Combined benzoporphyrin derivative monoacid ring photodynamic therapy and pulsed dye laser for port wine stain birthmarks

Summary

Background

Pulsed dye laser (PDL) is a commonly utilized treatment for port wine stain birthmarks (PWS) in the United States; however, results are variable and few patients achieve complete removal. Photodynamic therapy (PDT) is commonly used in China, but treatment associated photosensitivity lasts several weeks and scarring may occur. We propose an alternative treatment option, combined PDT + PDL and performed a proof-of-concept preliminary clinical trial.

Methods

Subjects with non-facial PWS were studied. Each subject had four test sites: control, PDL alone, PDT alone (benzoporphyrin derivative monoacid ring A photosensitizer with 576 nm light), and PDT + PDL. Radiant exposure time for PDT was increased in increments of 15 J/cm². Authors evaluated photographs and chromametric measurements before and 12 weeks post-treatment.

Results

No serious adverse events were reported; epidermal changes were mild and self-limited. No clinical blanching was noted in control or PDT-alone sites. At PDT radiant exposures of 15 and 30 J/cm², equivalent purpura and blanching was observed at PDL and PDT + PDL sites. At PDT radiant exposures over 30 J/cm², greater purpura was noted at PDT + PDL sites as compared to PDL alone. Starting at 75 J/cm², improved blanching was noted at PDT + PDL sites.

Conclusions

Preliminary results indicate that PDT + PDL is safe and may offer improved PWS treatment efficacy. Additional studies are warranted.

Introduction

Port wine stain birthmarks (PWS) are congenital, progressive vascular malformations of the skin which are present at birth in 0.3% of infants, are commonly found on the face and in many cases disfigure the bearer. The pulsed dye laser (PDL) is the current standard of care for treatment of such cutaneous vascular lesions. The PDL enables lesion lightening by causing selective photothermal injury to tissue vasculature. Yellow light (λ = 577–600 nm wavelength) emitted by the pulsed dye laser is preferentially absorbed by hemoglobin (the major blood chromophore) in the ectatic capillaries of the upper dermis. Radiant energy is converted to heat, causing thermal damage and thrombosis in targeted vessels [1].

However, with PDL alone, few patients (<10%) achieve complete blanching of their lesion, and multiple treatments (5–30 or more) are generally required. In a five-year study of 640 PWS patients at Bridgend General Hospital, Lanigan et al. concluded that the degree of fading achieved following PDL therapy is “variable and often unpredictable” [2]. Huikeshoven et al. [3] published a 10-year follow-up study of 51 patients who had undergone PDL treatment for PWS birthmarks. They reported significant re-darkening of PWS since an initial course of PDL therapy (although PWS remained significantly lighter as compared to pre-treatment).

Because of the limitations of PDL PWS therapy, the search continues for other safe and more effective treatment modalities. Photodynamic therapy (PDT) may offer such an alternative. PDT utilizes a photosensitizer and light to generate reactive oxygen species and creates an opportunity for targeted lesion destruction. PDT has been used to treat a wide range of benign, pre-malignant and malignant conditions, including age-related macular degeneration [4], actinic keratoses [5] and cancers of the skin, lung and gastrointestinal tract [6].

PDT may offer several advantages for treatment of cutaneous vascular lesions. However, careful protocol design is required because the potential exists for complete vascular network destruction, which can result in necrosis, ulceration, and subsequent scarring. A small number of studies have been conducted using PDT as a stand-alone treatment of PWS, with varied success and safety outcomes. Collectively, the use of PDT to treat PWS has been associated with promising blanching, but also with prolonged photosensitivity and a significant risk of complications [7], [8].

Careful photosensitizer and light source selection is required to achieve desired efficacy during PDT treatment of PWS, while limiting injury to vessels at the desired depth. In this study, we propose the use of benzoporphyrin derivative monoacid ring A (BPD) and yellow light for PDT. BPD is an excellent photosensitizer for PWS treatment based on the following characteristics: (1) vascular predominance [9], [10], [11]; (2) proven safety and efficacy in humans [4], [12] and (3) photosensitivity of relatively short duration (1–5 days depending on dose administered) [12].

We have proposed combining the photochemical and photothermal aspects of PDT and PDL therapy [9], [13]. Combining these approaches allows the use of lower radiant exposures for each portion of the procedure, avoiding adverse effects such as scarring, while providing enhanced vascular shutdown. Our preliminary animal experiments [9], [13] demonstrated that PDT + PDL combination therapy can achieve enhanced vascular effect without epidermal injury and may address limitations associated with the current standard of care treatment, PDL alone. We report observations from a proof-of-concept, tolerance and safety dose ranging study designed to evaluate and compare PDL alone, PDT alone and PDT + PDL for PWS treatment. This is the first published report evaluating clinical use of the PDT + PDL approach.