INTRODUCTION
Actinic keratoses (AKs) are frequently occurring dysplastic epidermal lesions seen on chronically sun-exposed skin, including the face, scalp, forearms, and dorsal hands. AKs typically present as erythematous, scaling or hyperkeratotic papules, patches, and plaques and have the potential to progress to squamous cell carcinoma (SCC).1 In fact, the 10-year conversion rate of AK to SCC is estimated to range from 6 to 20 percent.2 Thus, these lesions should be treated.
The most frequently utilized treatments for AKs are crotherapy, electrodessication and curettage, and topical 5-fluorouracil (5-FU) and imiquimod therapies. Each of these treatment options offer risks and benefits that must be weighed with each patient. For example, cryotherapy may cause painful blisters and can cause hypopigmentation3 while 5-FU causes erythema, scaling, and crusting.4 More recently, photodynamic therapy (PDT) has emerged as a field-directed treatment for the removal of widespread lesions. PDT is an attractive treatment option because large skin areas and multiple lesions can be treated with superior response rates and favorable cosmetic outcomes.5
PDT requires photosensitizer activation by light to produce singlet oxygen that selectively kills target cells.6,7 Kennedy et al introduced 5-aminolevulinic acid (ALA) as a tissue-specific photosensitizing agent for the treatment of AK, SCC, and superficial basal cell carcinoma.8 When topically applied, ALA enters abnormal tissue where it is converted to protoporphyrin IX (PpIX), a photosensitive compound activated by visible light.8 PpIX is almost completely cleared from normal skin within 24 hours of treatment (Kerastick Package insert). Thus, the use of topical ALA avoids persistent generalized photosensitivity, and the small amount of PpIX in normal unaffected skin is photobleached rapidly, indicating that localized phototoxicity to normal skin is a minor concern. Therefore, photodynamic therapy with ALA is a safe and highly effective treatment for grade 1 or 2 AKs.9,10
Photodynamic therapy with a 20% topical solution of ALA HCl (Levulan Kerastick; DUSA pharmaceuticals, Inc, Wilmington, MA) and activation by 10 J/cm2 blue light (BLU-U Blue Light Photodynamic Therapy Illuminator; DUSA Pharmaceuticals, Inc.) exposure is approved by the US Food and Drug Administration (FDA) for the spot treatment of grade 1 or 2 AKs of the face or scalp after a 14- to 18- hour incubation period. This prolonged incubation time is impractical in an office setting and often results in significant recovery time and pain. Consequently, clinicians are motivated to experiment with choice of light source, photosensitizer type and dose, dosimetry, incubation time, and number of treatments. This review aims to discuss various PDT enhancements in order to maximize results and minimize treatment time and side effects, including occlusion, temperature elevation, pretreatment with topical 5-FU, and microneedle or laser assistance.
Occlusion
Schmieder et al11 methodically examined the effects of occlusion on efficacy and safety of PDT with ALA. In a multicenter, randomized vehicle-controlled phase 2 trial, subjects were randomized to receive either ALA or vehicle (Levulan Kerastick or placebo Kerastick, DUSA Pharmaceuticals, Inc.) application to both upper extremities. Each subject’s left and right extremity were then randomly assigned to occlusion or non-occlusion during the 3 hours incubation period. A single broad-area treatment of PDT with ALA to the full forearm following occlusion cleared 75% of baseline AKs, as compared with 47.4% for the non-occluded arm. Up to 2 broad-area treatments resulted in 88.5% and 70% lesion clearance,
