Aminolevulinic Acid 20% Solution Combined With Photodynamic Therapy for Treatment of Actinic Keratoses: A Review

November 2021 | Volume 20 | Issue 11 | Original Article | 1239 | Copyright © November 2021


Published online November 1, 2021

Joe Gorelick MSN FNP-C,a Scott Freeman MCMS PA-Cb

aCalifornia Skin Institute, San Jose, CA
bAdvanced Dermatology, St. Petersburg, FL

curettage; laser therapy; and systemic therapy (eg, systemic retinoids). Light sources for PDT include red- and blue-spectrum; red narrow-spectrum sources require less illumination time and may be associated with a higher rate of response.3 The addition of photosensitizing agents to PDT induces apoptosis and necrosis of target tissue. Factors that influence treatment selection include efficacy, potential for side effects, number of lesions, grade, location of lesions, response to previous therapy, cosmetic impact, regimen flexibility and convenience, availability, patient preference, and cost.1,3

Treatments can be directed to specific lesions or the entire “field.” When isolated lesions are treated, for example, with cryotherapy, underlying subclinical actinic damage may not be visualized. By using field therapy techniques, both clinical and subclinical lesions receive treatment, achieving more comprehensive clearance of actinic damage.

Neither surgical excision nor biopsy is routinely performed.7 Biopsy may be appropriate if NMSC or other conditions such as Bowen’s disease cannot be ruled out with clinical evaluation and dermoscopy.8

Treatment Guidelines for AK
Several treatment guidelines for treatment of AK have been published, including Canadian, European, British, Italian, and Swiss guidelines.3,7-10 Additional treatment guidelines are available for patients at higher risk of SCC.11 There is significant heterogeneity among the organization and structure of available guidelines. For example, Canadian guidelines recommend surgical excision or curettage for isolated AKs and state that topical treatments including 5-FU, imiquimod, or ingenol mebutate (discontinued in 202012) may be used for isolated or clustered AKs (4 or more), whereas PDT or other field-directed therapies are recommended for clustered AKs.7 British guidelines provide an “A” recommendation for several therapies: diclofenac, cryotherapy, PDT with either 5-aminolevulinic acid or its methyl ester (methyl aminolevulinate; MAL) as a photosensitizing agent, 5-FU, imiquimod, or ingenol mebutate. Treatments with a “B” recommendation include laser resurfacing, chemical peels, dermabrasion, and other topical agents.3,13 Tirbanibulin— approved by the FDA for AK treatment in December 2020—is not yet included in treatment guidelines.14

Some guidelines suggest that treating AK is not always required; however, experts are divided on this issue.3 Guidelines from the British Association of Dermatologists indicate that patient preference and clinical circumstances (eg, extent, duration, symptoms, and risks for skin cancer) should be considered when determining whether to treat AK.3 In contrast, Canadian treatment guidelines state that AKs should be treated due to their chance of progression to SCC and because they can be difficult to distinguish from early SCC.7 The Progressing Evidence in AK (PEAK) Working Group recommends treatment of AK by default, especially in patients at increased risk of NMSC,2 although direct evidence that AK treatment prevents progression to NMSC is lacking.2 AK lesions that progress to SCC following treatment may have been SCC lesions that were initially diagnosed as AK and had a deep component that persisted through treatment.15 In the clinical setting, in light of the potential for malignancy, most identified AKs are treated.

A comprehensive review of available guidelines is beyond the scope of this article. In general, cryotherapy is the most widely recommended treatment for isolated AKs, whereas field therapies (5-FU, imiquimod, PDT with a photosensitizing agent, and likely tirbanibulin when added to guidelines) are recommended for multiple AKs.13 PDT for AK is considered highly effective, with efficacy at least comparable to other FDAapproved treatments. It is associated with improved cosmetic outcomes compared with cryotherapy.16

Aminolevulinic Acid 20% Solution Combined With Photodynamic Therapy (ALA-PDT)
Mechanism of Action of ALA-PDT
Due to its encouraging efficacy and safety profile, including favorable cosmetic outcomes, and field-directed nature, PDT with 5-aminolevulinic acid 20% solution as a photosensitizer (ALA-PDT) is often used in treatment of AK. 5-aminolevulinic acid is a prodrug that is absorbed and metabolized to protoporphyrin IX (PpIX). When PDT of the appropriate wavelength is applied, a cytotoxic reaction produces reactive oxygen species (ROS), resulting in apoptosis and necrosis of the treated lesion with minimal damage to untreated skin.15,17

Clinical Efficacy of ALA-PDT
Per US labeling, ALA-PDT combining 5-aminolevulinic acid 20% solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is indicated for photodynamic therapy (treatment) of minimally to moderately thick AKs of the face or scalp, or AKs of the upper extremities.18 In several phase 3 or 4 clinical trials, ALA-PDT was highly effective for treatment of minimally to moderately thick AKs when used as directed (Table 1).1,15,19,20 Initial trials investigated safety and efficacy of ALA-PDT for the treatment of AK on the face and scalp, while more recent trials have addressed AK on the upper extremities.15

In a phase 3 multicenter trial conducted by Piacquadio et al, 243 patients with 4 to 15 AK lesions on the face or scalp were randomized to treatment with PDT and either ALA or vehicle.19 At 8 weeks after treatment, ≥75% of AK lesions were cleared in 77% of patients receiving ALA-PDT vs 18% receiving vehicle- PDT (P<0.001).19 Complete response rates (100% clearance) at 8 weeks occurred in 66% of ALA-PDT treated patients vs 11% of vehicle-PDT treated patients (P <0.001).19 Photographs from a