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Department of Dermatology
University of Regensburg
Actinic keratosis (AK), which often occurs in people who have experienced chronic light exposure, has a potential for developing into invasive squamous cell carcinoma. Therefore, in addition to local discomfort and disfigurement, early treatment of these precancerous lesions is important. Common standard methods of removal of AK include cryotherapy, curettage and electrodesiccation, and topical application of podophyllotoxin or 5-fluorouracil (5-FU). Following therapy, pain, inflammation, irritation, crusting and scar formation of the treated lesions may occur. The need for a less destructive and cosmetically more acceptable therapy has led to the development of several alternative treatment modalities.
Treatments currently available
AKs are rough and scaly, premalignant skin lesions located on areas of maximum sun exposure (see Figure 1). The main cause of AK is chronic exposure to ultraviolet B (UVB) light (280–320nm). AK affects a high proportion of pale-skinned individuals worldwide, and is often accompanied by other signs of UV damage, such as skin elastosis or pigmentary changes. In the northern hemisphere the documented prevalence of AK ranges between 11% and 25% for people aged 40 years or older, whereas in the white-skinned population living in Australia the incidence is estimated to range from 40% to 60%.(1,2) Rarely, AK may develop in younger patients as a result of excessive sun exposure, genetic diseases such as xeroderma pigmentosum, or immunosuppression.
While a proportion of AKs regress spontaneously or after sun avoidance, transformation of AK (usually of hyperkeratotic lesions) into squamous cell carcinoma occurs at a rate of approximately 1% per year, or about 16% over 10 years.(3,4) The only histological parameter to differentiate between AK and squamous cell carcinoma is the level of invasiveness. It is impossible to predict the point at which an individual AK will evolve into invasive squamous cell carcinoma. Thus, the principal indications for treatment of AK are to prevent the development of skin cancer. This is especially important in immunosuppressed patients, in particular organ transplant patients. Another indication for treatment is symptomatic relief and improving cosmetic appearance. Usually, AK can be diagnosed clinically, but biopsy may be required in cases of uncertainty in diagnosis or to exclude malignancy.
Prevention of AK is fundamental and includes avoiding sun exposure and using sunscreens. It has been shown that the regular use of sunscreens prevents the development of AKs and increases remission of existing ones.(5) For early, thin lesions, salicylic acid (2–5% in aqueous cream or ointment base) or topical retinoids (eg, 0.1% tretinoin twice daily) are effective. Patients with few lesions can be treated with cryotherapy(6) or curettage.(7) Curettage can be used alone or in conjunction with electrosurgery or chemical applications. It has the great advantage of providing a specimen for histological analysis. Topical 5-FU or topical podophyllotoxin (25%) is useful for patients with large numbers of nonhyperkeratotic lesions. Recently, in a long-term randomised controlled clinical trial, a one-week course of topical 0.5% 5-FU before cryosurgery was shown to be significantly more effective in reducing the number of AKs compared with cryotherapy alone.(8) Dermabrasion and laser resurfacing using the carbon dioxide laser or the Er:YAG laser are techniques that may be considered where multiple AK and extensive coexistent photodamage are present. Dermabrasion is suggested to be not only therapeutic but also prophylactic in the treatment of AK.(9) Also, full-face laser resurfacing has been shown to provide a long-term effective prophylaxis against AKs, and seems to reduce the incidence of AK-related squamous cell carcinoma.(10)
Masoprocol, imiquimod and topical diclofenac are new, alternative treatments. Olsen et al conducted a controlled study to evaluate the efficacy and safety of the topical antineoplastic agent masoprocol. There was a mean decrease of AK of the head and neck from 15.0 to 5.4, and a median percent reduction from baseline AK count of 71% at one-month follow-up. Eleven percent of AKs were cured.(11) In 62% of masoprocol-treated patients, irritation due to hypersensitivity occurred.
A 3% diclofenac formulation in 2.5% hyaluronic gel (diclofenac HA gel, Solaraze; Shire Deutschland GmbH) is a nonsteroidal anti-inflammatory drug (NSAID) approved for the treatment of AK.(12) The efficacy of the diclofenac gel applied topically twice daily in patients with AK has been evaluated in several randomised, double-blind studies. Efficacy was assessed 30 days after the end of treatment. Diclofenac gel produced significant reductions in the number of AKs, and could produce complete clearance of lesions when applied twice daily for 60 or 90 days. Fifty percent of patients treated for 90 days with diclofenac gel had total lesion number scores and cumulative lesion number scores of 0. Pruritus, dry skin and rash were the most frequently reported adverse events.(12,13)
Imiquimod 5% cream (Aldara; 3M Pharmaceuticals) is indicated for the treatment of external genital warts. Imiquimod stimulates the immune system by activating antigen-presenting cells, such as monocytes/macrophages and dendritic cells, to produce interferon and other cytokines and chemokines. To evaluate the efficacy of topically applied imiquimod 5% cream versus vehicle cream for the treatment of AK lesions on face and scalp, two randomised, double-blind studies were conducted.(14) Imiquimod cream used twice a week for 16 weeks was shown to be an effective and safe treatment of AK, with a complete clearance rate of 45.1% and a median percent reduction in AK lesions of 83.3%. The most commonly reported side-effects were itching, burning, erythema, crusting and scaling at the application sites.(14)
Another new alternative for the treatment of AK is photodynamic therapy (PDT; see Figures 2 and 3). Topical PDT using 5-aminolevulinic acid (ALA) or the methyl ester of 5-aminolevulinic acid (MAL, 160mg/g, Metvix; Photocure/ Galderma) is based on the photosensitisation of the target tissue by ALA- or MAL-induced porphyrins and subsequent irradiation with red light, inducing cell death in a dose-dependent manner via generation of reactive oxygen species. The ALA- or MAL-based photosensitisers are not photoactive as such, but show a preferential intracellular accumulation inside the tumour cells and are metabolised in the haeme biosynthesis to photosensitising porphyrins.
The efficacy of ALA- and MAL-PDT in the treatment of patients with AKs has been investigated in several phase II and III clinical trials. Currently, in Europe, Australia and New Zealand, MAL (Metvix) is approved for the photodynamic treatment of AKs and basal cell carcinomas in combination with red light. In the USA, MAL has been approved in July 2004 for the treatment of AK in combination with red light. ALA (Levulan Kerastick; DUSA) in combination with blue light has been approved in the USA in 2000 for the photodynamic treatment of AKs. In Europe, ALA as hydrochloride has been applied in custom-made formulations, either creams or gels, in a concentration of up to 20% ALA. ALA preparations or the MAL formulation Metvix are applied under occlusion to AKs with little overlap to the surrounding tissues for 4–6 hours (for ALA) or three hours (for MAL) before irradiation. For irradiation, incoherent light sources – lamps (PDT 1200L; Waldmann Medizintechnik) or LEDs (light-emitting diodes, such as Aktilite; Galderma or Omnilux; Waldmann) – which match the absorption maxima of the ALA- or MAL-induced porphyrins, are generally used.
Side-effects of therapy are stinging and burning during irradiation and a couple of hours thereafter. A few days after irradiation, a dry necrosis sharply restricted to the tumour-bearing areas is seen, and after 10–21 days, crusts come off and complete re-epithelialisation is observed. Due to the photosensitisation, which is restricted to cells of epithelial origin, no scarring or ulceration is usually observed clinically.
The efficacy of ALA–PDT has been observed in several open studies showing clearance rates of AK already ranging from 71% to 100% after a single treatment.(15,16) Recently, a randomised, placebo-controlled study with ALA (Levulan Kerastick) followed by illumination with blue light was published.(17) Complete response rates for ALA–PDT patients with >-75% of the treated lesions clearing at eight and 12 weeks were 77% and 89%, respectively, whereas in the placebo group clearing rates were only 18% and 13%. In several controlled, randomised prospective studies, MAL–PDT was compared with cryosurgery or placebo in the treatment of AK.(18–20) Patients received either a single or double treatment with MAL–PDT, placebo or cryosurgery. The complete response rates for MAL–PDT ranged between 69% and 91%, and were superior to placebo–PDT and at least as effective as cryotherapy. Cosmetic outcome with MAL–PDT was excellent to good, and was judged to be better than with cryotherapy.
So far, the proven advantages of PDT include clinical outcomes comparable to those of standard treatments, the possibility to treat multiple tumours and incipient lesions simultaneously, relatively short healing times, tumour control in immunocompromised patients (ie, transplant recipients), good patient tolerance and an excellent cosmesis.(21)
Treatment of AKs, which have the potential to progress to malignant skin cancer, is mandatory. Several new therapeutic options for the treatment of AKs offer alternatives to established and often more aggressive or invasive therapies. Advantages of new therapies, such as topical diclofenac, imiquimod or PDT, are the possibility to manage widespread lesions and treat subclinical lesions; in addition, these treatments are well tolerated and lead to excellent cosmetic results. The decision as to which therapy might be best should be based on the patient’s history, characteristics and compliance, and type (hypertrophic or nonhypertrophic), localisation and number of AKs.