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Department of Dermatology
University of Regensburg
At the beginning of the 20th century, Hermann von Tappeiner, then director of the Institute of Pharmacology at the University of Munich (Germany), first coined the term “photodynamic reaction”.(1) This term was chosen because of the observation of one of his doctoral students, Oscar Raab, that the toxicity of acridine orange on protozoae was dependent not only on the dye concentration, but also on the intensity of the ambient light.
In the standardised experiments he conducted, Raab observed that the toxicity of the dye increased with increasing incident light. Raab and von Tappeiner hypothesised a damaging effect of the fluorescent dye on the protozoae in the presence of daylight. In 1905, in cooperation with the dermatologist Jesionek, von Tappeiner successfully treated patients suffering from lupus vulgaris, secondary syphilis and superficial skin cancer with a topical eosin solution (1–5%).
In 1911, Hausmann reported photodynamic effects on mice injected with haematoporphyrin, showing extensive oedema and erythema after light exposure. In 1942, Auler and Banzer observed a specific uptake and retention of haematoporphyrin with subsequent higher fluorescence in tumour, compared with surrounding tissue. Following irradiation with powerful quartz lamp, these researchers could also demonstrate histologically widespread necrosis.
Photodynamic therapy (PDT) was then abandoned until Dougherty initiated a renaissance in the mid-1970s by treating patients with cutaneous and subcutaneous tumours through injection of the photosensitiser dihaematoporphyrin and light irradiation. The majority of the treated tumours showed either complete or partial remission.(1)
There is currently only one photosensitiser approved in Europe for topical application, the methylester of 5-aminolevulinic acid (5-ALA: Metvix(®); manufactured by Photocure [Norway] and Galderma [France]). Metvix is approved for superficial basal cell carcinoma and actinic keratoses.
In addition to PDT, 5-ALA in general and Metvix in particular are increasingly used for fluorescence diagnosis. The 5-ALA-based photosensitiser is not photoactive in itself but is metabolised during the haeme biosynthesis to photosensitising porphyrins inside tumour cells.(2) In the USA, Levulan(®) Kerastick(™) (DUSA, USA), containing 5-ALA hydrochloride, is approved with an incubation time of 16–18h, but without occlusion and light-protecting dressing.
For simultaneous irradiation of large areas (which is necessary in actinic keratoses or basal cell naevus syndrome), incoherent light sources are preferred, either as lamps (PDT 1200L [Waldmann Medizintechnik, Germany]) or LEDs (light-emitting diodes: Aktilite(™) [Galderma] or Omnilux(™) [Waldmann]), which match the absorption maxima of the 5-ALA- or Metvix-induced porphyrins.
Small areas or single lesion can be efficiently irradiated with different lasers as long as they match the absorption maxima of the photosensitiser used.(3) However, the costs of purchasing and maintaining these laser systems generally exceed those of incoherent light sources.
Mechanisms of action
Following activation of a photosensitiser with light of the appropriate wavelength, reactive oxygen species (ROS), in particular singlet oxygen, are generated. Depending on their number and localisation in the tissue, these ROS either modify cellular functions or induce cell death by necrosis or apoptosis. Thus, one can distinguish between a high-dose PDT for oncological indications, leading to tissue destruction, and a low-dose PDT for inflammatory dermatoses, which modulates cell functions.
For tissue destruction, a light dose, or fluence (using red light), of 100–150J/cm(2) (100–200mW/cm(2)) is chosen, versus 10–20J/cm(2) (40–60mW/cm(2)) for the modulation of cellular functions. The light intensity, or fluence rate, should not exceed 200mW/cm2 to avoid hyperthermic effects. Similarly, the concentration of 5-ALA used for oncological indications differs from that used for the treatment of inflammatory dermatoses (20% versus 3%).(4)
Until the approval of Metvix, 5-ALA hydrochloride (Photonamic GmbH, Germany) was applied in custom-made formulations, either creams or gels, with penetration enhancers (eg, DMSO [40%]) in concentrations of 3–20%. Since June 2001, an approved medicinal product, Metvix, has been available. To avoid photobleaching of the induced porphyrins before PDT or fluorescence diagnosis, incubated areas should be covered with foil in addition to a light-protecting dressing or clothing.
Due to the specific accumulation of the 5-ALA-induced porphyrins in tumour cells following either topical or systemic administration, light-induced fluorescence makes tumour cells visible. Following activation by light of the appropriate wavelength, photosensitiser molecules are excited to a higher energy state and light is emitted during decay fluorescence. As ROS should not be induced in fluorescence diagnosis, significantly lower light intensities (2–5mW/cm(2)) than with PDT are used.
Using an optical detection system, such as Dyaderm Professional (Biocam GmbH, Germany), the induced fluorescence is displayed on a screen under ambient light, and the localisation and extension of skin tumours can be determined. For fluorescence diagnosis, the strong absorption of porphyrins around 400nm (Soret-band), is used; thus, blue light activates porphyrins. Because the penetration of blue light is limited to 1mm, only superficial lesions can be detected, but the method is used very efficiently intraoperatively.(5)
Fluorescence diagnosis is particularly useful in pretreated areas with scars and erythema, for which even an experienced dermatologist can encounter difficulties in distinguishing scar from precancerous lesions or skin cancer. Fluorescence diagnosis provides the investigator with an independent procedure to choose the appropriate biopsy site. Using digital image analysis and reference algorithms, the suspected area can be shown in false colours to give maximal contrast between tumour and surrounding tissue. The probability of false-negative biopsies is thus significantly reduced.(6)
Another option is fluorescence-guided resection of skin tumours to minimise tissue defects, in particular in the skin, but also to reduce the number of re-excisions. Due to image analysis, a fluorescence threshold can be determined that defines the tumour margins. Thus, the surgeon can control the resection margins intraoperatively.(7)
Approved indications for Metvix are actinic keratoses (AKs) and superficial basal cell carcinomas, in which the efficacy of PDT with 5-ALA-induced porphyrins is well documented in the literature. In addition, treatment of Bowen’s disease is also indicated for PDT with 5-ALA-induced porphyrins, as recommended by evidence-based guidelines.(8) For the treatment of single lesions, several efficient alternative treatments are available (eg, cryotherapy or surgery), whereas for therapy of multiple lesions PDT is the first choice, in particular for actinic keratoses of the scalp and face or basal cell naevus syndrome.
Before incubation of hyperkeratotic lesions with the photosensitiser formulation, keratolysis should be performed with an ointment, a wet cloth or a slight, nonbleeding curettage. Hyperkeratosis is the reason for a poor response in AKs localised on the hands.(9) Subsequently, the photosensitiser formulation is applied to the lesions, with little overlap to the surrounding tissue.
The entire area is covered with foil (see Figure 1), to allow for better penetration, and light-protecting dressing or clothes to stop photobleaching of the induced porphyrins. After the incubation time, which depends on the photosensitiser formulation used, the entire area is irradiated with 100J/cm(2) and 160mW/cm(2). The well-known stinging or burning sensation during topical PDT is usually well tolerated; however, if larger areas are treated, it may cause significant discomfort, making analgesia with metamizole or piritramide, or even anaesthesia, necessary. Directly after irradiation, erythema and oedema occur in the incubated area; subsequently, sterile pustules may form, in particular on the face and scalp, finally leading to a crust, which represents the killed cells. Complete healing can be expected within 2–3 weeks after PDT. Irreversible alopecia has not yet been observed in our patients.
Depending on localisation, degree of infiltration and keratosis, complete remission ranges from 50–98% up to 2 years after PDT, with a weighted clearance rate of 88% for facial actinic keratoses.(8) Several studies demonstrate a significant superiority of PDT compared with cryotherapy regarding efficacy as well as cosmetic outcome. PDT can be repeated at least twice.
The protocol for PDT in the treatment of Bowen’s disease or superficial basal cell carcinoma (<2–3mm) is the same as for actinic keratoses. A single treatment is usually sufficient for superficial lesions; however, for thicker lesions, PDT can be repeated with the same parameters directly at the first control visit 3–5 weeks after the first PDT. Irradiation is performed only with red light, due to deeper tissue penetration. Irradiation with blue or green light for these lesions is contraindicated.
The advantages of PDT, compared with surgery or cryotherapy, are excellent cosmetic results and good tolerability despite a certain discomfort, in particular when larger areas are treated. In addition, large areas can be treated in one session. In the overwhelming majority of the patients treated for oncological indications, PDT is very well tolerated.
Due to a lack of invasiveness and to excellent cosmetic results, topical PDT with 5-ALA-induced porphyrins represents a highly valuable alternative in the treatment of nonmelanoma skin cancer, in particular actinic keratoses, Bowen’s disease and superficial basal cell carcinoma. Moreover, large or multiple lesions can be successfully treated with PDT in one session, giving advantage over certain standard therapies for these indications.
The value of PDT in the treatment of inflammatory conditions (eg, psoriasis) has still to be determined by conducting randomised, prospective clinical trials.