Synergistic photodynamic and photothermal treatment of port‐wine stain?

Lasers in Surgery and Medicine 34:80–82 (2004) Letter to the Editor Synergistic Photodynamic and Photothermal Treatment of Port-Wine Stain? Sol Kimel, PhD , Lars O. Svaasand, PhD , Kristen M. Kelly, MD , and J. Stuart Nelson, Beckman Laser Institute, University of California-Irvine, Irvine, California The objective of port-wine stain (PWS) laser treatment is to maximize thermal damage to targeted blood vessels while preventing injury to the normal epidermis. Pulsed dye laser (PDL) treatment produces reasonably good results in a limited population of PWS patients due to its ability to destroy selectively dermal blood vessels. Yellow light emitted by the PDL is preferentially absorbed by hemoglobin in dilated PWS blood vessels where, after being converted to heat, causes thermal damage and thrombosis [1,2]. Although laser manufacturers have introduced con- trols which permit the operator to vary treatment para- meters such as wavelength, pulse duration, light dosage, and skin cooling [3,4], the degree of PWS blanching fol- lowing PDL therapy remains variable and unpredictable. If the ultimate standard required is complete blanching of the lesion, the average success rate is below 25%, even after undergoing multiple PDL treatments [5,6]. Because of the failure of PDL therapy to remove the PWS completely in the majority of patients, any new approach that shows therapeutic promise deserves careful examination. In Photodynamic therapy (PDT), a photosensitizing drug is administered to the patient as the first step in treatment. In the second step, the tissue-localized drug is exposed to light at a wavelength appropriate for absorption by the photosensitizer. Excited molecules subsequently react with a substrate, such as oxygen, to generate short-lived highly reactive species, including singlet oxygen, which causes irreversible oxidative damage to biologically important intracellular structures. On the molecular level, phototoxic reactions take place within the cell on a time scale of nan- oseconds, while associated macroscopic events occur within minutes. PDT is now a modality of great interest for imaging and eradication of a variety of benign, pre- malignant, and malignant conditions [7]. However, appli- cation of PDT for treatment of PWS has not been fully developed [8]. Why is PDT a potentially promising approach to the clinical management of patients with PWS? Histopathology shows local hemorrhage and red blood cell extravasation are common findings after PDT, both in animals [9,10] and humans [7]. This suggests that effects of PDT are not exclusively the result of direct tumor cell kill but can be secondary to vascular effects such as constriction, throm- bosis, endothelial cell damage, and loss of vessel wall s 2004 Wiley-Liss, Inc. MD , PhD * integrity with increased permeability, which disrupts the microvasculature. Taken together, these studies suggest that the vascular compartment represents an important target for PDT of tumors and, possibly, for hypervascular skin lesion such as PWS (Fig. 1) and hemangiomas. Persistent generalized skin photosensitivity is the most significant disadvantage of PDT when using photo- sensitizers systemically. Several second-generation photo- sensitizers with rapid metabolic clearance, thus reducing the duration of skin photosensitivity, are currently under development. Ideally, for treatment of PWS, the photo- sensitizer should remain confined to the vascular com- partment. Benzoporphyrin derivative monoacid (BPD) is a photosensitizing drug that meets these requirements [11–14]. Moreover, BPD is intriguing because of its strong absorbance at 576 nm (molar extinction coefficient e ¼ 15,000 M 1 cm 1 ), and at 690 nm (e ¼ 30,000 M 1 cm 1 ) [12]. Successive treatments, using yellow and red light in that order, can achieve progressively deeper PDT treat- ments which might be useful, especially in the presence of thick PWS or hemangiomas. Prior to clinical use for PWS, the complex nature of the response of human skin to photoactivated BPD must be elucidated with studies devoted to structural changes produced in skin [11–14]. After PDT, the structural integrity of collagen and other supporting structures is generally superior to that after photothermal treatment [15]. Despite full thickness necrosis produced by both treatment modalities, healing proceeds only after PDT. This might explain the excellent cosmetic results produced after PDT of human skin lesions [7,16–18]. Unlike PDL, which delivers short pulses at high irra- diance, in PDT a laser or filtered non-coherent source merely has to provide photons at the desired wavelength in order to drive photodynamic reactions without heat gen- eration. Milliwatt light exposure used with PDT will avoid *Correspondence to: J. Stuart Nelson, MD, PhD, Beckman Laser Institute, 1002 Health Sciences Road East, University of Calif. -Irvine, Irvine, CA 92612. E-mail: snelson@bli.uci. edu Accepted 8 September 2003 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/lsm.10238