Dr. Harvey Lui, Vancouver
Although PDT remains an investigational treatment modality in dermatology, several important areas of development may ultimately lead to official and practical acceptance of PDT for the skin. Indeed the skin is usually the first organ in which many of the newer second generation photosensitizers are evaluated.
Photodynamic Therapy, PUVA, PDT, Psoriasis
The modern era of PDT began in the 1970s with the pioneering work by Dougherty et al at the Roswell Park Memorial Cancer Institute in Buffalo using hematoporphyrin derivative.1 It is perhaps somewhat ironic that although the skin was the first organ in which PDT was systematically evaluated, as of mid 1997 the only official regulatory approvals for PDT are for the treatment of internal malignancies involving the lung, genitourinary system, and gastrointestinal tract using porfimer sodium (Photofrin®), the first generation photosensitizer.
For treating diseased tissue, PDT, like PUVA, involves the sequential administration of drug followed by light. However, PDT involves the photochemical generation of reactive singlet oxygen that interacts with tissue components, whereas PUVA’s effects appear to depend more on reactions independent of O2.
Persistent generalized cutaneous photosensitivity due to photosensitizer retention in the skin has been the main limitation of porfimer sodium, which is administered parenterally. This has led to the development of second generation photosensitizers, some of which appear to be cleared far more rapidly from the skin than porfimer sodium (Table). With topically active agents such as 5-aminolevulinic acid (5-ALA) and ATMPn, skin photosensitivity is restricted to areas of direct drug application. 5-ALA is unique in that it is actually a low molecular weight porphyrin precursor that is metabolized in situ within the skin to protoporphyrin IX, which possesses significant PDT activity.
Are lasers essential for PDT?
PDT has become synonymous with the use of porphyrins and lasers for treating skin cancer. While lasers are indispensable for delivering light to internal organs via fiberoptic endoscopy, they are relatively expensive and inefficient light sources for photosensitizer activation in the skin. The critical property for any PDT light source is that its spectral output provides sufficient power at an activation wavelength that is appropriate for the photosensitizer being used. In the future, non-coherent, broad or narrow band light sources such as incandescent bulbs, arc lamps, fluorescent tubes, and light-emitting diodes may prove to be the light sources of choice for dermatologic PDT. These latter devices are usually cheaper to operate, more compact, and more effective for irradiating large surfaces than lasers.
Does PDT work?
- Skin cancer Although the literature documents an extensive collective experience for PDT of skin cancer (reviewed in Reference 2) there is a dearth of either long term follow-up data (i.e. more than 2-5 years of reported follow up) or histologic evaluation of treated sites. Moreover, in dermatology, there is only one published, controlled trial of PDT. In treating Bowen’s disease, the combination of ALA and a broad band lamp was felt to be as effective as cryotherapy, but with fewer adverse effects.3 More studies such as this will be needed in order to more precisely define the role of PDT for skin cancer management.
Novel indications for PDT
- Non-hypertrophic actinic keratoses of the face and scalp In a vehicle-controlled study, topical ALA and red laser light have recently been shown to clear up to 91% of these keratoses.4 Multicenter phase III studies of topical ALA for this indication are currently underway in the US.
- Psoriasis PDT has been shown to demonstrate significant immunomodulatory effects in animal models of arthritis.5 Thus there is a rationale for using PDT in treating inflammatory disorders such as psoriasis. One potential advantage of PDT over PUVA is that PDT may not be intrinsically carcinogenic. Pilot studies have demonstrated clearing of psoriasis using topical6 and systemic photosensitizers.7
- Removal of unwanted terminal hair Topical ALA selectively photosensitizes pilosebaceous structures and Grossman et al have used ALA-PDT to remove unwanted terminal hair with some degree of success.8 How this modality will compare to the current generation of hair removal lasers will await controlled clinical studies.
If the potential therapeutic advantages of using PDT to treat actinic keratoses, non-melanoma skin cancers, psoriasis and hair removal continue to be demonstrated in clinical trials, Dermatologists would welcome PDT as an effective, safe and cheaper treatment alternative to current therapy, including lasers. Photodynamic therapy should no longer be looked upon as a procedure looking for a disease to treat.
Dr. Stuart Maddin, Editor
Table: Photosensitizers for PDT
|Photosensitizer||Status||Dermatologic Indications and Comments||Manufacturer|
|Porfimer sodium (Photofrin)||Approved: US, Canada, Netherlands, Japan, France, Germany Investigational||QLT Phototherapeutics|
|BPD verteporfin (benzoporphyrin)||Investigational||Non-melanoma skin cancer, cutaneous metastases, psoriasis||QLT Phototherapeutics|
|SnET2||Investigational||Non-melanoma skin cancer, Kaposi’s sarcoma, cutaneous metastases||PDT Inc.|
|NPe6||Investigational||Non-melanoma skin cancer, cutaneous metastases||Nippon Pharmaceuticals|
|mTHPCI||Investigational||Clinical trials are ongoing.||Scotia Pharmaceuticals|
|Lutetium texaphyrin||Investigational||Melanoma and non-melanoma skin cancer||Pharmacyclics Inc.|
|ATMPn (porphycene)||Investigational||May possess significant topical activity||Glaxo-Wellcome|
|5-Aminolevulinic acid (Levulan)||Investigational||Actinic keratosis, non-melanoma skin cancer, mycosis fungoides, psoriasis, acne, hypertrichosis.|
Topical, oral, and parenteral activity.
- Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation therapy for the treatment of malignant tumors. Cancer Research 1978;38:2628-35.
- Bissonnette R, Lui H. Current Status of Photodynamic Therapy in Dermatology. Dermatologic Clinics 1997;15:507-519.
- Morton CA, Whitehurst C, Moseley H, McColl JH, Moore JV, Mackie RM. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen’s disease. British Journal of Dermatology 1996;135:766-71.
- Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic Therapy of Actinic Keratosis With Topical 5-Aminolevulinic Acid – a Pilot Dose-Ranging Study. Archives of Dermatology 1997;133:727-732.
- Chowdhary RK, Ratkay LG, Neyndorff HC, et al. The use of transcutaneous photodynamic therapy in the prevention of adjuvant-enhanced arthritis in MRL/lpr mice. Clinical Immunology & Immunopathology 1994;72:255-63.
- Boehncke WH, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with polychromatic light [letter]. Lancet 1994;343:801.
- Hruza L, Lui H, Hruza G, al e. Response of psoriasis to photodynamic therapy using benzoporphyrin derivative monoacid ring A. Lasers Surg Med Suppl 1995;7:43.
- Grossman M, Wimberly J, Dwyer P, Flotte T, Anderson RR. PDT for hirsutism. Lasers Surg Med Suppl 1995;7:44.