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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

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 <1cm in diameter.
  • 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:

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 two 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 are 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 patients)
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%
  • 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).