Original Research

CO2 Laser Ablative Fractional Resurfacing Photodynamic Therapy for Actinic Keratosis and Nonmelanoma Skin Cancer: A Randomized Split-Side Study

Author and Disclosure Information

Aminolevulinic acid (ALA) photodynamic therapy (PDT) is a preferred method for treatment of multiple actinic keratoses (AKs) in broad skin areas (referred to as field cancerization). Pretreatment with CO2 laser ablative fractional resurfacing (AFR) may increase the efficacy of PDT. This study compared the effect and durability of CO2 laser AFR-assisted ALA-PDT vs ALA-PDT alone in the treatment of AKs and nonmelanoma skin cancers (NMSCs) at various body locations. In this randomized, split-side study, 19 patients had 1 side pretreated with AFR before treatment of both sides with ALA-PDT. Results indicated that pretreatment with AFR provided superior clearance of AKs and thin NMSCs at 6 months compared to ALA-PDT alone.

Practice Points

  • Pretreatment with CO2 laser ablative fractional resurfacing (AFR) before photodynamic therapy (PDT) provided efficient clearance of actinic keratosis (AK).
  • Superior clearance of lesions was seen at 6 months for AK and thin nonmelanoma skin cancers (NMSCs) on pretreated sites compared to PDT alone, with no novel adverse events reported.
  • A reduced incubation period for aminolevulinic acid (ALA) absorption before PDT was used, leading to a shorter overall treatment time.



Actinic keratosis (AK) is the most common cutaneous lesion and is regarded as a precursor to nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma (SCC).1 Field cancerization refers to broad areas of chronically sun-exposed skin that show cumulative sun damage in the form of clinical and subclinical lesions. It is not feasible to treat large areas with multiple overt and subclinical lesions using surgical methods, and photodynamic therapy (PDT) has become a preferred method for treatment of field cancerization.2 Topical PDT uses the heme biosynthesis pathway precursors aminolevulinic acid (ALA) or methyl ALA (MAL), which localizes in the treatment area and is metabolized to protoporphyrin IX.3 After an incubation period, activation by a light source results in the formation of cytotoxic oxygen species,4 with reports of efficacy over large areas and excellent cosmetic outcomes.2

Laser ablative fractional resurfacing (AFR) also has been investigated as a treatment of AKs; CO2 laser AFR treatment resulted in a short-term reduction in the number of AK lesions and appeared to reduce the development of new lesions.5 However, case reports and small studies have indicated that pretreatment with laser AFR can increase the efficacy of PDT by creating microscopic vertical channels facilitating deeper penetration and uptake of the ALA.6 The use of erbium:YAG lasers in combination with PDT has demonstrated notable clinical and aesthetic improvements in treating basal cell carcinomas (BCCs)7 and AKs,8 with enhanced efficacy in moderate to thick AKs in particular. Hædersdal et al6 reported that CO2 laser AFR facilitated delivery of MAL into porcine skin, with AFR appearing to bypass the stratum corneum and deliver the treatment to the deep dermis.

The combination of CO2 laser AFR and PDT has shown statistically significant increases in efficacy for treatment of AKs compared to PDT alone (P<.001).9 In a small study, Alexiades10 reported a statistically significant improvement in AKs at 4 and 8 weeks posttreatment for 10 patients receiving CO2 laser AFR-PDT vs conventional PDT (P<.05). Studies of organ transplant recipients—who are at higher risk for AK and NMSC development—demonstrated favorable results for combined CO2 laser AFR and PDT vs either laser treatment11 or PDT9,12 alone, with significant reductions in the number of AKs (P=.002). Results were maintained for 3 to 4 months after treatment. Additional studies have shown that combining CO2 laser AFR and PDT may reduce the PDT incubation time or number of treatments required to achieve a response over conventional PDT.13,14

Our proof-of-concept study was designed to assess efficacy of CO2 laser AFR to enhance an approved drug delivery system in the treatment of AK and NMSC. The objective was to compare effect and durability of AFR-PDT vs standard ALA-PDT in the treatment of AK and NMSCs in a split-sided study of various body locations.


This randomized, split-sided study compared CO2 laser AFR-PDT to standard ALA-PDT for the treatment of AK and NMSC conducted at 1 site in Los Gatos, California. Patients who had a skin cancer screening and received a biopsy diagnosis of AK or NMSC were invited to attend an enrollment visit. Key inclusion criteria for enrollment were male or female patients aged 40 to 85 years with notable symmetrically comparable photodamage (at least 1 AK per square centimeter) in 1 or more skin areas—scalp, face, or distal extremities—with presence of clinically identifiable NMSCs proven by biopsy. Key exclusion criteria were patients who were pregnant; patients with epilepsy, seizures, or a photosensitive disorder; those taking photosensitizing medication (eg, doxycycline, hydrochlorothiazide); or immunocompromised patients. The study was approved by an institutional review board (Salus IRB [Austin, Texas]), and each participant underwent a complete and informed consent process.

Laterality for pretreatment with AFR followed by ALA-PDT vs ALA-PDT alone was determined at the time of treatment using a computer-based random number generator; even numbers resulted in pretreatment of the right side, and odd numbers resulted in pretreatment of the left side. Because of the difference in pretreatment methods for the 2 sides, it was not possible to perform the procedure under blinded conditions.

The treatment area was prepared by defatting the entire site with 70% isopropyl alcohol, followed by benzalkonium chloride antibacterial cleansing for the AFR pretreatment side. A 7% lidocaine/7% tetracaine ointment was applied under polyethylene wrap occlusion to the AFR pretreatment side for 20 minutes. Additionally, nerve blocks and field blocks with a mixture of 1.1% lidocaine with epinephrine/0.5% bupivacaine with epinephrine were performed wherever feasible. After 20 minutes, the lidocaine-tetracaine ointment was removed with isopropanol, and AFR treatment commenced immediately with the SmartXide DOT laser (DEKA)(1 pass of 25 W, 1200-microsecond duration at 500-µm spacing, 200-µm spot size, achieving 12% surface area ablation). Hyperkeratotic treated areas were debrided with saline and received a second pass with the laser. Aminolevulinic acid solution 20% (Levulan Kerastick; DUSA Pharmaceuticals, Inc)15 was applied to both sides of the treatment area and allowed to absorb for a 1-hour incubation period, which was followed by blue-light exposure at a power density of 10 mW/cm2 for 16 minutes and 40 seconds using the BLU-U Photodynamic Therapy Illuminator (DUSA Pharmaceuticals, Inc). Areas treated with AFR were then covered with a layer of Aquaphor ointment (Beiersdorf, Inc) and an absorptive hydrogel dressing for48 to 96 hours, with continued application of the ointment until resolution of all crusting. After treatment, patients were instructed to avoid direct sun exposure, wear a hat or visor for the first 2 weeks posttreatment when outdoors, and apply sunscreen with a sun protection factor greater than 30 once skin had healed.

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