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endogenous porphyrin derivative, protoporphyrin IX (PplX), which has an absorption spectrum of light in the 415- to 630-nm range (Fig. 6.1).

The history of PDT can trace its routes back to 1900 when Raab (Kalka 2000) found that Paramecium caudatum cells died quickly when exposed to light in the presence of acridine orange. In 1904, this process was first described as the "photodynamic effect." This work involved the study of protozoa and described oxygen-consuming chemical reactions and fluorescence patterns after the applications of analine dyes. In 1905 5% eosin was first utilized as a skin photosensitizer. Artificial light was used to successfully treat human nonmelanoma skin cancer, condylomata lata, and lupus vul-garis. The next forty-odd years found very few substantial studies being described using PDT.

In 1948, hematoporphyrin was found to be selectively absorbed in neoplastic tissues, embryonic tissues, and traumatized tissues. This work led to the development of a purified synthetic compound, a hematoporphyrin derivative, which then became the standard for PDT research and treatment in that time. Dougherty et al. (Dougherty et al. 1978) reported in 1978 the use of this hematoporphyrin derivative and its photoactivation with a red light source. This group described its effectiveness in treating a variety of cutaneous malignancies and other cancers as well. PDT has been studied and continues to be investigated for its role in treating a variety of malignancies including lung, colon, esophagus, peritoneum, pleura, gastrointestinal tract, brain, eye, and skin (Rowe 1988). A variety of nononcologic applications utilizing PDT includes atherosclerosis, infectious diseases, and rheumatologic diseases, as well as skin concerns where the pilosebaceous units are involved. Svaasand (Svassand et al. 1996) described a dosimetry model for PDT which further delineated the necessary three steps for the PDT process to occur: (1) ALA diffusion through the stratum corneum and ability to penetrate the epidermis and dermis, (2) synthesis and production of the photosensitive PplX from the exogenous ALA applied to the skin, and (3) the production of singlet oxygen when PplX is properly irradiated with a wavelength of light which is absorbed by PpIX.

In the United States, PDT therapy emerged in the late 1990s as a treatment for nonhyper-keratotic AKs of the face and scalp. AKs are a problem which dermatologists encounter on a daily basis in their clinical practices. The Actinic Keratosis Consensus Conference of 2001 reported that AKs serve as a marker for photodamage and that their principle etiology is ultraviolet light, specifically ultraviolet B light. They found that AKs are associated with alterations of DNA that are associated with squamous cell carcinomas (SCCs), specifically mutations in the tumor-suppressing gene P53.

The conference reported that AKs are a carcinoma in situ and some of them will naturally

Table 6.1. Treatment options for actinic keratoses

Surgical options for AK treatment Cryosurgery Curettage Excisional surgery

Diffuse superficial destructive processes Chemical peels Dermabrasion Laser resurfacing ALA-PDT photodynamic therapy Medical treatments for AKs 5-Fluorouracil Imiquimod

Retinoids - tretinoin, adapalene, tazarotene Dicofenac regress, some will remain stable, or some will progress to the formation of SCCs. Which will regress or which will progress cannot as yet be determined. The natural history of AKs is unpredictable, and therefore all AKs should be treated in some fashion to prevent the potential onset of cutaneous malignancies. Conversion rates to SCCs have been reported from 0.1% to 20%. Additionally, 97% of SCCs are associated with a nearby AK. Nearby AKs have been found in 44% of cutaneous SCCs which had metasta-sized. These findings also support the concept that all AKs should be treated to prevent further potential conversion to SCCs.

A variety of treatment options are currently available for the treatment of AKs. These include both medical and surgical options (Table 6.1). Most contend that the principle treatment for AKs involve a destructive process. ALA-PDT fits nicely into this destructive category for the treatment of AKs and has received a great deal of recent attention for its role in the treatment of AKs and other cutaneous concerns.

In Europe, ALA research has focused on its use in treating not only AKs but also for the treatment of superficial cutaneous malignancies. These malignancies include squamous cell carcinoma in situ (Bowen's Disease) basal (BCCs) and squamous cell carcinomas. Numerous clinical reports have now described this role for PDT (Lui and Anderson 1993). A variety of lasers and light sources have been used to treat AKs, Bowen's Dis ease, BCCs, and SCCs. For AKs, response rates from 80% to 100% are routinely reported. For Bowen's Disease, response rates from 90% to 100% are reported with PDT. For BCCs and SCCs, 67%-100% of treated lesions respond to PDT. A variety of treatment protocols have been utilized but most have used multiple treatment applications with sufficient follow-up to document the effectiveness of ALA-PDT in the treatment of cutaneous malignancies.

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