A ctinic keratosis (AK) is the third most common reason patients visit us, and its prevalence has now reached epidemic proportions.1
More than 1 million new cases of AK are reported annually, with lifetime risks of developing SCC estimated at 7% to 11%.3 Based on data collected from five clinical studies, the risk for progression of AK to invasive SCC ranged from 0.025% to 16% per year, calculated on the basis of thousands of keratoses distributed in a large population.4
All AK lesions, if left untreated, can progress, involve deeper tissues and eventually metastasize.7 Therefore, regardless of stage, treatment of all AKs is justifiable.
The primary treatments for AK include cryosurgery, curettage and topical 5-fluorouracil (5-FU). Despite the popularity of these surgical and medical approaches to the management of AK, they’re associated with distinct limitations relative to tolerability, convenience and short- and long-term cosmetic impact.
A clinical need has existed for new therapeutic alternatives that feature enhanced patient tolerance, compliance and cosmetic outcome. Photodynamic therapy (PDT) with aminolevulinic acid (ALA) is a recent answer to problems with previous therapies.
Here, we’ll discuss the clinical and epidemiological aspects of AK and treatment options, including benefits and limitations of these therapies and where each fits into a proposed treatment algorithm based on lesion count. Plus, see “PDT and Laser: Novel Treatments for AKs,” on page 67 for information about a new treatment method under investigation.

Treatment Algorithm
The ideal treatment of AKs is defined by patient needs and must take into account:
• short- and long-term efficacy (percentage of lesions cleared and durability of response)
• cosmetic impact (deleterious effects such as scarring, hypo- and hyperpigmentation, versus any cosmetic improvement to the treated areas)
• tolerability(pain intensity and duration, degree and persistence of post-treatment disfigurement)
• patient compliance and satisfaction (frequency of visits to physician, pharmacy, rapidity of recurrent lesions developing).
Lesion characteristics (for example, size, number, location, stage) must also be considered carefully in selecting the most appropriate treatment modality. For more on the advantages and disadvantages of treatment options, see “Benefits and Limitations of Common AK Treatments,” on page 64.
Low Lesion Count (1 to 5). Cryosurgery is often the choice of therapy for single lesions or a low lesion count. It’s quick and effective, and the pain and disfigurement issues are limited when only a few lesions are treated. Curettage should be considered for a low lesion count if the AKs are markedly hyperkeratotic or on high-risk sites, or if there’s clinical suspicion of SCC.
Occasionally, 5-FU is used to “spot treat” limited numbers of lesions on patients highly adverse to pain. However, this approach is unpredictable with regard to efficacy and eliminates the advantages of diffuse therapy with 5-FU. ALA/PDT is traditionally reserved for higher lesion counts. PDT represents an ideal treatment for the subset of patients with cosmetic concerns. In these patients, often younger, ALA/PDT allows more rapid healing and minimizes the risk of long-term scarring and hypopigmentation. For some, this far outweighs the small inconvenience of returning for a second visit.
Moderate Lesion Count (6 to 15). For a moderate lesion count, cryosurgery remains the most popular choice, for similar reasons as with low lesion counts. The impact of the ease of using cryotherapy for the physician continues to be a factor as well. ALA/PDT becomes a more appropriate choice with a larger lesion count. The excellent efficacy, patient tolerance and short- and long-term cosmetic outcome associated with ALA/PDT make it preferable to cryosurgery for many patients as the lesion count increases. Using
5-FU is a possible option, with a benefit being the potential for treatment of subclinical lesions with diffuse treatment. But, the short-term cosmetic impact and discomfort of 5-FU appears to far outweigh any advantage with this modality for patients in this group.
High Lesion Count (>15). ALA/PDT is optimal therapy for this group, given its established high efficacy rates and improved cosmetic outcome. This treatment modality involves topical administration of a photosensitizing compound, aminolevulinic acid (ALA). ALA is a prodrug, which is preferentially taken up by AK cells and converted to protoporphyrin IX (PpIX), a potent endogenous photosensitizer. Upon exposure of PpIX to light, singlet oxygen is produced with resultant cytotoxic effects on target tissue. ALA/PDT is administered as a two-step process, according to a standardized protocol. First, a stick applicator is used to apply the 20% ALA solution (Levulan Kerastick), which is created by mixing ALA in powder form with a solvent. The second step, administered 14 to 18 hours later, involves blue light irradiation of the AK lesions at a wavelength of
417 nm for 1000 seconds (light dose of 10 J/cm2).
The tolerability advantage of ALA/PDT verus cryotherapy is heightened as more lesions are treated. Cryosurgery is less ideal for multiple lesions, since efficacy may decline at high lesion counts due to poor tolerability of aggressive treatment for numerous lesions. The cosmetic impact of cryosurgery is also quite severe with high lesion counts. The standard of care for high lesion counts is still 5-FU for many physicians.

Other Considerations
Besides lesion count, degree of patient acceptance and tolerability are important criteria in selecting any dermatologic treatment. So ALA/PDT may continue to gain in popularity. In the pivotal studies of ALA/PDT, a substantial number of patients (94%) rated cosmetic response as excellent or good, whereas 85% of patients previously treated with cryosurgery or 5-FU indicated they would prefer ALA/PDT for the management of AK in the future.
Side effects of ALA/PDT reported during Phase III clinical trials included stinging and/or burning, itching, erythema and edema, all of which were mild or moderate in severity and rarely required medication. Erythema was experienced by virtually all patients after treatment, resolving to near-baseline levels by week 1 after light treatment. Edema was experienced by 28% to 41% of patients after treatment, resolving to near-baseline levels by week 1 after light treatment. Pigmentation changes occurred rarely; hyper- and hypopigmentation was noted in only 5% of patients, treated with ALA/PDT, versus 12% in vehicle-treated patients. Patients experienced no systemic photosensitivity.

Broad-Based Application of ALA/PDT
Based on the tolerance and cosmetic superiority of ALA/PDT, a number of clinicians have begun using this treatment in a variety of ways. So-named “broad-based PDT” or “confluent PDT” treatments are performed by applying the ALA solution not just to individual lesions, but diffusely to a larger area of sun-damaged skin, such as the face, scalp, arms or legs. Light treatments are then performed normally. It’s presumed that such diffuse treatments will also destroy sub-clinical AK lesions, increasing the likelihood of extended remission. Formal evaluation is still needed. Also, such treatments may provide diffuse cosmetic improvement to sun-damaged skin in general, with a reduction in abnormal pigmentation, rough skin texture and some benign skin lesions (based on personal communication with Michael Gold, M.D., June 2001).
If future studies confirm that broad-based ALA/PDT does provide superior long-term control of AK, along with cosmetic benefits, this would further strengthen its position in the treatment algorithm. You could argue that broad-based PDT would become the treatment of choice for patients with high lesion counts, based on superior tolerability compared with equivalent cryotherapy, similar remittive effects as those seen with topical 5-FU and improved cosmetic outcome.

Curbing the Rising Epidemic
AK has reached epidemic proportions in the United States, underscoring the clinical importance of early detection and treatment. Viewing AK on a biologic continuum with SCC, with the progression of one to the other, implies that patients must be followed closely and educated about protection against sun exposure. With early AK diagnosis and management, high cure rates and prevention are possible.
Although the goal of treatment for AKs is complete eradication of the tumor, you must consider cosmetic and functional issues when choosing the most appropriate therapy. A number of limitations related to patient discomfort and compliance have been identified with respect to the more traditional treatments for AK (cryotherapy, curettage and 5-FU). As such, a critical need for safe and innovative therapies that are aesthetically pleasing for the patient was realized.
Recent advances in dermatology have provided several new options for the treatment of AK. Though PDT isn’t entirely new as a treatment concept, the introduction of ALA/PDT incorporates advanced technology into an effective and easily integrated therapy that targets affected tissue, limits damage of normal tissue, and reduces adverse events. Demonstrating excellent tolerability and strong patient acceptance, ALA/PDT appears promising for the treatment of patients with multiple AK lesions.
This treatment technique is a welcome addition to the armamentarium of AK destruction techniques, offering therapeutic promise and distinct advantages.