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Surgery and Cosmetics

Luis Fernando Tovo, MD, PhD

Update on the Treatment of Actinic Keratoses (AKs)

Luis Tovo

Tuesday, July 03, 2007

Actinic keratoses (AKs) are very common premalignant epidermal lesions that, in certain cases, can develop into non-melanoma skin cancer.1-3 AKs result from carcinogens, principally UV light exposure.1,2,4 The histologic pattern of AK is characterized by disordered epidermal differentiation that does not extend through the full thickness of the epidermis.5 When the full thickness of the epidermis is involved, the lesion is then classified as carcinoma-in-situ.5

AKs occasionally progress to invasive skin cancer. Richard Glogau evaluated that the risk of progression of AKs to invasive squamous cell carcinoma (SCC) for individual lesions ranged from 0.025% to 16% per year. Extrapolation from these clinical studies suggests a rate risk of progression of AKs to SCC of ~8% (average among the rates in the studies reviewed).6

Considering that AK is a pre-malignant lesion, the primary treatment is to destroy the abnormally differentiated epithelium.7 This can be accomplished by a variety of treatment options including cryosurgery, biopsy, curettage and electrodesiccation, and excision. AKs can also be treated by lasers and chemical peels; although, these are not standard treatments.1,8 Topical chemotherapy with 5-fluorouracil is also indicated.1,9 Unfortunately, its distribution by the pharmaceutical industry was discontinued in Brazil for a long time and has only recently been made available in our country again.

The choice of therapy depends on localization, age, gender, extent of disease, patient's compliance, number of lesions, and the risk of transformation into SCC (e.g. immunosupression). Among the mentioned methods, curettage has the advantage of being quick and easy and of a low cost. Disadvantages include risk of scarring, the need for local anesthesia before the procedure, and its limitations to small areas.10

Cryotherapy is a low-cost, quick, and easy method as well. The disadvantages are pain, hypopigmentation, depressed scars, and limitation to small areas.11

A good treatment option for field AKs is 5-fluorouracil, a cytotoxic agent that has been used since 1968, and with recent phase III clinical trial results. Although it is a good treatment option for field AKs, it has the disadvantages of prolonged erythema, erosion, ulceration, exsudation and pain, lack of patient compliance, and only partial effectiveness in removing deep or hyperkeratotic lesions.10

All these treatment modalities, despite the mentioned disadvantages, are well-established therapies currently in use in dermatology practice.

Besides the most commonly performed treatments, there are two new treatment modalities that are very promising: topical imiquimod, and photodynamic therapy.

Topical Imiquimod and Photodynamic Therapy

Imiquimod is an immune response modifier, with an anti-viral and anti-tumoral activity resulting from the immune modulation of cytokines (interferon alpha, and others), and cellular immunity. It is topically applied for the treatment of AK lesions or AK field areas.12  There are different protocols to treat AKs. In Europe, it is prescribed topically 3 times per week for 4 weeks, repeated after a 4-week interval in case of incomplete response and in the United States, it is prescribed twice per week for 16 consecutive weeks.13  The incidence of erosion, scabbing, and erythema depends on the clinical stage of the treated area. Cure rates vary from 40% to 87.5%.13,14 The main limitations of this method are the long treatment duration, limited compliance related to the side effects and the cost of treatment.

Photodynamic therapy (PDT) involves the use of a photosensitizing agent, oxygen, and light of a specific wavelength to produce controlled cell death, and it is a very good treatment modality for the treatment of AKs and field AKs, and also for superficial basal cell carcinoma and Bowen's disease. The treatment offers cure rates similar to or better than conventional non-surgical procedures like cryosurgery, curettage, and electrodesiccation with improved cosmetic outcome.15 PDT using topical 5-aminolevulinic acid (ALA) is effective in the treatment of AKs. The development of a new photosensitizer: methyl aminolevulinate (MAL) improved the PDT with better skin penetration, greater selectivity for neoplastic cells than ALA, and lower pain during the PDT procedure.15

According to a recent publication: "PDT with MAL and ALA is a highly effective treatment for AK offering the advantage of excellent cosmetic outcome and could therefore be considered as a first-line therapy."16 This treatment is sometimes painful (when treating field AKs), and the cost is considered high by the Brazilian public health system.

The Financial Structure in Brazil Compared to Other Countries

In Brazil, the financial structure to support the medical services is based on the Public Health System (SUS), and the National Agency of Supplemental Health (ANS) that regulates the private groups that operate health services, like "Medicare" and reimbursement plans.17

Responsible for supervising health services for more than 37 million consumers, the ANS has a budget proportionally bigger than the SUS, which takes care of the Brazilian population (more than 180 million people).17

The SUS pays for different treatment modalities for AK, except for imiquimod and PDT. The resources are not sufficient to offer the best possible approach to the treatment of AKs for the whole population, like in some countries with very good public health systems (including Australia and Germany).

Despite the better financial structure (private system), the ANS, which provides medical care for about 25% of the population, pays for destructive treatment modalities (cryosurgery, electric desiccation, curettage) in AK treatment but not for imiquimod and PDT.17

I asked 59 colleagues to fill out a brief survey at the last Regional Meeting of the Brazilian Society of Dermatology in São José do Rio Preto - SP to find out how AKs are treated in Brazil. The question was: Which is your first therapeutical choice when treating AKs?

  • 50.85% said cryotherapy
  • 10.17% said curettage and electrodessication
  • 10.17% said chemosurgery with tricloacetic acid
  • 8.47% said 5-fluorouacil
  • 3.39% said imiquimod
  • 15.25% said they used more than one option depending on the clinical stage of the AK

The Brazilian Society of Dermatology promoted a dermatological census that showed the most prevalent diseases in our specialty with the purpose to contribute to the development of healthcare policy in Brazil.18

One of the subjects of the research was the most prevalent cause of consultation. The most frequent complaint was acne, followed by superficial mycosis and pigmentary abnormalities. The fourth cause was AK, which is a very high prevalence among all skin diseases.18

Considering the high prevalence of AKs in our public database,18 the potential malignant transformations of some AKs into squamous cell carcinoma,1 the fact that people can have 3 to 10 times more subclinical lesions than visible ones,19 and that the treatment of skin cancers should not only be focused on the tumor but also on the surrounding skin with actinic damage,20 the Brazilian Public Health System and third-party payers should dedicate special attention to prevention of AKs with efforts on education, and the treatment of AKs in the most complete approach, including incentives for the treatment of AKs fields like: 5-fluorouracil, imiquimod, and PDT. The high cost of imiquimod, the cure rates for PDT, and patient compliance (especially for PDT)16 should be considered.

Conclusion

Brazil is a country with different approaches in medical care. As mentioned, the ANS and the public health system have different budgets for medical assistance. The need of a pharmacoeconomical study to decide the best therapeutical modatilities for the treatment of AKs is necessary in order to make decisions about the methods mentioned in this commentary.

References

  1. Feldman SR, Fleischer AB, Williford PM, et al. Destructive procedures are the standard of care for treatment of actinic keratoses. J Am Acad Dermatol. 1999;40(1):43-7.
  2. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997;36(4):650-3.
  3. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000;42(1 Pt 2):4-7.
  4. Dinehart SM, Nelson-Adesokan P, Cockerell C, et al. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer. 1997;79(5):920-3.
  5. Schwartz RA. Premalignant keratinocytic neoplasms. J Am Acad Dermatol. 1996;35(2 Pt 1):223-42.
  6. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42(1 Pt 2):23-4.
  7. University of Pennsylvania Cancer Center. Actinic keratosis. NCI/PDQ Physician Statement 1996.
  8. Coleman III WP, Yarborough JM, Mandy SH. Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg. 1996;22(1):17-21.
  9. Breza T, Taylor R, Eaglstein WH. Noninflammatory destruction of actinic keratoses by fluorouracil. Arch Dermatol. 1976;112(9):1256-8.
  10. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol. 2000;42(1 Pt 2):25-8.
  11. Zouboulis CC. Cryosurgery in dermatology. Eur J Dermatol.  1998;8(7):466-74.
  12. Flowers F. Imiquimod in the treatment of actinic keratoses and other intraepithelial neoplasms. Int J Dermatol. 2002;41 Suppl 1:12-5.
  13. Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004;50(5):714-21.
  14. Persaud A, Lebwolh M. Imiquimod cream in the treatment of actinic keratoses. J Am Acad Dermatol. 2002;47(4):S236-9.
  15. 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. 2003;48(2):227-32.
  16. Braathen LR, Szeimies RM, Basset-Sequin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus. J Am Acad Dermatol.  2007;56(1):125-143.
  17. Brazilian Ministry of Health. National Agency of Supplemental Health. www.ans.gov.br.
  18. Brazilian Society of Dermatology. Dermatological Census. www.sbd.org.br.
  19. Maddin S. Dermatologic therapy. In: Moschella SL, Hurley HJ, eds. Dermatology. 2nd ed. Philadelphia: WB Saunders Co; 1985:1946-79.
  20. Braakhuis BJ, Tabor MP, Kummer JA, et al. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63(8):1727-30.
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