution that is packaged in 25 mL glass bottles, accompanied by a nylon brush that allows for easy application. It is recommended for application once daily to a total area of up to 25 cm2, which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks (Table 1).

• If the lesions are located in areas with thin epidermis, the solution may be applied less frequently (e.g., 3 times per week).
• The solution should be allowed to dry on the skin but prior to re-application on subsequent days, the existing film should be peeled off, which can be facilitated by using warm water.
• A significant reduction in lesions is usually seen within 6 weeks of starting treatment, and patients most likely to benefit from the full 12-week course are those who have failed previous treatments with other modalities.¹⁵
• Patients should be advised that lesions may continue to regress for up to 8 weeks after cessation of therapy.
• 5-FU-SA is contraindicated for use during lactation or pregnancy. Other contraindications include renal insufficiency and concurrent usage of brivudine, sorivudine, or similar analogues. Of note, although these agents are structurally similar to acyclovir, which does not inhibit dihydropyrimidine dehydrogenase to any significant extent and is therefore safe to administer concurrently with 5-FU-SA.
• Additionally, instances of phenytoin toxicity related to the concurrent use of topical 5-FU-SA have been reported, so these patients should be tested at monthly intervals for plasma levels of phenytoin when this combination of therapies exists.¹¹
• 5-FU-SA should not be applied on bleeding lesions and has not been evaluated for the treatment of recurrent lesions.
• Patients should be educated on FU-SA’s flammability, propensity to desiccate quickly (the bottle needs to be closed tightly after use and it should be discarded if crystallization occurs), and ability to cause permanent stains on textiles and acrylics.

Conclusion

5-FU-SA represents a new addition to our treatment of AK, especially
for individuals who want to avoid the pain or potential consequences
associated with destructive therapy for isolated lesions. An emerging
role for 5-FU-SA may be in combination therapy with other agents
that have been unsuccessful in clearing hyperkeratotic lesions in the
treatment zone.

References

1. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988 Apr 9;1(8589):795-7.
2. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):11-7.
3. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg. 2006 Oct;32(10):1261-5.
4. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol. 2006 Jul-Aug;16(4):335-9.
5. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007 Sep;33(9):1099-101.
6. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30.
7. Stockfleth E, Ortonne JP, Alomar A. Actinic Keratosis and field cancerisation. Eur J Dermatol. 2011 Feb; 21(Suppl 1):3-12.
8. Samrao A, Cockerell CJ. Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. Am J Clin Dermatol. 2013 Aug;14(4):273-7.
9. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2:34-40.
10. Perl M, Goldenberg G. Field therapy in the treatment of actinic keratosis. Cutis. 2014 Apr;93(4):172-3.
11. The electronic Medicines Compendium (eMC). Actikerall 5mg/g and 100mg/g cutaneous solution. Summary of product characteristics. Almirall Limited, Uxbridge, Middlesex, UK. Last updated June 4, 2014.
12. Olsen EA, Abernethy ML, Kulp-Shorten C, et al. A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J Am Acad Dermatol. 1991 May;24(5 Pt 1):738-43.
13. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011 Nov;165(5):1101-8.
14. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queensland community. J Invest Dermatol. 2000 Aug;115(2):273-7.
15. Szeimies RM, Dirschka T, Prechtl A, et al. Efficacy of low-dose 5-fluorouracil/salicylic acid in actinic keratoses in relation to treatment duration. J Dtsch Dermatol Ges. 2015 May;13(5):430-8.
16. Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015 May;29(5):881-9.

¹MD/MBA/MPH Candidate at Yale University, New Haven, CT, USA;
²Baylor College of Medicine, Houston, TX, USA
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Pacific Dermaesthetics, Vancouver, BC, Canada

Conflict of interest:
Jason Rivers has been a consultant for Almirall; Harrison Nguyen has no conflicts to report.

ABSTRACT
Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AKs. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm², which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most common side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patient applied therapeutic option for the treatment of both overt and subclinical AKs.

Key Words:
Actikerall, actinic keratosis, antineoplastic antimetabolite, drug combinations, immunosuppressive agents, keratolytic agents, salicylic acid, skin neoplasms, topical therapy

Introduction

Actinic keratosis (AK) is a lesion considered to be on a continuum with squamous cell carcinoma (SCC).^1-6 Invasive disease occurs in up to 10% of cases over time, which highlights the need for early recognition and adequate treatment of all AKs, including subclinical lesions.⁷ Although many AKs never progress to SCC, their treatment has been recommended to preempt this eventuality.

Treatment options can generally be stratified based on whether only discrete lesions are treated, or whether subclinical lesions are also targeted, which is referred to as eld-directed therapy. Lesion-directed therapy has historically consisted of ablative and/or surgical procedures. However, several topical agents have emerged as attractive alternatives in the treatment of AKs. Examples of topical agents available in Canada and/or the United States include 5- fluorouracil (5-FU), imiquimod (2.5%, 3.75%, and 5% formulations), diclofenac 3%, methylaminolevulinate/ aminolevulinic acid (for photodynamic therapy), and ingenol mebutate.⁸

In one controlled clinical trial, topical 5-FU applied to AKs resulted in 96% clearance after 4 weeks of twice daily application.⁹ However, high rates of severe localized tissue reactions with 5-FU have led to reduced patient compliance, and this, in part, may explain why the long-term clearance of AKs in clinical practice is around 50%.⁸ This problem has resulted in a search for therapeutic agents less likely to induce skin irritation.¹⁰ In 2011, a topical formulation combining 0.5% 5-FU with 10% salicylic acid (5-FU-SA) was introduced to the European market under the trade name Actikerall™ for the topical treatment of grade I/II AKs (slightly palpable and/or moderately thick hyperkeratotic lesions) in immunocompetent adult patients.^11,12 This preparation is not novel as the same agent has been used in Europe for more than 30 years in the treatment of plantar warts (Verrumal®).

Functionally, 5-FU is a pyrimidine analogue that inhibits nucleic acid synthesis and its efficacy is thought to be enhanced by the addition of salicylic acid, a keratolytic agent that facilitates penetration of 5-FU into AKs.¹³ In this brief review, we present some of the clinical data to support the use of 5-FU-SA in patient-directed* management of AKs and we summarize the salient information that the provider should be aware of when prescribing this product.

^{*Health Canada has elected to classify Actikerall™ as neither lesion-directed nor field-directed. This was done to support the individual needs of patients; the locational distribution of a patient’s lesions will dictate whether a lesion-directed versus a field-directed approach is preferred.}

Evidence from Clinical Trials

The primary evidence used to support the efficacy of 5-FU-SA in the treatment of AKs comes from a single randomized, multi- center, phase III trial.¹⁴ The study included 470 patients with histologically diagnosed AK on the face, forehead, or bald scalp. Subjects were randomly assigned to 5-FU-SA, diclofenac 3% gel in hyaluronic acid (diclofenac HA), or placebo (5-FU-SA vehicle) and treatment was continued until complete resolution of the lesions, or for a maximum of 12 weeks. Subjects were instructed to apply their assigned intervention directly to the lesions – once daily for the 5-FU-SA and vehicle groups, and twice daily for the diclofenac group. The primary outcome – histological clearance of one defined lesion within 8 weeks of treatment cessation – was achieved in 72.0%, 59.1%, and 44.8% of patients treated with low- dose 5-FU-SA, diclofenac and placebo, respectively. Of note, up to 25% of untreated AKs may regress spontaneously over a 1 year period,¹⁵ and therefore, this phenomenon does not fully explain the high rate of clearance noted in the aforementioned study’s placebo group.

In addition to the histological data, the rate of complete clinical clearance was also highest in the study group (55.4% vs. 32.0% and 15.1% for 5-FU-SA, diclofenac HA, and vehicle groups, respectively).¹⁴ Similar to the temporary lesion increase associated with other topical therapies, an ephemeral increase in mean lesion area was observed only in patients treated with 5-FU-SA at week 2. However, by the end of the treatment period, reduction in mean lesion area was more evident in the study medication group compared to the comparator and placebo groups (355.9 mm², 345.7 mm², and 341.4 mm², respectively). In a more recent non- interventional study, the reduction in number and size of AKs after 0.5% 5-FU-SA therapy was observed even after a short period of use: target results were achieved in approximately half of patients within 6 weeks of treatment commencement.¹⁶

Another study assessed the efficacy of low-dose 5-FU-SA versus cryosurgery in patients with grade II/III hyperkeratotic AKs.¹⁷ In this open labelled, randomized trial, patients with histologically con rmed AK received either a 6-week course of once daily topical 5-FU-SA applied directly to lesions or up to two cryosurgical treatments spaced 3 weeks apart. Although the sample size (33 per treatment arm) was not powered to draw statistically significant conclusions, 5-FU-SA achieved greater histological clearance as measured by mean lesion area and lower recurrence of lesions compared to cryosurgery at the 6-month follow-up.

Non-invasive assessment using reflectance confocal microscopy and high-definition optical coherence tomography has provided insight into the in vivo pharmacodynamic changes induced by 5-FU-SA. In one study, AKs were assessed 2 weeks after the last treatment with 5-FU-SA, and the measurement of stratum corneum and epidermis thickness showed significant reduction in both clinical and subclinical lesions.¹⁸ Moreover, histological characteristics of AK – including scaling, detached corneocytes, atypical honeycombing, round nucleated cells in the spinosum granulosum, round vessels, and inflammatory cells were all markedly reduced in lesions treated with 5-FU-SA.¹⁸

Unlike 5-FU alone, there have been no studies to assess 5-FU- SA’s ability to treat superficial basal cell carcinoma or Bowen’s disease.¹⁹

Adverse Effects

In the first trial mentioned above,¹⁴ 7.4% (35/470) of patients withdrew from the study prematurely: 14 patients from the 5-FU-SA group, 16 patients from the diclofenac group, and 5 patients from the vehicle group. About 95% of patients in the study medication group reported treatment-emergent adverse effects (TEAEs), with local inflammation and pruritus at the application site being the most common. Approximately 60% of patients in the vehicle group also reported application site burning, suggesting the etiology of this sensation was likely related to dimethyl sulfoxide, which facilitates tissue absorption and is a known irritant present in the 5-FU-SA excipients. For patients who have difficulty tolerating the side effects, dosing can be reduced from daily application to treatment 3 times a week. In spite of the relatively high rate of TEAEs, patients have reported a high level of satisfaction with the use of low-dose 5-FU-SA.¹⁶ No serious adverse effects directly related to 5-FU-SA treatment, including usage as Verrumal® for warts, have been reported in either clinical studies or post-marketing surveillance.

Dosing and Administration

Actikerall™ is a transparent, colorless to slightly orange-white solution packaged in 25 mL glass bottles, accompanied by a nylon brush that allows for easy application. 5-FU-SA is recommended for application once daily to a total area of up to 25 cm², which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks (Table 1). However, if the patient has lesions in areas with thin epidermis, the solution may be applied less frequently (e.g., 3 times per week). To avoid excess application, the brush can be wiped on the neck of the bottle. The solution should be allowed to dry on the skin but prior to re-application on subsequent days, the existing film should be peeled off, which can be facilitated by using warm water.

As noted, significant reduction in the lesion count is usually
observed within 6 weeks of starting treatment, and patients most
likely to benefit from the full 12-week course are those who have
failed previous therapy with other modalities.¹⁶ Patients should be advised that lesions may continue to regress for up to 8 weeks after cessation of therapy.

The use of 5-FU-SA in areas other than the face and scalp has
only been reported in the setting of small case series. In one
publication,²¹ two patients with multiple AKs on the dorsal aspect of the hands achieved complete clearance after sequential treatment with diclofenac 3% gel and 5-FU-SA. A notable observation has been a lower therapeutic response of AKs located on the upper extremities compared to lesions on the face and scalp.¹⁶ This finding has also been observed with photodynamic therapy, ingenol mebutate and other topical agents used to treat AKs. Although the reason for this observation remains poorly understood, one hypothesis is that increased skin thickness in the upper extremities restricts drug absorption, thus limiting its therapeutic efficacy.²²

5-FU-SA is contraindicated for use during lactation or pregnancy.
Other contraindications include renal insufficiency and
concurrent usage of brivudine, sorivudine, or similar analogues.
The latter consideration is related to the ability of these agents to inhibit the enzyme dihydropyrimidine dehydrogenase, which plays a critical role in breakdown of fluorouracil.²³ Of note, although these agents are structurally similar to acyclovir, the latter drug does not inhibit dihydropyrimidine dehydrogenase to any significant extent and is therefore safe to administer concurrently with 5-FU-SA. Additionally, instances of phenytoin toxicity related to the concurrent use of topical 5-FU-SA have been reported, so these patients should be tested at monthly intervals for plasma levels of phenytoin when this combination of therapies exists.¹¹ 5-FU-SA should not be applied on bleeding lesions and has not been evaluated for the treatment of recurrent lesions. With regards to user experience and safety, the patient should be educated on the solution’s flammability, propensity to desiccate quickly (the bottle needs to be closed tightly after use and it should be discarded if crystallization occurs), and ability to cause permanent stains on textiles and acrylics

Cipher Pharmaceuticals, which owns the rights to Actikerall™ in Canada, has indicated that each bottle will be sold for a
wholesale price of $36.25.²⁴ Commercial availability commenced in February 2016.

Conclusion

5-FU-SA represents a new addition to our treatment of AK,
especially for individuals who want to avoid the pain or potential consequences associated with destructive therapy for isolated lesions. An emerging role for 5-FU-SA may be in combination therapy with other agents that have been unsuccessful in clearing hyperkeratotic lesions in the treatment zone.

References

1. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988 Apr 9;1(8589):795-7.
2. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):11-7.
3. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg. 2006 Oct;32(10):1261-5.
4. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol. 2006 Jul-Aug;16(4):335-9.
5. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007 Sep;33(9):1099-101.
6. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30.
7. Stockfleth E, Ortonne JP, Alomar A. Actinic Keratosis and field cancerisation. Eur J Dermatol. 2011 Feb; 21(Suppl 1):3-12.
8. Samrao A, Cockerell CJ. Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. Am J Clin Dermatol. 2013 Aug;14(4):273-7.
9. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2: 34-40.
10. Perl M, Goldenberg G. Field therapy in the treatment of actinic keratosis. Cutis. 2014 Apr;93(4):172-3.
11. The electronic Medicines Compendium (eMC). Actikerall 5mg/g and 100mg/g cutaneous solution. Summary of product characteristics. Almirall Limited, Uxbridge, Middlesex, UK. Last updated June 4, 2014. Available at: https://www. medicines.org.uk/emc/medicine/24614. Accessed April 3, 2016.
12. Olsen EA, Abernethy ML, Kulp-Shorten C, et al. A double-blind, vehiclecontrolled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J Am Acad Dermatol. 1991 May;24(5 Pt 1): 738-43.
13. Ceilley RI. Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders. J Dermatolog Treat. 2012 Apr;23(2):83-9.
14. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011 Nov;165(5):1101-8.
15. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest Dermatol. 2000 Aug;115(2):273-7.
16. Szeimies RM, Dirschka T, Prechtl A, et al. Efficacy of low-dose 5-fluorouracil/salicylic acid in actinic keratoses in relation to treatment duration. J Dtsch Dermatol Ges. 2015 May;13(5):430-8.
17. Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015 May;29(5):881-9.
18. Malvehy J, Alarcon I, Montoya J, et al. Treatment monitoring of 0.5% 5-fluorouracil and 10% salicylic acid in clinical and subclinical actinic keratoses with the combination of optical coherence tomography and reflectance confocal microscopy. J Eur Acad Dermatol Venereol. 2016 Feb;30(2):258-65.
19. Metterle L, Nelson C, Patel N. Intralesional 5-fluorouracil (FU) as a treatment for nonmelanoma skin cancer (NMSC): A review. J Am Acad Dermatol. 2016 Mar;74(3):552-7.
20. Actikerall™: fluorouracil and salicylic acid solution (0.5%/10%) topical antineoplastic agent [Product monograph]; August 7, 2015. Cipher Pharmaceuticals Inc., Mississauga, ON.
21. Dirschka T, Lear JT. Sequential treatment of multiple actinic keratoses with solaraze and actikerall. Case Rep Dermatol. 2014 May;6(2):164-8.
22. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012 Mar 15;366(11):1010-9.
23. De Clercq E. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem Pharmacol. 2004 Dec 15;68(12):2301-15.
24. Markowitz L. Personal communication. January 18, 2016.

¹Faculty of Medicine, University of Alberta, Edmonton, AB
²Division of Dermatology & Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
³Toronto Dermatology Centre, Toronto, ON

Introduction

Actinic keratosis (AK) is a prevalent skin condition that warrants 5.2 million office visits in the US each year.¹ Strongly associated with ultraviolet (UV) exposure, AK is widely regarded as a premalignant condition that can progress to squamous cell carcinoma (SCC).^2-8 Data regarding the risk of progression to malignant disease ranges from 0.025% to 16% per year.⁷ Prevalence of AK has been reported to be as high as 38% and 46% in certain Dutch and Australian communities respectively.^9,10 Given the prevalence and risk of progression to invasive disease, general consensus is that treatment and prevention^11-14 of AK in a timely manner is important in reducing the incidence of non-melanoma skin cancer. Studies have shown that a large proportion of SCC lesions arise from pre-existing AK.^4,5,15

Presentation & Diagnosis of AK

• AK is characterized by abnormal proliferation of keratinocytes that have large and variably shaped nuclei, found in the basal cell layer of the epidermis.¹²
• It typically presents as pink-red dry, rough, scaly papules or plaques measuring a few millimetres in diameter to no larger than 1 cm.^12,16
• Lesions can sometimes be sensitive.
• AK is found more commonly on areas of the body exposed to the sun, such as the face, upper chest, and dorsal surface of the arms and hands.¹²
• Diagnosis is typically made on a clinical basis but one study demonstrated high sensitivity and specificity (95.6% and 95% respectively) with use of dermoscopy.¹¹
• The differential diagnosis for AK includes SCC, Bowen’s disease, basal cell carcinoma (BCC), and lentigo maligna melanoma.¹²
• Many risk factors have been linked to the development of AK, most notably sun exposure, fair skin, male gender, and older age.^9,17-19
• UV radiation from the sun is damaging to skin DNA and has been directly implicated in the pathogenesis of AK.
• UV radiation hampers the natural immune response and increases immunosuppression, ultimately increasing the risk of SCC.²⁰ Therefore, sunscreen use as well as clothing, hats and sunglasses have long been encouraged as a preventative measure against AK.¹⁴

Overview of Treatment Options

Treatment for AK can be divided into two categories:

1. Targeted (local) therapy
2. Field therapy

Targeted Therapy

• Examples of targeted treatment include cryotherapy with liquid nitrogen and curettage with electrodessication.
• One limitation is that only a small number of lesions can be treated at once.
• Additionally, because subclinical changes can occur to the DNA of skin (also known as field cancerization²⁰), targeted therapy is not ideal for extensive UV-damaged skin.²

Field Therapy

• Field therapy can address both clinically apparent as well as occult disease.
• It encompasses topical treatments such as 5-fluorouracil, imiquimod, ingenol mebutate, and diclofenac sodium gel.
• Although many of the field therapies have been shown to be highly efficacious, targeted therapy (specifically cryosurgery) continues to be the mainstay first-line treatment for AK.
• There is a growing literature to show that a combination of targeted and field therapy has an advantage over either of the therapies as standalone.¹²

Local Treatments

Cryotherapy Treatment Regimen:

1. One freeze-thaw cycle, 5-15 seconds, and 1mm margin.²¹

Overview

• Cryotherapy is a widely used treatment option that involves cold temperature to physically destroy cells of skin lesions.
• It is one of the most commonly used treatments for AK.22,23
• Liquid nitrogen is sprayed onto the lesion, bringing the skin to a temperature where cell death occurs. Early studies suggested that temperatures of -30°C to -40°C were needed to kill keratinocytes.²¹ However, more recent studies have demonstrated good clearance with a temperature of -5°C.²⁴
• Cryotherapy has been shown to be both highly efficacious and tolerable but the range of clearance rates varies significantly (39-100%^24,25). Another study demonstrated a complete clearance rate of 75% at 3 months.²⁶
• The duration of freezing likely has an effect on the response to treatment.²⁵
• Side effects include hypopigmentation, erythema, crusting, blistering, and ulceration.²⁴
• As a stand-alone therapy, cryotherapy is better suited for disease that involves only a small number of lesions. When combined sequentially with a field-directed treatment, AK lesion clearance increases and recurrence diminishes.^27-30

Curettage with Electrodessication

• Curettage and electrodessication involve the scraping down of an AK lesion followed by electrocautery
• This procedure is often reserved for hypertrophic AK and has the potential for scarring.³¹
• Curettage can also be performed on hypertrophic lesions prior to administration of a field-therapy such as photodynamic therapy, which is better suited for superficial lesions.

Field-Directed Treatments

Imiquimod Treatment Regimens:

1. Imiquimod 5% cream (Aldara®): Treatment should be limited to areas ≤25 cm² ; apply twice weekly for 16 weeks. Apply at bed-time and leave on skin for approximately 8 hours, then remove with soap and water.
2. Imiquimod 3.75% cream (Zyclara®): Treatment is indicated for a surface area of up to 200 cm².³² Apply once daily for 2 weeks, then 2 weeks off, then daily for 2 more weeks. Apply at bed-time and leave on skin for approximately 8 hours, then remove with soap and water. Treatment holidays of several days are possible with this formulation, allowing for the management of any possible skin reactions.
3. Imiquimod 3.75% solution is also available in a pump formulation for easier dispensing and improved adherence.

Overview

• Imiquimod is an immunomodulator that has been shown to stimulate immune function by inducing cytokine expression, particularly interferon-α (IFN-α), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α).³³ Consequently, this topical agent exhibits both antitumor and antiviral effects.
• Imiquimod 5% cream was initially approved for use in Human papillomavirus genital warts in Canada in 1999, and was approved for treatment of AK in 2004.
• Numerous studies have shown that imiquimod is both efficacious and tolerable.^34-37
• Results from two randomized control trials demonstrated a mean initial reduction of AK lesions of 83%.³⁷
• Because AK lesions have a high recurrence rate, researchers have also performed longitudinal studies to look at sustained clearance rates. One study demonstrated that imiquimod has both a high initial clearance rate (85%) as well as sustained clearance rate at 1 year (73%).³⁶
• Several studies also show added benefit when imiquimod is combined with another therapy. When preceded by phototherapy, better clinical as well as histological outcomes are achieved.³⁶
• Additionally, imiquimod combined with cryotherapy is more effective in treating hypertrophic AK compared to cryotherapy alone.²⁸
• Common side effects of imiquimod therapy include erythema, crusting and dryness.³⁷
• Patients receiving imiquimod are generally satisfied with the outcome.³⁵

5-Fluorouracil Treatment Regimens:

1. Efudex®: apply to lesions twice daily for 2-4 weeks; complete healing may not be evident for 1-2 months following treatment.
2. Fluoroplex®: apply to lesions twice daily for 2-6 weeks.

Overview

• 5-fluorouracil (5FU) is an antimetabolite drug used as chemotherapy for treatment of colorectal cancer.³⁹
• 5FU is taken up by cells as if it were uracil. Its active metabolites are subsequently incorporated into DNA and RNA, thereby disrupting replication and causing cell destruction.
• Besides its role in cancer treatment, 5FU has been used for many years in treating dermatological conditions, including AK, warts, keratoacanthoma, and SCC.⁴⁰
• 5FU has been shown to significantly reduce AK lesions initially but is less effective in long-term clearance. One study found that 5FU resulted in a reduction of AK lesions by 83% and a sustained clearance rate of 53% after one month.⁴¹ Another study showed a very high initial clearance rate (96%) but much lower sustained clearance rate (54%) at one year follow-up.³⁸
• Like other field therapies, 5FU is more effective and results in lower recurrence rates when combined with targeted therapy such as cryotherapy.²⁷
• Common nuisance side effects include erythema, burning, and eye irritation.⁴¹ Despite these side effects, discontinuation rates are low.⁴²

Ingenol Mebutate Treatment Regimens:⁴²

1. Ingenol mebutate gel (Picato®) 0.015% for face and scalp: apply to affected area once daily for 3 consecutive days.
2. Ingenol mebutate gel (Picato®) 0.05% for trunk and extremities: apply to affected area once daily for 2 consecutive days.

Overview

• Ingenol mebutate is indicated for a 25 cm² contiguous field.⁴⁷
• Ingenol mebutate is the naturally occurring active substance found in the sap of Euphorbia peplus. This plant has been used for many decades in Australia as a natural remedy for AK, and early subjective reports on its use indicate good outcomes.⁴⁴
• Ingenol mebutate is the newest field therapy. The short duration of application lasting 2 or 3 days is appealing, however patient response can be brisk and may last for 2 weeks, although it typically peaks at day 4.^44,46
• The quick action of ingenol mebutate is thought to arise because of two simultaneous mechanisms of action: direct cytotoxicity leading to cell death and activation of a neutrophil-mediated inflammatory response.⁴⁶
• Results of two phase II and III trials have demonstrated promise.^45,47,48 Pooled analysis of the two phase III trials show a complete clearance of 42% on the face and scalp and 34% on the trunk and extremities. In a long-term follow-up study at 1 year, lesion clearance rates were approximately 87% for the face, scalp, trunk or extremities.⁴⁹ Further lesions either developed or recurred in the treated field in 53.9% of patients. Skin reactions of up to 2 weeks were generally mild to moderate, and the most common side effects were erythema, dryness, and flaking.⁴⁷

Diclofenac Sodium 3% Gel Treatment Regimen:

1. Diclofenac sodium 3% (Solaraze® gel): apply to affected area twice daily for 60-90 days.

Overview

• Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) widely used for its analgesic properties.
• It is a non-selective cyclooxygenase (COX) inhibitor which also exhibits antitumor effects, given that COX-2 has been implicated in keratinocyte proliferation.^50,51
• Diclofenac has also been shown to induce apoptosis via death receptor signalling.⁵²
• A number of studies have demonstrated that diclofenac is a well-tolerated and effective field therapy for AK.^53-55
• One study showed no difference in efficacy between topical diclofenac 3% sodium and imiquimod 5%.⁵³
• Another study comparing diclofenac with imiquimod demonstrated similar clearance rates between the two drugs but recurrence occurred quicker following diclofenac treatment.⁵⁴
• As is the case with other field therapy options, diclofenac used sequentially with cryotherapy increases clearance rates as well as decreases recurrence rates.^29,30
• Side effects are usually tolerable and may include dryness, itchiness and erythema.^53,55

Photodynamic Therapy (PDT)

Treatment procedure:

1. Prior to PDT: curettage of hypertrophic AK or acetone scrubs or microdermabrasion.
2. Apply methyl-aminolevulinate (MAL) (Metvix®) or 5-aminolevulinic acid (ALA), 1mm thick, 10-15mm margins.
3. Allow 1-3 hours for MAL/ALA to penetrate.
4. Remove MAL / ALA.
5. Illuminate with blue or red light emitting diode, or use other laser/light sources or even daylight activation for MAL.

Overview

• PDT uses a combination of a topical photosensitizer, such as ALA or MAL, and a light source to treat AK lesions. These photosensitizers are converted to protoporphyrin IX (PpIX), which then induce apoptosis and necrosis.^56,57
• PDT has been shown to be similar in efficacy to cryotherapy.⁵⁸
• One of the drawbacks of PDT is that its use is limited to superficial lesions and is less effective in hypertrophic AK.⁵⁹
• The most common side effects are erythema, edema and crusting.⁶⁰
• The procedure can be painful for patients, but spraying cold water on the treatment site has been shown to improve tolerability.⁵⁶ Otherwise, PDT is quite well tolerated and results in good cosmetic outcome with minimal downtime.

Conclusion

AK is a premalignant skin condition that should be identified and treated promptly. Untreated AKs can lead to SCC. There are many treatment options that all have comparable efficacy. Cryosurgery is often first-line therapy for disease with a small number of lesions. Field-directed therapy is recommended when the skin is extensively photodamaged or there are many AK lesions or frequent AK recurrences. Combining a local treatment such as cryotherapy with a topical agent has been shown to be more effective than either therapy alone.

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57. Nakaseko H, et al. Br J Dermatol. 2003;148(1):122-127.
58. Morton C, et al. Br J Dermatol. 2006;155(5):1029-1036.
59. Wiegell SR, et al. Br J Dermatol. 2012;166(6):1327-1332.
60. Dragieva G, et al. Br J Dermatol. 2004;151(1):196-200.

ERRATA

In the adapted version “Ceramide-based Moisturizers as Treatment for Pediatric Atopic Dermatitis” published in the May 2013 issue of Skin Therapy Letter (Family Practice Edition) by Dušan Sajic, MD, PhD and Sandy Skotnicki-Grant, MD, FRCPC, the following correction should be made:

On page 3, left column, under Other Non-steroidal Barrier Repair Products, the second bullet should read “Similar findings were seen in another recent study that demonstrated non-superiority of topical pimecrolimus when compared to a prescription medical device cream containing a combination of OTC components, suggesting that correction of numerous epidermal barrier derangements may be an effective way of controlling AD.¹⁴“

Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

Actinic keratoses (AKs), or solar keratoses, are pre-malignant cutaneous lesions that predominantly manifest in sun-exposed areas. They are one of the most common skin conditions seen by dermatologists, preceded only by acne vulgaris and dermatitis.¹ AKs are clinically relevant lesions due to their potential to evolve into invasive squamous cell carcinoma (SCC).² Additionally, they are considered a risk factor for the subsequent development of melanoma and non-melanoma skin cancer. There are numerous treatments available for managing AKs including those broadly categorized as destructive, topical field, and procedural field therapies. The recent introduction of imiquimod 3.75%, approved for the treatment AKs on the face and scalp, widens the therapeutic arsenal.

Prevalence and Risk Factors

• In the northern hemisphere, it is estimated that between 11-25% of adults have at least one AK.³
• These lesions are most commonly seen in the older fair-skinned population or in individuals classified under Fitzpatrick skin phototypes I-III.
• Cumulative ultraviolet (UV) radiation exposure and older age are the most important contributing risk factors.
• Immunocompromised individuals or those with certain genetic syndromes (e.g., xeroderma pigmentosum and albinism) are at greater risk.

Pathogenesis

• UV radiation is involved in the pathogenesis of AKs through inducing cellular DNA mutations in the skin, which may affect cell proliferation genes (e.g., p53 and ras) or prompt evasion of apoptosis.2
• Disruption of one of these genes may lead to formation of atypical keratinocytes in the basal layer and development of an AK; all of these histopathologic changes are limited to the epidermis.
• The absence of further UV light exposure may result in resolution through inherent repair mechanisms. However, additional UV light exposure may induce further DNA mutations resulting in the development of invasive SCC.

Diagnostic Features

• AKs typically manifest as small (1-3mm), erythematous, scaly papules with a hyperkeratotic texture.
• They are best identified with touch rather than visual inspection alone.
• AKs are characteristically distributed in sun-exposed areas, including the face, bald scalp, ears, neck, anterior chest, dorsal forearms, and dorsal hands. Surrounding areas may show evidence of solar elastosis (e.g., telangiectasia, blotchy hyperpigmentation, and yellow discolouration of the skin).⁴
• The clinical variants of AKs include the cutaneous horn, lichen planus-like keratosis, pigmented actinic keratosis, and actinic cheilitis.^4,5
• The natural history of AKs is variable and unpredictable; a lesion can follow one of three paths: it can persist, regress, or transform into an invasive SCC.
• It is impossible to predict which path any given AK may take.
• The risk of a single lesion progressing from an AK to a SCC ranges from 0.025-16% per year.⁶
• Over several years, these lesions can progress, becoming thicker and developing into a hypertrophic AK, Bowen’s disease (SCC in situ), or an invasive SCC.
• The stages of this biologic continuum are clinically indistinguishable, therefore, a biopsy should be performed if a SCC is suspected.
• A presentation that includes pain, pruritus, induration, larger size, rapid growth, ulceration, bleeding, or resistance to treatment may point towards a more sinister pathology (i.e., SCC).^4,5

Treatment Overview

It is recommended that all AKs be treated, as there are no reliable clinical predictors to discern an AK from a SCC. If a SCC is missed, it may become locally invasive and destructive; these lesions are capable of metastases, resulting in death. Therapeutic choices are guided by efficacy, adverse effects, cosmetic results, and patient adherence.

Destructive Therapy

The most common therapies for individual AKs work destructively by physically removing the lesion. These modalities should be considered first-line for isolated lesions or early presentations of AKs. Destructive therapies include liquid nitrogen cryotherapy, curettage with or without electrodessication, and shave excision. The main advantages of these procedures are that they are quick, procedurally simple, and provide adequate clearance of abnormal tissue.

Cryotherapy

Cryotherapy is the most frequently utilized technique, with liquid nitrogen being the most commonly applied cryogen. Applying cryotherapy to the affected area lowers the skin to temperatures that destroy atypical AK cells.⁷

• This technique is ideal if lesions are scattered, limited in number, or for patients who are nonadherent to topical regimes.⁷
• Reported cure rates range from 39-83%.⁸
• Treatments are generally well-tolerated and do not require local anesthetic, but the procedure can be painful and result in permanent hypopigmentation.
• Potential side-effects include blisters, scarring, textural skin changes, infection, and hyperpigmentation.

Curettage and Shave Excision

Curettage consists of using a curette to mechanically remove atypical cells. A shave excision using a surgical blade is another technique. These may be followed by electrocautery, which will destroy additional atypical cell layers, as well as provide hemostasis.

• These techniques are most appropriate for treating individual AKs, cases where a biopsy is required to rule out frank carcinoma, or for hypertrophic AKs that are refractory to other treatments.
• Potential side-effects include infection, scarring, and dyspigmentation, as well as anesthetic related side-effects.

Topical Field Therapy

Commonly, physicians are faced with patients who are covered in actinic damage, a clinical scenario now described as field cancerization, which includes both clinical and subclinical lesions within a given anatomical region.9 For these patients, a different therapeutic approach, known as field therapy, is needed for the clearance of both clinically visible and subclinical AKs within the treatment area.

Topical 5-fluorouracil (5-FU)

The antimetabolite 5-FU was the first approved agent for topical field therapy. Discovered serendipitously whenAKs were noted to become inflamed and subsequently resolved in patients receiving systemic 5-FU as a chemotherapeutic agent; it was eventually designed into an effective topical formulation. It acts as a thymidylate synthase inhibitor by blocking a methylation reaction, which in turn disrupts DNA and RNA synthesis and effectively stops the growth of the rapidly proliferating or cancerous cells.10 As such, 5-FU preferentially targets the atypical cells over normal skin tissue.

• The average cure rate is 62.5%,11 but for optimal results full patient adherence is necessary. Recommended dosing is twice-daily for 3 weeks.
• There is evidence showing concurrent treatment with topical tretinoin enhances the effectiveness of 5-FU.¹²
• It is common for all patients undergoing successful treatment with 5-FU to experience inflammation, erythema, and erosions.
• Common side-effects include pain, pruritus, photo- sensitivity, and burning at the site of application.
• 5-FU can worsen preexisting cutaneous conditions (e.g., melasma or acne rosacea), as such, use should be avoided in these patients.⁷

Diclofenac

Diclofenac 3% gel is a nonsteroidal anti-inflammatory drug, which is believed to exert its effects through the inhibition of cyclooxygenase (COX), especially COX-2. The production of prostaglandins is thought to suppress the immune system, thereby allowing tumours to form.¹³ Without COX, prostaglandin production is reduced and the cascade is disrupted.¹³

• Despite the more rigorous treatment regimen (twice daily for 90 days), only mild to moderate local skin reactions are noted.
• Though rare, drug-induced hepatotoxicity reports have surfaced, consequently transaminases should be measured periodically in patients on long-term therapy.

Imiquimod

Topical 5% imiquimod cream was originally indicated as a treatment for genital and perianal warts; additional approved indications for treating AKs and superficial basal cell carcinomas followed. It is used off-label for Bowen’s disease, invasive SCC, lentigo maligna, molluscum contagiosum, keloid scars, and others.¹⁴ Imiquimod acts as a toll-like receptor-7 agonist, which results in modification of the immune response and stimulation of apoptosis, thereby disrupting tumour proliferation.¹⁵ Stockfleth et al.¹⁶ demonstrated that 84% of treated AKs showed clinical clearance with one 12-week cycle of 5% imiquimod therapy.

• Common localized irritation coupled with its long duration of treatment (twice-weekly for 16 weeks) can discourage patient adherence.
• Treatment should be applied to both the lesion and surrounding tissue to target subclinical AKs.
• Rare systemic effects include fatigue, flu-like symptoms, headaches, myalgias, and angioedema.

In December 2009, Health Canada approved the use of imiquimod 3.75% for the treatment of AKs on the face or balding scalp. Two identical placebo-controlled trials have evaluated the safety and efficacy of imiquimod 3.75%.^17,18

• In the trial by Swanson et al.,¹⁷ creams were applied daily to the entire face or balding scalp for two 2-week treatment cycles, separated by a 2-week interval without treatment.
  • Patients applying imiquimod 3.75% achieved a median lesion reduction of 82%, while just over one-third experienced complete clearance.
  • These efficacy data rival those achieved using imiquimod 5% twice-weekly for 16 weeks, but with the advantage of signif icantly improved patient tolerance.
  • Therapy was found to be safe and did not result in any serious adverse events.
  • Erythema was observed in most patients, with
  • about 25% developing severe erythema. However, no patients withdrew from the study as a result of this.
  • Compliance rates were noted to be >90%.^17,18

   

• Overall, the newly approved formulation of imiquimod 3.75% is a reasonable alternative to imiquimod 5%, as it demonstrated comparable efficacy, but with a much more simplified, shorter dosing regimen.
• Additionally, imiquimod 3.75% is approved for the treatment of a larger surface area of up to 200cm2, compared with 25cm2 for the 5% formulation, and thus, is able to target more AKs.

Procedural Field Therapy

Procedural field therapies may be an appropriate option for patients who require minimal down time, are unlikely to adhere to a topical approach, have AKs resistant to topical therapy, or favour an improved cosmetic result.

• Treatment options for procedural field therapy include photodynamic therapy, manual dermabrasion, laser resurfacing, cryopeeling, and chemical peels.
• Each of these techniques treats AKs by destroying the superficial layers of the skin through physical or chemical means.

Photodynamic Therapy (PDT)

PDT is a procedural field therapy that utilizes topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate to target AKs. These molecules preferentially find their way into the hyperproliferating cells, which lack normal cell to cell adhesion junctions, and are converted intracellularly to protoporphyrin IX (PpIX).¹⁹ This photosensitizer is then exposed to blue or red light, which corresponds to the peaks in the absorption spectrum of PpIX, resulting in a phototoxic reaction that destroys the abnormal cell.¹⁹

• PDT is effective for the treatment of multiple and diffuse AKs, and the cosmetic results are generally excellent.
• PDT is not suited for treating thicker or deeper AKs19 and is generally reserved for patients who exhibit an inadqueate response to topical field therapy or cryosurgery.
• Patients may experience erythema, edema, and a burning sensation during therapy.

Top

Conclusion

There is no widely accepted algorithm for the treatment of AKs. Often several different treatment regiments must be employed to manage AKs, especially with widespread or resistant cases. As always, the best way to manage AKs is prevention by avoiding exposure to significant or unnecessary UV radiation. Family physicians can play an important role in encouraging patients to wear broad-based sunscreens, wide-brimmed hat, protective eyewear, and avoiding the sun during peak hours, which may prevent recurrence or limit the progression of AKs. Furthermore, patients are well-served by offering education on the potential side-effects and expected onset of action of topical field therapies.

References

1. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S4-7 (2000 Jan).
2. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer. Arch Dermatol 133(10):1263-70 (1997 Oct).
3. Gupta AK, Cooper EA, Feldman SR, et al. A survey of office visits for actinic keratosis as reported by NAMCS, 1990–1999. National Ambulatory Medical Care Survey. Cutis 70(2 Suppl):S8-13 (2002 Aug).
4. Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S8–10 (2000 Jan).
5. Duncan KO, Geisse JK, Leffell DJ. Chapter 113. Epithelial Precancerous Lesions. In: Wolff K, Goldsmith LA, Katz SI, et al. (eds.) Fitzpatrick’s Dermatology in General Medicine: 7th edition. New York, USA: McGraw-Hill Companies (2008).
6. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 42(1 Pt 2):S23-4 (2000 Jan).
7. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42 (1 Pt 2):S25-8 (2000 Jan).
8. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 43(9):687-92 (2004 Sep).
9. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of SlaughterÂ’s concept of field cancerization: evidence and clinical implications. Cancer Res 63(8): 1727-30 (2003 Apr 15).
10. Eaglstein WH,Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses, I: effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
11. Gupta AK. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 70(2 Suppl):30-6 (2002 Aug).
12. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: A double-blind controlled study. Br J Dermatol 116(4):549-52 (1987 Apr).
13. Stockfleth E, Kerl H; Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratoses. Eur J Dermatol 16(6):599-606 (2006 Nov-Dec).
14. Ganjian S, Ourian AJ, Shamtoub G, et al. Off-label indications for imiquimod. Dermatology Online Journal 15(5):4 (2009 May).
15. Dummer R, Urosevic M, Kempf W, et al. Imiquimod in basal cell carcinoma: how does it work? Br J Dermatol 149(suppl 66):57-58 (2003 Nov).
16. Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
17. Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62(4):582-90 (2010 Apr).
18. Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 62(4):573-81 (2010 Apr).
19. Silapunt S, Goldberg LH, Alam M. Topical and light-based treatments for actinic keratoses. Semin Cutan Med Surg 22(3):162–70 (2003 Sep).

Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

Actinic keratoses (AKs), or solar keratoses, are pre-malignant cutaneous lesions that predominantly manifest in sun-exposed areas. They are one of the most common skin conditions seen by dermatologists, preceded only by acne vulgaris and dermatitis.¹ AKs are clinically relevant lesions due to their potential to evolve into invasive squamous cell carcinoma (SCC).² Additionally, they are considered a risk factor for the subsequent development of melanoma and non-melanoma skin cancer. There are numerous treatments available for managing AKs including those broadly categorized as destructive, topical field, and procedural field therapies. The recent introduction of imiquimod 3.75%, approved for the treatment AKs on the face and scalp, widens the therapeutic arsenal.

Prevalence and Risk Factors

• In the northern hemisphere, it is estimated that between 11-25% of adults have at least one AK.³
• These lesions are most commonly seen in the older fair-skinned population or in individuals classified under Fitzpatrick skin phototypes I-III.
• Cumulative ultraviolet (UV) radiation exposure and older age are the most important contributing risk factors.
• Immunocompromised individuals or those with certain genetic syndromes (e.g., xeroderma pigmentosum and albinism) are at greater risk.

Pathogenesis

• UV radiation is involved in the pathogenesis of AKs through inducing cellular DNA mutations in the skin, which may affect cell proliferation genes (e.g., p53 and ras) or prompt evasion of apoptosis.2
• Disruption of one of these genes may lead to formation of atypical keratinocytes in the basal layer and development of an AK; all of these histopathologic changes are limited to the epidermis.
• The absence of further UV light exposure may result in resolution through inherent repair mechanisms. However, additional UV light exposure may induce further DNA mutations resulting in the development of invasive SCC.

Diagnostic Features

• AKs typically manifest as small (1-3mm), erythematous, scaly papules with a hyperkeratotic texture.
• They are best identified with touch rather than visual inspection alone.
• AKs are characteristically distributed in sun-exposed areas, including the face, bald scalp, ears, neck, anterior chest, dorsal forearms, and dorsal hands. Surrounding areas may show evidence of solar elastosis (e.g., telangiectasia, blotchy hyperpigmentation, and yellow discolouration of the skin).⁴
• The clinical variants of AKs include the cutaneous horn, lichen planus-like keratosis, pigmented actinic keratosis, and actinic cheilitis.^4,5
• The natural history of AKs is variable and unpredictable; a lesion can follow one of three paths: it can persist, regress, or transform into an invasive SCC.
• It is impossible to predict which path any given AK may take.
• The risk of a single lesion progressing from an AK to a SCC ranges from 0.025-16% per year.⁶
• Over several years, these lesions can progress, becoming thicker and developing into a hypertrophic AK, Bowen’s disease (SCC in situ), or an invasive SCC.
• The stages of this biologic continuum are clinically indistinguishable, therefore, a biopsy should be performed if a SCC is suspected.
• A presentation that includes pain, pruritus, induration, larger size, rapid growth, ulceration, bleeding, or resistance to treatment may point towards a more sinister pathology (i.e., SCC).^4,5

Treatment Overview

It is recommended that all AKs be treated, as there are no reliable clinical predictors to discern an AK from a SCC. If a SCC is missed, it may become locally invasive and destructive; these lesions are capable of metastases, resulting in death. Therapeutic choices are guided by efficacy, adverse effects, cosmetic results, and patient adherence.

Destructive Therapy

The most common therapies for individual AKs work destructively by physically removing the lesion. These modalities should be considered first-line for isolated lesions or early presentations of AKs. Destructive therapies include liquid nitrogen cryotherapy, curettage with or without electrodessication, and shave excision. The main advantages of these procedures are that they are quick, procedurally simple, and provide adequate clearance of abnormal tissue.

Cryotherapy

Cryotherapy is the most frequently utilized technique, with liquid nitrogen being the most commonly applied cryogen. Applying cryotherapy to the affected area lowers the skin to temperatures that destroy atypical AK cells.⁷

• This technique is ideal if lesions are scattered, limited in number, or for patients who are nonadherent to topical regimes.⁷
• Reported cure rates range from 39-83%.⁸
• Treatments are generally well-tolerated and do not require local anesthetic, but the procedure can be painful and result in permanent hypopigmentation.
• Potential side-effects include blisters, scarring, textural skin changes, infection, and hyperpigmentation.

Curettage and Shave Excision

Curettage consists of using a curette to mechanically remove atypical cells. A shave excision using a surgical blade is another technique. These may be followed by electrocautery, which will destroy additional atypical cell layers, as well as provide hemostasis.

• These techniques are most appropriate for treating individual AKs, cases where a biopsy is required to rule out frank carcinoma, or for hypertrophic AKs that are refractory to other treatments.
• Potential side-effects include infection, scarring, and dyspigmentation, as well as anesthetic related side-effects.

Topical Field Therapy

Commonly, physicians are faced with patients who are covered in actinic damage, a clinical scenario now described as field cancerization, which includes both clinical and subclinical lesions within a given anatomical region.9 For these patients, a different therapeutic approach, known as field therapy, is needed for the clearance of both clinically visible and subclinical AKs within the treatment area.

Topical 5-fluorouracil (5-FU)

The antimetabolite 5-FU was the first approved agent for topical field therapy. Discovered serendipitously whenAKs were noted to become inflamed and subsequently resolved in patients receiving systemic 5-FU as a chemotherapeutic agent; it was eventually designed into an effective topical formulation. It acts as a thymidylate synthase inhibitor by blocking a methylation reaction, which in turn disrupts DNA and RNA synthesis and effectively stops the growth of the rapidly proliferating or cancerous cells.10 As such, 5-FU preferentially targets the atypical cells over normal skin tissue.

• The average cure rate is 62.5%,11 but for optimal results full patient adherence is necessary. Recommended dosing is twice-daily for 3 weeks.
• There is evidence showing concurrent treatment with topical tretinoin enhances the effectiveness of 5-FU.¹²
• It is common for all patients undergoing successful treatment with 5-FU to experience inflammation, erythema, and erosions.
• Common side-effects include pain, pruritus, photo- sensitivity, and burning at the site of application.
• 5-FU can worsen preexisting cutaneous conditions (e.g., melasma or acne rosacea), as such, use should be avoided in these patients.⁷

Diclofenac

Diclofenac 3% gel is a nonsteroidal anti-inflammatory drug, which is believed to exert its effects through the inhibition of cyclooxygenase (COX), especially COX-2. The production of prostaglandins is thought to suppress the immune system, thereby allowing tumours to form.¹³ Without COX, prostaglandin production is reduced and the cascade is disrupted.¹³

• Despite the more rigorous treatment regimen (twice daily for 90 days), only mild to moderate local skin reactions are noted.
• Though rare, drug-induced hepatotoxicity reports have surfaced, consequently transaminases should be measured periodically in patients on long-term therapy.

Imiquimod

Topical 5% imiquimod cream was originally indicated as a treatment for genital and perianal warts; additional approved indications for treating AKs and superficial basal cell carcinomas followed. It is used off-label for Bowen’s disease, invasive SCC, lentigo maligna, molluscum contagiosum, keloid scars, and others.¹⁴ Imiquimod acts as a toll-like receptor-7 agonist, which results in modification of the immune response and stimulation of apoptosis, thereby disrupting tumour proliferation.¹⁵ Stockfleth et al.¹⁶ demonstrated that 84% of treated AKs showed clinical clearance with one 12-week cycle of 5% imiquimod therapy.

• Common localized irritation coupled with its long duration of treatment (twice-weekly for 16 weeks) can discourage patient adherence.
• Treatment should be applied to both the lesion and surrounding tissue to target subclinical AKs.
• Rare systemic effects include fatigue, flu-like symptoms, headaches, myalgias, and angioedema.

In December 2009, Health Canada approved the use of imiquimod 3.75% for the treatment of AKs on the face or balding scalp. Two identical placebo-controlled trials have evaluated the safety and efficacy of imiquimod 3.75%.^17,18

• In the trial by Swanson et al.,¹⁷ creams were applied daily to the entire face or balding scalp for two 2-week treatment cycles, separated by a 2-week interval without treatment.
  • Patients applying imiquimod 3.75% achieved a median lesion reduction of 82%, while just over one-third experienced complete clearance.
  • These efficacy data rival those achieved using imiquimod 5% twice-weekly for 16 weeks, but with the advantage of signif icantly improved patient tolerance.
  • Therapy was found to be safe and did not result in any serious adverse events.
  • Erythema was observed in most patients, with
  • about 25% developing severe erythema. However, no patients withdrew from the study as a result of this.
  • Compliance rates were noted to be >90%.^17,18

   

• Overall, the newly approved formulation of imiquimod 3.75% is a reasonable alternative to imiquimod 5%, as it demonstrated comparable efficacy, but with a much more simplified, shorter dosing regimen.
• Additionally, imiquimod 3.75% is approved for the treatment of a larger surface area of up to 200cm2, compared with 25cm2 for the 5% formulation, and thus, is able to target more AKs.

Procedural Field Therapy

Procedural field therapies may be an appropriate option for patients who require minimal down time, are unlikely to adhere to a topical approach, have AKs resistant to topical therapy, or favour an improved cosmetic result.

• Treatment options for procedural field therapy include photodynamic therapy, manual dermabrasion, laser resurfacing, cryopeeling, and chemical peels.
• Each of these techniques treats AKs by destroying the superficial layers of the skin through physical or chemical means.

Photodynamic Therapy (PDT)

PDT is a procedural field therapy that utilizes topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate to target AKs. These molecules preferentially find their way into the hyperproliferating cells, which lack normal cell to cell adhesion junctions, and are converted intracellularly to protoporphyrin IX (PpIX).¹⁹ This photosensitizer is then exposed to blue or red light, which corresponds to the peaks in the absorption spectrum of PpIX, resulting in a phototoxic reaction that destroys the abnormal cell.¹⁹

• PDT is effective for the treatment of multiple and diffuse AKs, and the cosmetic results are generally excellent.
• PDT is not suited for treating thicker or deeper AKs19 and is generally reserved for patients who exhibit an inadqueate response to topical field therapy or cryosurgery.
• Patients may experience erythema, edema, and a burning sensation during therapy.

Top

Conclusion

There is no widely accepted algorithm for the treatment of AKs. Often several different treatment regiments must be employed to manage AKs, especially with widespread or resistant cases. As always, the best way to manage AKs is prevention by avoiding exposure to significant or unnecessary UV radiation. Family physicians can play an important role in encouraging patients to wear broad-based sunscreens, wide-brimmed hat, protective eyewear, and avoiding the sun during peak hours, which may prevent recurrence or limit the progression of AKs. Furthermore, patients are well-served by offering education on the potential side-effects and expected onset of action of topical field therapies.

References

1. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S4-7 (2000 Jan).
2. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer. Arch Dermatol 133(10):1263-70 (1997 Oct).
3. Gupta AK, Cooper EA, Feldman SR, et al. A survey of office visits for actinic keratosis as reported by NAMCS, 1990–1999. National Ambulatory Medical Care Survey. Cutis 70(2 Suppl):S8-13 (2002 Aug).
4. Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S8–10 (2000 Jan).
5. Duncan KO, Geisse JK, Leffell DJ. Chapter 113. Epithelial Precancerous Lesions. In: Wolff K, Goldsmith LA, Katz SI, et al. (eds.) Fitzpatrick’s Dermatology in General Medicine: 7th edition. New York, USA: McGraw-Hill Companies (2008).
6. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 42(1 Pt 2):S23-4 (2000 Jan).
7. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42 (1 Pt 2):S25-8 (2000 Jan).
8. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 43(9):687-92 (2004 Sep).
9. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of SlaughterÂ’s concept of field cancerization: evidence and clinical implications. Cancer Res 63(8): 1727-30 (2003 Apr 15).
10. Eaglstein WH,Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses, I: effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
11. Gupta AK. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 70(2 Suppl):30-6 (2002 Aug).
12. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: A double-blind controlled study. Br J Dermatol 116(4):549-52 (1987 Apr).
13. Stockfleth E, Kerl H; Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratoses. Eur J Dermatol 16(6):599-606 (2006 Nov-Dec).
14. Ganjian S, Ourian AJ, Shamtoub G, et al. Off-label indications for imiquimod. Dermatology Online Journal 15(5):4 (2009 May).
15. Dummer R, Urosevic M, Kempf W, et al. Imiquimod in basal cell carcinoma: how does it work? Br J Dermatol 149(suppl 66):57-58 (2003 Nov).
16. Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
17. Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62(4):582-90 (2010 Apr).
18. Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 62(4):573-81 (2010 Apr).
19. Silapunt S, Goldberg LH, Alam M. Topical and light-based treatments for actinic keratoses. Semin Cutan Med Surg 22(3):162–70 (2003 Sep).

ABSTRACT

An actinic keratosis (AK) is a pre-malignant cutaneous lesion that frequently manifests in sun-exposed areas of the skin as a small, rough, scaly erythematous papule. They are one of the most common presenting complaints for dermatologists. AKs should be treated due to their potential to progress into a squamous cell carcinoma (SCC). There are numerous treatments available for managing AKs including those broadly categorized as destructive, topical field, and procedural field therapies. The topical field therapies include 5-fluorouracil, imiquimod, and diclofenac gel. Recently, imiquimod 3.75% (Zyclara™) has been approved for the treatment of AKs on the face and scalp. It is a reasonable alternative to imiquimod 5%, as the approved indication includes a larger surface area for treatment, shorter duration course, and the potential for less severe local skin reactions. There is no widely accepted algorithm for the treatment of AKs, as comparative data is unavailable between all approaches. Therapy choices are guided by efficacy, adverse effects, cosmetic results, and patient compliance.

Key Words:
actinic keratosis, imiquimod, squamous cell carcinoma, skin cancer, Zyclara™

Actinic keratoses (AKs), or solar keratoses, are pre-malignant cutaneous lesions that predominantly manifest in sun-exposed areas. They are one of the most common pathologies seen by dermatologists, preceded only by acne vulgaris and dermatitis as more frequent complaints.¹ AKs are clinically relevant lesions due to their potential to progress into a squamous cell carcinoma (SCC).² Additionally, they are considered a risk factor for the subsequent development of melanoma and non-melanoma skin cancer (NMSC).

In the northern hemisphere, 11-25% of adults are believed to have at least one AK.³ These lesions are most commonly seen in the older fair-skinned population (Fitzpatrick skin phototypes I-III). Cumulative ultraviolet (UV) radiation exposure and older age are the most important risk factors for this condition. Individuals who are immunocompromised or have certain genetic syndromes, such as xeroderma pigmentosum and albinism, are at greater risk.

Pathophysiology

Grossman and Leffell² explain that UV radiation is involved in the pathogenesis of AKs through inducing cellular DNA mutations in the skin, which may affect cell proliferation genes, such as p53 and ras, or prompt evasion of apoptosis. Disruption of one of these genes may lead to the formation of atypical keratinocytes in the basal layer and development of an AK; all of these histopathologic changes are limited to the epidermis. The absence of further UV light exposure may result in resolution through repair mechanisms. However, additional UV light exposure may induce further DNA mutations, resulting in the development of an invasive SCC.

AKs typically manifest as small (1-3mm) erythematous scaly papules with a hyperkeratotic texture. As such, they are best identified with touch rather than visual inspection alone. AKs are characteristically distributed in sun-exposed areas, including the face, bald scalp, ears, neck, anterior chest, dorsal forearms, and dorsal hands. Surrounding areas may show evidence of solar elastosis, such as telangiectasia, blotchy hyperpigmentation, and yellow discoloration of the skin.⁴ The clinical variants of actinic keratosis include the cutaneous horn, lichen planus-like keratosis, pigmented actinic keratosis, and actinic cheilitis.^4,5 Over several years, these lesions can progress, becoming thicker and developing into a hypertrophic AK, Bowen’s disease (SCC in situ), or an invasive SCC. Unfortunately, the stages of this biologic continuum are clinically indistinguishable and a biopsy should be performed if a SCC is suspected. However, a presentation that includes pain, pruritus, induration, larger size, rapid growth, ulceration, bleeding, or resistance to treatment may point towards a more sinister pathology
(i.e., SCC).^4,5

The natural history of AKs is variable and unpredictable. The lesion can follow one of three paths: it can persist, regress, or transform into an invasive SCC. It is impossible to predict which path any given AK may take. The risk of a single lesion progressing from an AK to a SCC ranges from 0.025-16% per year.⁶ Nonetheless, it is recommended that all AKs be treated as there are no reliable clinical predictors to discern an AK from a SCC. If a SCC is missed, it may become locally invasive and destructive; these lesions are capable of metastases resulting in death.

Destructive Therapy

The most common therapies for individual AKs work destructively by physically removing the lesion. These should always be considered for isolated lesions or early presentations of AKs. Destructive therapies include liquid nitrogen cryotherapy, curettage with or without electrodessication, and shave excision. The main advantages of these procedures are that they are quick, procedurally simple, and provide adequate clearance of abnormal tissue. A major limitation of such targeted approaches is that they fail to address field cancerization.

Cryotherapy

Cryotherapy is the most commonly utilized technique, with liquid nitrogen being the most frequently selected cryogen. Applying cryotherapy to the affected area lowers the skin to temperatures that destroy atypical AK cells.⁷ This technique is ideal if lesions are scattered or limited in number, or for patients who are non-compliant with topical regimes.⁷ Reported cure rates range from 39-83%.⁸ Cryotherapy is advantageous in that it is generally well-tolerated and does not require local anesthetic, but downsides include pain during the procedure and frequent permanent hypopigmentation. Potential side-effects include blisters, scarring, textural skin changes, infection, and hyperpigmentation.

Curettage and Shave Excision

Curettage consists of using a curette to mechanically remove atypical cells. A shave excision using a surgical blade is another technique. These may be followed by electrocautery, which will destroy additional atypical cell layers as well as provide hemostasis. There are no studies documenting cure rates with these treatment modalities. These techniques are most appropriate for treating individual AKs, cases where a biopsy is required to rule out frank carcinoma, or for hypertrophic AKs that are refractory to other treatments. Potential side-effects include infection, scarring, anesthetic related side-effects, and dyspigmentation.

Topical Field Therapy

Commonly, physicians are faced with patients who are covered in actinic damage, a clinical scenario now described as field cancerization. This describes both clinical and subclinical lesions within a given anatomical region.9 For these patients, a different therapeutic approach, known as field therapy, is needed. The goal of field therapy is the eradication of both the clinically visible and subclinical AKs within the treatment area.

Topical 5-fluorouracil

The antimetabolite 5-fluorouracil (5-FU) was the first approved topical field therapy. Discovered serendipitously when AKs were noted to become inflamed and subsequently resolved in patients receiving systemic 5-FU as a chemotherapeutic agent, it was eventually designed into an effective topical formulation. It acts as a thymidylate synthase inhibitor by blocking a methylation reaction; this in turn disrupts DNA and RNA synthesis and effectively stops the growth of the rapidly proliferating or cancerous cells.¹⁰ As such, 5-FU preferentially targets the atypical cells over normal cutaneous tissue. The average cure rate is 62.5%,¹¹ but for optimal results full patient adherence is necessary. Interestingly, there is evidence showing concurrent treatment with topical tretinoin enhances the effectiveness of 5-FU.¹² All patients undergoing successful treatment should experience erythema, inflammation, and erosions. Commonly experienced side-effects include pain, pruritus, photosensitivity, and burning at the site of application. Additionally, topical 5-FU can exacerbate other pre-existing cutaneous conditions, such as melasma or acne rosacea; therefore, use should be avoided in these cases.⁷

Diclofenac

Diclofenac 3% gel is a nonsteroidal anti-inflammatory drug that is believed to exert its effects through the inhibition of cyclooxygenase (COX), especially COX-2. The production of prostaglandins is thought to suppress the immune system, thereby allowing tumors to form.¹³ Without COX, prostaglandin production is reduced and the cascade is disrupted.¹³ Despite the more rigorous treatment regimen (twice-daily for 90 days), only mild to moderate local skin reactions are noted. Though rare, drug-induced hepatotoxicity reports have surfaced, consequently transaminases should be measured periodically in patients receiving long-term therapy.¹⁴

Imiquimod

Topical 5% imiquimod cream (Aldara®) was originally indicated as a treatment for genital and perianal warts; additional approved indications for treating AKs and superficial basal cell carcinomas followed. It is also used off label for treating Bowen’s disease, invasive SCC, lentigo maligna, molluscum contagiosum, keloid scars, and others.¹⁵ Imiquimod acts as a toll-like receptor-7 agonist, which results in modification of the immune response and stimulation of apoptosis, thereby disrupting tumor proliferation.¹⁶ Stockfleth et al.¹⁷ demonstrated that 84% of treated AKs showed clinical clearance with one 12-week cycle of 5% imiquimod therapy. As with 5-FU, local irritant reactions are common. Coupled with its long duration of application (twice-weekly for 16 weeks), treatment adherence may be challenging with this agent. Administration to both the lesion and surrounding tissue targets both visible and subclinical AKs. Systemic effects, such as fatigue, flu-like symptoms, headaches, myalgias, and angioedema are rare.

Recently, regulatory approval was granted by Health Canada in December 2009 and by the US FDA in March 2010 to imiquimod 3.75% (Zyclara™) for the treatment of AKs on the face or balding scalp. Two identical placebo-controlled trials have evaluated the safety and efficacy of imiquimod 3.75%.^18,19 In the trial by Swanson et al.,¹⁸ creams were applied daily to the entire face or balding scalp for two 2-week treatment cycles, separated by a 2-week interval without treatment. Patients applying imiquimod 3.75% achieved a median lesion reduction of 82%, while just over one-third demonstrated complete clearance. These efficacy data rival those achieved using imiquimod 5% twice-weekly for 16 weeks, with the advantage of significantly improved patient tolerance exhibited by the lower dosage. The therapy was found to be safe and did not result in any serious adverse events. Erythema was observed in most patients, with about 25% developing severe erythema. However, no patients withdrew from the study as a result of this; compliance rates were noted to be greater than 90%.^18,19 Overall, the newly approved imiquimod 3.75% is a reasonable alternative to imiquimod 5%, as it demonstrates comparable efficacy, allows for a much simplified, shorter dosing regimen, and seemingly yields less severe adverse effects. Additionally, imiquimod 3.75% is approved for the treatment of a larger surface area of up to 200cm2, compared with 25cm2 for the 5% formulation, and thus, is able to target more AKs.

Procedural Field Therapy

Procedural field therapies may be an appropriate option for patients who require minimal down time, are unlikely to adhere to a topical approach, have AKs resistant to topical therapy, or favor an optimal cosmetic result. Treatment options for procedural field therapy include photodynamic therapy, manual dermabrasion, laser resurfacing, cryopeeling, and chemical peels. Each of these techniques treats AKs by destroying the superficial layers of the skin through physical or chemical means.

Photodynamic Therapy

Photodynamic therapy (PDT) is a procedural field therapy that utilizes topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate (Metvix®/Metvixia®) to target AKs. These molecules preferentially find their way into the hyperproliferating cells, which lack normal cell to cell adhesion junctions, and are converted intracellularly to protoporphyrin IX (PpIX).²⁰ This photosensitizer is then exposed to blue or red light, which corresponds to the peaks in the absorption spectrum of PpIX, resulting in a phototoxic reaction that destroys the abnormal cell.20 PDT is effective for the treatment of multiple and diffuse AKs, and the cosmetic results are generally excellent. However, it is not ideal for treating thicker or deeper AKs²⁰ and is generally reserved for patients who exhibit an inadequate response to topical field therapy or cryosurgery. Patients may experience erythema, edema, and a burning sensation during the light therapy.

Conclusion

There is no widely accepted algorithm for the treatment of AKs. Often several different treatment regiments must be employed to manage AKs, especially with widespread or resistant cases. As always, the best way to manage AKs is prevention by avoiding exposure to significant or unnecessary UV radiation. Encouraging patients to wear broad-based sunscreens, wide-brimmed hat, sunglasses, and avoiding the sun during peak hours may prevent recurrence or limit the progression of AKs.

References

1. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S4-7 (2000 Jan).
2. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer. Arch Dermatol 133(10):1263-70 (1997 Oct).
3. Gupta AK, Cooper EA, Feldman SR, et al. A survey of office visits for actinic keratosis as reported by NAMCS, 1990–1999. National Ambulatory Medical Care Survey. Cutis 70(2 Suppl):S8-13 (2002 Aug).
4. Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):S8-10 (2000 Jan).
5. Duncan Karynne O, Geisse John K, Leffell David J. Chapter 113. Epithelial precancerous lesions. In: Wolff K, Goldsmith LA, Katz SI, et al. (eds). Fitzpatrick’s dermatology in general medicine: 7th ed. New York: McGraw-Hill Companies, p1007-25 (2008).
6. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 42(1 Pt 2):S23-4 (2000 Jan).
7. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42 (1 Pt 2):S25-8 (2000 Jan).
8. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 43(9):687-92 (2004 Sep).
9. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63(8):1727-30 (2003 Apr 15).
10. Eaglstein WH,Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses, I: effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
11. Gupta AK. The management of actinic keratoses in the United States with topical fluorouracil: a pharmacoeconomic evaluation. Cutis 70(2 Suppl):30-6 (2002 Aug).
12. Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: a double-blind controlled study. Br J Dermatol 116(4):549-52 (1987 Apr).
13. Stockfleth E, Kerl H; Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratoses. Eur J Dermatol 16(6):599-606 (2006 Nov-Dec).
14. US FDA 2009 safety alerts for human medical products: Voltaren gel (diclofenac sodium topical gel) 1% – hepatic effects labeling changes (issued December 4, 2009).
15. Ganjian S, Ourian AJ, Shamtoub G, et al. Off-label indications for imiquimod. Dermatology Online Journal 15(5):4 (2009 May).
16. Dummer R, Urosevic M, Kempf W, et al. Imiquimod in basal cell carcinoma: how does it work? Br J Dermatol 149(suppl 66):57-8 (2003 Nov).
17. Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
18. Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62(4):582-90 (2010 Apr).
19. Hanke CW, Beer KR, Stockfleth E, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of 2 placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. J Am Acad Dermatol 62(4):573-81 (2010 Apr).
20. Silapunt S, Goldberg LH, Alam M. Topical and light-based treatments for actinic keratoses. Semin Cutan Med Surg 22(3):162–70 (2003 Sep).

Key Words:
actinic keratosis; basal cell carcinoma; Bowen’s disease; methyl aminolevulinate; PDT; photodynamic therapy

Topical Methyl Aminolevulinate (MAL)-PDT

Photodynamic therapy (PDT) treats superficial skin cancers and pre-cancerous lesions through photosensitized reactions requiring oxygen. Over the past several decades, PDT has been extensively investigated as an experimental therapy for human cancers. There is now growing interest in the use of PDT not only for nonmelanoma skin cancer (NMSC), but also for other skin tumors such as lymphoma, as well as for nononcological indications, such as psoriasis, localized scleroderma, acne, and skin rejuvenation.^1-4 In Europe, as well as in the US, porphyrin-inducing precursors, such as 5-aminolevulinic-acid (ALA) and MAL have been proven effective for the treatment of actinic keratoses (AKs) and basal cell carcinomas.^5-7 Both ALA and MAL induce protoporphyrin IX (PpIX) locally in the skin. Photodynamic therapy combines the simultaneous presence of a photosensitizer activated by an appropriate wavelength of light. For topical PDT, upon illumination, PpIX is transformed to the excited state and then returns to its ground state through a type-II photo-oxidative reaction.5 In this reaction, these molecules transfer energy to oxygen producing highly reactive oxygen species (ROS), singlet oxygen in particular. ROS accumulates locally within the affected tissue leading to direct cellular damage by apoptosis or necrosis, and indirect stimulation of inflammatory cell mediators.⁶

Previous studies have shown that MAL in combination with red light (570-670nm) has provided good clinical outcomes in the treatment of NMSC (both sBCC and Bowen’s disease) and AKs.⁷ MAL, the methylated ester of ALA, is a new topical photosensitizer that may offer advantages over ALA in terms of its deeper skin penetration (up to 2mm in depth) due to potentially enhanced lipophilicity and greater specificity for neoplastic cells.⁸ In a typical PDT session, the lesion surface is prepared by light curettage of any surface crusts and scales. The 3 hour application of 160mg/g MAL prior to irradiation with 37J/cm2 from a light-emitting diode system (emission peak of 632nm) corresponds to the time point of the highest ratio of fluorescence depth to tumor depth2 under occlusion. Two treatments 1 week apart for AKs, sBCC, and BD have been recommended; however, a single treatment session is possible and may be potentially sufficient for very thin AKs. For partially cleared responses, a second treatment course (consisting of two weekly PDT sessions) at 3 months may be considered.⁹ This article reviews key published trials of topical MAL-PDT for AK, sBCC, and BD.

AKs

A US randomized, multicenter, double-blind, placebo controlled study was performed in 80 patients with mild-to-moderate AKs on the face and scalp. Forty-two patients (260 lesions) were treated with MAL-PDT and 38 patients (242 lesions) received the placebo cream. MAL was applied for 3 hours followed by illumination with noncoherent red light (75J/cm2). Treatment was repeated after 1 week. A complete response rate of 89% with MAL-PDT and 38% with placebo was assessed after 3 months follow-up. An excellent or good cosmetic outcome was reported in more than 90% of patients treated with MAL.¹⁰

Tarstedt et al.11 reported response rates in an open label, prospective study that compared 2 regimens:

1. A single treatment session
2. 2 MAL-PDT sessions 1 week apart.

One hundred six patients received the single treatment and 105 patients received the second regimen. For thin lesions, clearance rates showed no significant difference (93% with single session vs. 89% with double sessions) For thicker lesions, clearance rates were higher for double sessions (84%) when compared with single treatment (70%). The authors concluded that single treatment is effective for thin AKs. Repeated treatments were needed for thicker or resistant lesions.

In another randomized, multicenter study, MAL-PDT (n=360 lesions) was compared with a single-thaw cycle of cryotherapy (n=421 lesions) or placebo (n=74 lesions). The PDT treatment arm consisted of 2 treatment sessions 1 week apart using 75J/cm2 with a noncoherent red light (570-670nm). After 3 months, clearance rates for MAL-PDT were significantly higher (91%) compared with cryosurgery (68%) and placebo (30%). Of the MAL-PDT treated patients, 83% were rated as having an excellent cosmetic outcome by an investigator vs. 51% of those treated with cryotherapy; the corresponding patient assessments were 76% and 56% respectively.¹²

A large randomized, intraindividual, right-left comparative study of 119 patients with face/scalp AKs was performed.14 The aim of the study was to compare 1 MAL PDT session to double freeze-thaw cryotherapy. After a 3-hour application of MAL using 37J/cm2 with double treatment 7 days apart, cure rates were seen when using MAL-PDT (87%) compared with cryotherapy (76%). Of patients treated with MAL-PDT, 10% required re-treatment after 3 months vs. 21% for cryotherapy. Cosmetic outcome significantly favored MAL-PDT (i.e., 77% vs. 50%).13 A recent study, however, showed lower efficacy with MAL-PDT (78% clearance) on the extremities compared with cryotherapy (88% clearance).¹⁴

In a recent multicenter, double-blind, randomized study by Pariser,15 the efficacy of MAL-PDT using a red light-emitting diode (n=363 lesions) was evaluated vs. placebo (n=360 lesions) for grade 1 (slightly palpable) and grade 2 (moderately thick) AKs on the face and scalp. Lesion complete response rates were significantly superior for MAL-PDT (86.2%) vs. placebo (52.5%). The patient complete response rate was 59.2% for MAL-PDT subjects, and lower for those who had vehicle PDT alone (14.9%). Scalp lesions responded better with MAL-PDT (93%) than did facial lesions (87%). Grade 1 lesions had slightly higher complete response rates than grade 2 lesions (89% vs. 80%). Furthermore, larger lesions with diameters of >20mm had poorer response rates compared with smaller lesions (74% vs. 86%).

When treating AKs, biopsies should be considered for thick, keratotic lesions to rule out squamous cell carcinoma. Calzavara-Pinton et al.¹⁶ have shown that even if squamous cell carcinoma is limited to microinvasive involvement, the treatment outcome is poor.

Superficial BCCs

The recent British Photodermatology Group guidelines for topical PDT concluded MAL-PDT to be effective for sBCC.⁹ In an attempt to compare clearance rates and cosmetic outcomes between MAL-PDT (n=60) and double freeze-thaw cryotherapy (n=58) in sBCC, a 5-year European randomized trial was performed in 118 patients. This protocol used MAL applied for 3 hours at 75J/cm2 with noncoherent red light (570-670nm) for 1 session. Partially treated patients at 3 months were given 2 further MAL-PDT sessions (n=20) or repeat cryotherapy (n=16). Complete clinical response rates after 3 months’ follow-up for MAL-PDT were 97% of 102 lesions, while that of cryotherapy was 95% of 98 lesions; the difference between these 2 treatments was not statistically significant. At 5 years’ follow-up, clearance rates were similar for the MAL-PDT group (75%) and cryotherapy (74%). Of the lesions initially cleared with MAL-PDT, 22% had recurred vs. 20% after cryotherapy. Cosmetic outcome was judged superior following PDT (87% vs. 49%).¹⁷
Double MAL-PDT treatment cycles for ‘difficult-to-treat’ sBCC (and nBCC) were reported by 2 prospective multicenter studies. This included recurrent, large-sized lesions and/or those occurring on the mid-face or ears. In the first study, 87% of patients (n=94) had ‘difficult-to-treat’ lesions occurring on the face or scalp. The protocol was a single cycle of MAL-PDT (MAL 3h, 75J/cm2, 570-670nm or 580-740nm, 50-200mW/cm2) involving 2 treatment sessions 1 week apart. For partially treated lesions after 3 months’ follow-up, a second cycle was repeated. Complete clearance at 3 months was 85% for sBCC after histological review (75% for nBCC). After 2 years, the recurrence rate was 22% for sBCC (14% for nBCC). Ninety-four percent of patients were assessed to have a good to excellent cosmetic outcome.¹⁸
In the second study, efficacy, safety, and cosmetic outcomes were examined in 95 patients with BCCs that were ‘difficult-to-treat’ and at high risk for surgical complications. A total of 148 BCCs (sBCC and nBCC) were treated with the same PDT protocol (MAL 3h, 75J/cm2, 570-670nm, 50-200mW/cm2) with re-treatment for non-complete response lesions at 3 months. Overall, histologically-confirmed lesion complete response rate was 89% (93% sBCC and 82% nBCC) after 3 months’ follow-up. Fifteen percent of lesions had histologically confirmed recurrence within 2 years increasing to 20% within 4 years. Ninety-seven percent of patients rated their cosmetic outcome as good to excellent at 3 months.¹⁹

Bowen’s Disease

A large randomized, controlled, multicenter study reported similar clearance response rates following MAL-PDT (86%), single freeze-thaw cryotherapy (82%), and 1 month application of 5-fluorouracil (83%) in 225 patients with histologically confirmed Bowen’s disease. MAL-PDT (MAL 3h, 75J/cm2, 570-670nm, 70-200mW/cm2) was given as a single cycle 1 week apart. Lesions with a partial response at 3 months were re-treated. Cosmetic outcome was superior for MAL-PDT in 94% of patients vs. 66% with cryotherapy, and 76% with fluorouracil.²⁰ Clearance rates after 2 years for MAL-PDT was 68% vs. 60% with cryotherapy and 59% with fluorouracil.⁷

Conclusion

MAL is an effective low molecular weight topical porphyrin-inducer that is typically used in combination with a red light-emitting diode for PDT. It offers therapeutic benefit for thin and moderate thickness AKs. It should be considered as a treatment option for superficial BCCs and Bowen’s disease, particularly in situations where surgery may be problematic or where patients have multiple lesions. However, long-term cure rates, as mentioned above for Bowen’s disease and sBCC, are only 68% and 75% respectively. Because of the appreciable nonresponse and recurrence rates, patients treated with PDT for either disease should be monitored closely during the first 2-3 years after PDT, which is when most lesion recurrences occur. According to studies, patients’ high preference for MAL-PDT may be mainly due to its good to excellent cosmetic outcome and general tolerability of side-effects. No direct comparative studies have yet been reported with MAL and ALA. Important parameters, such as the depth of penetration of MAL-PDT, tumor thickness, location, and careful patient selection are key elements for efficacy. In the US, MAL-PDT is currently FDA-approved for the treatment of AKs only, whereas in Canada, MAL-PDT is officially indicated for the treatment of both AKs and sBCCs.

References

1. Ibbotson SH. 5-aminolevulinic acid photodynamic therapy for the treatment of skin conditions other than non-melanoma skin cancer. Br J Dermatol 146(2):178-88 (2002 Feb).
2. Albert MR, Weinstock MA. Keratinocyte carcinoma. CA Cancer J Clin 53(5):292-302 (2003 Sep-Oct).
3. Karrer S, Abels C, Landthaler M, et al. Topical photodynamic therapy for localized scleroderma. Acta Derm Venereol 80(1):26-7 (2000 Jan-Feb).
4. Tandon YK, Yank MF, Baron ED. Role of photodynamic therapy in psoriasis: a brief review. Photodermatol Photoimmunol Photomed 24(5):222-30 (2008 Oct).
5. Lim HW, Honigsmann H, Hawk JLM. Photodermatology. In: Ibbotson SH, Szeimies RM, editors. Photodynamic therapy. New York: Informa Healthcare USA, Inc. p.236-345 (2007).
6. Babilas P, Karrer S, Sidoroff A, et al. Photodynamic therapy in dermatology: an update. Photodermatol Photoimmunol Photomed 21(3):142-9 (2005 Jun).
7. Lehmann P. Methyl aminolaevulinate-photodynamic therapy: a review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. Br J Dermatol 156(5):793-801 (2007 May).
8. Peng Q, Soler AM, Warloe T, et al. Selective distribution of porphyrins in thick basal cell carcinoma after topical application of methyl 5-aminolevulinate. J Photochem Photobiol B 62(3):140-5 (2001 Sep).
9. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: update. Br J Dermatol 159(6):1245-66 (2008 Dec).
10. Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 48(2):227-32 (2003 Feb).
11. Tarstedt M, Rosdahl I, Berne B, et al. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol 85(5):424-8 (2005).
12. Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 14(2):99-106 (2003 Jun).
13. Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 155(5):1029-36 (2006 Nov).
14. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 158(5):994-9 (2008 May).
15. Pariser D, Loss R, Jarratt M, et al. Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study. J Am Acad Dermatol 59(4):569-76 (2008 Oct).
16. Calzavara-Pinton PG, Venturini M, Sala R, et al. Methylaminolaevulinate-based photodynamic therapy of Bowen’s disease and squamous cell carcinoma. Br J Dermatol 159(1):137-44 (2008 Jul).
17. Basset-Seguin N, Ibbotson SH, Emtestam L, et al. Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. Eur J Dermatol 18(5):547-53 (2008 Sep-Oct).
18. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 149(6):1242-9 (2003 Dec).
19. Vinciullo C. MAL-PDT in ‘difficult-to-treat’ basal cell carcinoma, an Australian study: 48 month follow-up data. Presented at: the 3rd Meeting of the European Association of Dermato-Oncology Rome, June 23-25, 2006. J Invest Dermatol 126(Suppl 2):534 (2006).
20. Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or fluorouracil for treatment of squamous cell carcinoma in situ: results of a multicenter randomized trial. Arch Dermatol 142(6):729-35 (2006 Jun).

Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB
Western Canada Dermatology Institute, Surgical Unit, Edmonton, AB

Background

Cutaneous concerns continue to be a significant part of family and specialty practices, as increasingly, patients are seeking medical consultation for the management of photodamage, actinic keratoses, and nonmelanoma skin cancer (NMSC), which is now a global epidemic. The 2 most prevalent forms of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

• The earliest clinically recognizable manifestation of SCC is actinic keratosis (AK).
• The impact of skin malignancies is substantial. They commonly result in considerable deformities, either from the disease itself or from the results of selected therapies.
• The incidence of both AKs and SCC continues to rise.

Actinic Keratoses

• All AKs deserve our attention and treatment.
• They represent clinical evidence that patients have sustained sufficient UV damage to the epidermis to cause visually abnormal skin changes and alteration in the DNA structure.
• The risk of progression of AK to invasive SCC has been estimated to range from 0.025% to 16% per year.¹

Diagnosis

Actinic keratoses are skin neoplasms that reflect cumulative UV damage to the epidermis.

• Present as skin-colored, lightly pigmented, or erythematous scaly papules localized on chronically sun-exposed areas.
• Are generally
• Frequently, confirmation of diagnosis is achieved by palpation rather than visual examination alone.
• Predominantly found on skin areas receiving the highest levels of sun-exposure, such as the face, scalp, ears, neck, arms, and hands.
• Any lesion with induration or epidermal thickening should be biopsied.
• Risk factors for their development include blonde hair, blue eyes, fair complexion, an inability to tan, a history of long-term sun exposure, and immunosuppression, such as that seen in organ-transplant recipients.

Treatment

Successful treatment of AK rests on the:

• choice of appropriate modality
• medical status of the patient
• patient’s lesion count
• lesion characteristics (e.g., size, duration, and growth pattern)
• anatomic location.

Several treatment options are available for AKs, including local destruction and topical drug therapy.

Locally Destructive Measures

Locally destructive measures are specialized, office-based, physician-administered, and are well suited to treat:

• individual lesions (i.e., cryosurgery, curettage, electrosurgery, or excision).
• extensive diffuse disease (i.e., chemical peels, dermabrasion, or laser ablation).

Cryosurgery

• Considered the “gold standard” of locally destructive measures.
• Can be associated with patient discomfort.
• Can result in scar formation or dyschromia (abnormal skin color).
• Success rate is highly technique-dependent.

Topical Drug Therapy

Imiquimod

• The only topical immune response modifier approved by Health Canada and the US FDA for the topical treatment of AKs and superficial BCCs (sBCCs).
• Enhances both the innate and acquired immune responses by increasing regional antiviral, antitumor and immunoregulatory activities.
  • Stimulates cytokine production, especially interferon, which explains imiquimod’s success in the treatment of AKs and sBCCs.

5-fluorouracil (5-FU)

• 5-FU is one of the most commonly used topical treatments.
• It is a structural analog of the DNA precursor thymine.
• The majority of people being treated with 5-FU will have moderate-to-severe erythema.
• Works by inhibiting the enzyme thymidylate synthetase, and:
  • interferes with the DNA synthesis.
  • creates unbalanced growth and cell death.
  • has its greatest effect in more rapidly dividing cells.

Photodynamic Therapy

• Based on the activation of a photosensitizer by visible light.
• Creates cytotoxic oxygen species and free radicals, which selectively destroy rapidly proliferating cells.
• 5-aminolevulinic acid (5-ALA) is:
  • a topical form of a photosensitizer.
  • absorbed to a greater extent by rapidly proliferating cells than by normal cells.
  • converted to protoporphyrin IX (PpIX), which is a potent photosensitizer within the cell. Activation of PpIX by physician-administered visible light produces singlet oxygen and free radicals, which leads to cell destruction.

Combination Therapy

In clinical practice, physicians frequently combine physical/destructive modalities, such as liquid nitrogen cryotherapy, to deal with visible AKs and imiquimod to treat the underlying field cancerization. This combination of cryotherapy and topical immunomodifier brings together a targeted approach through the precise immune system destruction of subclinical AK lesions that likely offers enhanced AK clearance. A recent study reported²:

• • imiquimod or vehicle used twice weekly was applied for 8 weeks following 3- to 5-second cryotherapy of target AKs within 50cm2 fields on the face or scalp.
• • at 12 weeks, more subjects treated with imiquimod achieved clearance of subclinical and total AKs.

Head-to-Head European Study

A recent comparative study evaluated 5% imiquimod with cryotherapy and 5-FU for the treatment of patients with AKs.³ This pivotal study by Stockfleth and colleagues addressed several critical components in the therapeutic management of AKs:

• clinical observation
• histologic assessment
• cosmetic outcome
• sustained clearance.

Histologically confirmed AKs were treated as follows:

The assessment was performed after the treatments (Test of Cure [TOC] 6 weeks after cryotherapy, 4 weeks after 5-FU and 8 weeks after imiquimod therapies), and at 12 months following the end of treatment. Treatment dosages are based on levels approved by the European Medicines Agency.

• TOC clearance rate is similar between 5-FU and imiquimod.
• In terms of extended efficacy, imiquimod demonstrates significantly greater sustained clearance rates at 12 months.
• The cosmetic outcome at 12 months also favors the use of imiquimod.

The differences in the results may be explained by their mode of action.

• Cryotherapy indiscriminately destroys good and bad cells.
• 5-FU interferes with DNA synthesis (again, good and bad cells are affected).
• Imiquimod selectively stimulates the immune system to act against both subclinical and clinically visible abnormal cells.
• Targeted lesion treatment using cryotherapy in combination with field therapy with imiquimod may yield optimal rates of clearance.

Previous research initiatives lacked the thorough comparative approach taken by this evidence-based study in exploring these common AK treatments. The data presented confirms that treatment with a topical immunomodifier provided superior sustained clearance and cosmetic outcomes in comparison to other commonly used therapies. Furthermore, these new study findings suggest that imiquimod can be considered by physicians as one of the first therapeutic options in the treatment of actinic keratoses.

References

1. Glogau RG. J Am Acad Dermatol 42(1 Pt 2):23-4 (2000 Jan).
2. Tan JK, et al. J Cutan Med Surg 11(6):195-201 (2007 Nov-Dec).
3. Krawtchenko N, et al. Br J Dermatol 157(Suppl 2):34-40 (2007 Dec).