Photodynamic Therapy with Ablative Carbon Dioxide Fractional Laser for Treating Bowen Disease

Topical photodynamic therapy (PDT) has been increasingly used to treat malignant skin tumors, including Bowen disease (BD)1. Clinicians prefer PDT because of its minimal invasiveness and favorable cosmetic outcomes. PDT produces superior cosmetic results compared with those of cryotherapy and 5-fluorouracil2.

Transcutaneous penetration of photosensitizer is important to improve clinical outcomes of PDT. Therefore, a long incubation time (usually 3~4 hours) is needed after applying the photosensitizer; however, patients are often displeased with the long incubation time. Pretreatments of hyperkeratotic skin lesions by curettage, debulking, tape stripping, micro-dermabrasion or laser ablation, are useful procedures to increase photosensetizer absorption3, 4.

Ablative fractional lasers have been used to treat photodamaged facial skin, rhytides, and various types of scars. Ablative fractional laser creates microscopic vertical holes of ablated tissue, each surrounded by a thin layer of coagulated tissue, which constitutes microscopic treatment zones5. Therefore, the penetration of topically applied photosensitizer can be enhanced through these channels formed by the ablative fractional laser.

Based on this concept, we evaluated the efficacy and safety of PDT with a short photosensitizer incubation time after ablative CO₂ fractional laser pretreatment when dealing with BD.

Among the 10 patients with BD whom have completed the evaluation, five were male and five were female. Their ages ranged from 35 to 80 years (mean, 61.9 years; median, 60.5 years). The ten lesions were located on the face (n=4), extremities (n=4), trunk (n=1), and penis (n=1). The baseline clinical characteristics of the ten patients including lesion locations are shown in Table 1.

Table 1
Summary of the baseline characteristics and the results of photodynamic therapy following pretreatment with an ablative CO₂ fractional laser

• Click for larger image

Five of the ten (50%) lesions showed a CR within three PDT sessions (two lesions showed a clinical CR and three lesions showed both clinical and histological CR) (Fig. 1, 2).

Fig. 1
Clinical clearance of Bowen disease on right cheek with ablative CO₂ fractional laser pretreatment following methyl aminolevulinate-photodynamic therapy (MAL-PDT). (A) Before treatment, (B) after treatment.

• Click for larger image

Fig. 2
Histological clearance of Bowen disease following pretreatment with a ablative CO₂ fractional laser following methyl aminolevulinate-photodynamic therapy (MAL-PDT) (H&E, ×200). (A) Before treatment, (B) after treatment.

• Click for larger image

All lesions except the penile shaft lesion (90%) achieved a clinical and histological CR or clinical CR after four treatment sessions. However, the one patient with the penile shaft lesion showed a clinical and histological CR after eight treatment sessions. The average number of treatments to CR was 3.70±1.70. Except for the patient with the penile shaft lesion, with eight treatment sessions, the average number of treatments to CR decreased to 3.20±0.80 (Table 1).

Treatments were generally well-tolerated, except for some patients who experienced a mild burning sensation during the procedure. No additional complications, such as pigment changes or scarring, were observed. No recurrences of the BD lesions were observed during the 6~18 months of follow-up.

Among the various therapeutic modalities for treating BD, PDT is a promising therapeutic alternative, because of its good cosmetic outcomes6. However, a relatively long incubation time is one of the disadvantages of PDT; therefore, trials to increase photosensitizer penetration to shorten the incubation time are needed. Up until today, clinicians have tried to develop novel photosensitizer delivery methods such as biomodulation with drugs and using the stratum corneum (e.g., drug-vehicle optimization, liposomes, iontophoresis and electroporation), as well as physical modulation techniques such as micro-needling or topical keratolytic agents, that mediate intradermal delivery of photosensitizer4, 7-9. Ablative lasers, including the CO₂ laser and the erbium YAG laser, have been used to increase photosensitizer penetrations10-12. Biomodulation with drugs and using the stratum corneum shows limited deep penetrations into the skin. Various physical modulation techniques including curettage can induce bleeding and oozing of tissue fluids within a lesion, following elimination of the photosensitizer from the lesion. Compared to these pretreatment techniques, which have several limitations, ablative fractional laser treatment has certain advantages. Because of greater penetration depth of the ablative fractional laser, photosensitizer may reach into deeper skin layers. Additionally, photosensitizers are distributed evenly throughout the entire lesion with uniformly-distributed vertical holes made by the ablative fractional laser. Moreover, an ablative fractional laser rarely causes bleeding and oozing with their coagulation character. Based on this mechanism, the ablative fractional CO₂ laser could be used to shorten the conventional PDT incubation time. Recently, ablative fractional laser treatment greatly facilitates the delivery of topical MAL deep into the skin of an animal model through the cone-shaped channels created by the laser5, 13. Based on these results, we used ablative fractional CO₂ laser treatment before MAL-PDT for Bowen disease to shorten the incubation period.

Previous reports demonstrated that 73~93% of patients with BD achieve clinical CR after two MAL-PDT sessions14-17, which suggests a higher clearance rate than that of the present study. However, one of the limitations from previous studies is that only the clinical assessment was being evaluated without histological confirmation. Moreover, the Asian skin type (skin type IV/V) is more resistant to light penetrations than the Caucasian skin type (skin type II/III)18. According to a multi-center study in Korea, about 60% of patients with BD achieved CR19. Additionally, 3~4 treatment sessions are usually needed to achieve both clinical and histological CR of lesions using topical PDT and conventional methods during the 6 years at our center20. Therefore, the combined treatment of pretreating with an ablative fractional CO₂ laser and topical PDT with a shorter incubation time (70 minutes) showed similar treatment efficacy compared with the conventional PDT method, which requires a 3-hour incubation time.

A fluorescence photograph was taken after applying MAL to evaluate MAL penetration. The fluorescence of the penetrated photosensitizer applied with a shorter incubation time was similar to that of the conventional method (Fig. 3). Several limitations should be noted. Because of the small sample sizes, further larger studies will be needed to confirm the results. It is obvious that adding the ablative fractional CO₂ laser pretreatment contributed to the reduction of incubation time; however, a comparative study with various incubation times will be necessary to determine the most suitable time. In this study, we have fixed the incubation time as 70 minutes (38.9% of conventional 3-hour incubation time). In the preliminary study, we have performed the 5-aminolevulinic acid (ALA)-PDT with ablative carbon dioxide fractional laser of 90 minutes as 37.5% of 4 hours for incubation time in actinic keratosis (AK), and the CR was up to 90% (unpublished data). The CR was similar to the previously published data of AK, ranging from 71 to 100%1. It is well known that the efficacy of MAL-PDT is prior to that of ALA-PDT in the case of BD². Therefore, we have chosen MAL instead of ALA with similar percentages of incubation time as 33.3% (70 minutes) for 3 hour (the conventional incubation time of MAL is 3 hour). The parameter that we have chosen was based on the published data21. We expect that further study should be performed for accurate incubations and laser parameters with maximal efficacy and minimal adverse event.

Fig. 3
Fluorescence assessment of the lesion (arrows). (A) Before application of photosensitizer, (B) after 70 minutes as incubation time.

• Click for larger image

The risk of ablative fractional laser exists such as thermal injury, coagulation, or tissue necrosis. Our patients, however, received fractional laser only in lesional areas, and no serious effects mentioned above were noted either at the normal area or the lesional area. Furthermore, in our case, each lesion was not huge enough for patients to receive pretreatment like anesthetic cream or injection. Also, we assumed that the anesthetic cream could contribute the efficacy of PDT as pH changes22, and thus, we did not use any local anesthesia. The laser treatment time was very short and patients only complained about minimal pain, and there was no other adverse event. If the lesions were huge, multiple times of anesthesia might be necessary.

PDT itself is not a first-line therapy for all BD patients. Also, there had been no head-to-head study to compare the CR of various treatment modalities. Considering the sizes and numbers of the lesions or the medical conditions of patients, the surgical management or alternative management, like PDT, can be individualized. In our cases, some patients were old aged with generally poor conditions to undergo such surgical management, and they demanded for more conservative treatment instead of surgical management. Other patients did not want to receive surgery because expected cosmetic results.

In summary, the present data suggests that ablative fractional CO₂ laser pretreatment before PDT has similar treatment efficacy and requires a shorter photosensitizer incubation time compared with the conventional PDT method. Long treatment times, as being one of the major disadvantages of topical PDT, can be reduced with this combined treatment.