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New Evidence for the Treatment and Management of Actinic Keratoses

M. Sapijaszko, MD, FRCPC
Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB
Western Canada Dermatology Institute, Surgical Unit, Edmonton, AB

Background

Increasingly, patients are seeking medical consultation for the management of photodamage, actinic keratoses (AKs), 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 AKs.
  • 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

AKs are skin neoplasms that reflect cumulative UV damage to the epidermis. All AKs should be treated; 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 AKs to invasive SCC was estimated to range from 0.025%-16% per year.1
  • Risk factors for AK 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 AKs rests on the:
  • choice of appropriate modality
  • medical status of the patient
  • the patient’s lesion account
  • characteristics (e.g., size, duration, and growth pattern)
  • anatomic location.
Several treatment options are available for AKs, including topical drug therapy and local destruction.

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Locally Destructive Measures

Locally destructive therapies are specialized, office-based, and physician-administered, and are well suited to treat:
  • individual lesions (e.g., cryosurgery, curettage, excision, or electrosurgery)
  • extensive diffuse disease (e.g., dermabrasion, chemical peels, or laser ablation).

Cryosurgery

  • Is the “gold standard” of locally destructive measures.
  • Liquid nitrogen separates the epidermis from the dermis; it destroys both dysplastic and intact cells.
  • Can be associated with patient discomfort.
  • Can result in scar formation or dyschromia.
  • Success rate is highly technique-dependent.

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Topical Drug Therapy

Imiquimod

  • The only approved topical immune response modifier approved by Health Canada and the FDA for the topical treatment of AKs and superficial BCCs (sBCCs).
  • Enhances innate and acquired immune response by increasing regional antiviral, antitumor, and immunoregulatory activities.
    • Success in treating AKs and sBCCs is due to cytokine production stimulation, especially interferon.
  • Side-effects include erythema, itching, and burning.
  • Potential for improved patient compliance due to simplified dosing regimen.
    • Dosing at 2-3 times/week for imiquimod vs. twice daily for 5-fluorouracil (5-FU)

5-fluorouracil (5-FU)

  • 5-FU is a commonly used topical treatment.
  • 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.
  • Inhibits the enzyme thymidylate synthetase, and:
    • interferes with the DNA synthesis.
    • creates unbalanced growth and triggers cell death in both healthy and abnormal cells.
    • has its greatest effect on more rapidly dividing cells.

Photodynamic Therapy (PDT)

  • PDT photosensitizers are activated by visible light.
  • Creates cytotoxic oxygen species and free radicals, which selectively destroy rapidly proliferating cells.
  • 5-aminolevulinic acid is a topical photosensitizer that:
    • is absorbed more by rapidly dividing cells.
    • is 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.

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Combination Therapy

In clinical practice, physicians frequently combine a physical/destructive modality, e.g., liquid nitrogen cryotherapy to treat visible AKs, with imiquimod to target 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, likely offering enhanced AK clearance. In a recent study:2
  • imiquimod or vehicle was applied twice weekly for 8 weeks following 3- to 5-second cryotherapy of target AKs within a 50cm2 fields on the face or scalp.
  • at 12 weeks, more subjects treated with imiquimod achieved clearance of subclinical and total AKs.

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Head-to-Head European Study

A recent comparative study by Krawtchenko, Stockfleth, and colleagues3 evaluated 5% imiquimod with cryotherapy and 5-FU for the treatment of AKs. This pivotal study addresses several critical components in the therapeutic management of AKs that include clinical observation, histologic assessment, cosmetic outcome, and sustained clearance.

Histologically confirmed AKs were treated as follows:

Patients Therapy Used Therapy Details
26 patients 5% imiquimod 3 times/week for 4 weeks, 4 week rest period followed
by the second cycle of 3 times/week for 4 weeks
24 patients 5% 5-FU b.i.d. for 4 weeks
25 patients Cryotherapy with liquid nitrogen 20 - 40 seconds for each lesion for up to 2 treatments
 
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 were based on levels approved by the European Medicines Agency.

Therapy Group Clinical Clearance at TOC Histological Clearance at TOC Sustained Clearance at 12 months Excellent Cosmetic Outcome (% of pts)
Cryotherapy 68% (17 of 25) 32% (8 of 25) 4% (1 of 25) 4%
5% 5-FU 96% (23 of 24) 67% (16 of 24) 33% (8 of 24) 4%
5% imiquimod 85% (22 of 26) 73% (19 of 26) 73% (19 of 26) 81%
 
  • The TOC clearance rate was similar between 5-FU and imiquimod.
  • In terms of extended efficacy, imiquimod demonstrated significantly greater sustained clearance rates at 12 months.
  • The cosmetic outcome at 12 months also favoured 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).
  • Imiquimod selectively stimulates the immune system to act against subclinical and clinically visible abnormal cells.
  • Targeted treatment with cryotherapy combined with field therapy using imiquimod may yield optimal clearance rates.
Previous research initiatives lacked the thorough comparative approach taken by this evidence-based study in exploring these common AK treatments. Data presented confirms that treatment with a topical immunomodifier provided superior sustained clearance and cosmetic outcomes in comparison with other commonly used therapies. Furthermore, these new study findings suggest that imiquimod should be considered by physicians as one of the first therapeutic options in the treatment of AKs.

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References

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

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