Developments in photodynamic therapy

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Verena von Felbert
MD
E:[email protected]

Lasse Roger Braathen
MD
Professor
Chairman and Director
Department of Dermatology
Inselspital
University of Bern
Switzerland

At the beginning of the 20th century Oscar Raab, a German medical student, observed that acridine orange was lethal for paramecia in the presence of sunlight.(1) The term “photodynamic therapy” was coined by Hermann von Tappeiner as an oxygen-dependent tissue reaction after combined photosensitisation and irradiation with light. Today we know that PDT is a photo-oxidative reaction dependent on the three components: a photosensitiser, light and oxygen. The photosensitiser localises in the target cells and absorbs light energy which is transferred to oxygen and generates highly reactive oxygen species. The reactive oxygen species (mainly singlet oxygen) directly lead to cell and tissue damage by inducing necrosis or apoptosis and indirectly stimulate inflammatory cell mediators.

Over the last two decades, scientific interest in PDT has increased tremendously, especially in the fields of dermatology (premalignant lesions, skin cancer, inflammatory skin processes), urology (bladder cancer), gastroenterology (stomach, oesophageal cancer), pneumonology (lung cancer), and ophthalmology (age-related macular degeneration). In this review we briefly summarise current trends in PDT with special emphasis on applications in dermatology.

Photosensitisers
The ideal photosensitiser should be highly selective with homogenous distribution in the tissue to be treated. It should be activated by light with a wavelength long enough to permit penetration throughout the whole target tissue.(2) For dermatological applications, 5-aminolevulinic acid (ALA) shows a high selectivity with a tumour-tissue concentration ratio of 10:1.(3) 5-ALA is a prodrug that is metabolised by the haem biosynthetic pathway. The active metabolite is protoporphyrin IX (PpIX). PpIX is activated by illumination at 635nm.(3) 5-ALA is applied for periods between three and six hours before irradiation. 5-ALA delivery through the skin can be enhanced by iontophoresis,(4) penetration enhancers such as dimethylsulphoxide (DMSO), and iron chelators including desferrioxamine and ethylenediamine tetra-acetic acid disodium (EDTA).(5)

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The major advantage of 5-ALA is the fact that a topical application is effective in the treatment of several dermatological diseases. 5-ALA-PDT is a noninvasive, practical and safe outpatient procedure. Other than first generation photosensitisers such as haematoporphyrin derivative (HpD) or purified successor porfimer sodium (P-II), topical ALA application does not induce systemic photosensitivity. It is therefore not necessary to stay out of the sun or to avoid other strong light sources of light for several weeks. The cosmetic outcome is excellent in most cases, with minimal or no scarring.

“In-house preparations” of 10–20% ALA in cream, emulsion and ointment were initially used for topical PDT in dermatology. Most studies have therefore been performed with a 20% ALA concentration in an oil-in-water emulsion. No comparative studies of the different formulations exist in the literature. Crawford Pharmaceuticals (UK) supplies tubes of 4.5g 20% ALA in unguentum Merck base (Porphin). The FDA has approved the use of one particular formulation of 5-ALA, Levulan‚ for the treatment of actinic keratosis. ALA methylester (methylaminolevulinic acid; Metvix) shows enhanced tissue penetration, better lesion specificity and has been approved for the treatment of actinic keratosis and basal cell carcinoma in Scandinavia.(2)

Light sources and dosimetry
Several light sources have been used in clinical PDT studies for cutaneous applications, including lasers, xenonarc/ discharge lamps, incandescent filament lamps and solid-state light-emitting diodes (LEDs). Limited comparative data from randomised studies exist.(6) At present, no single light source is ideal for every possible indication of topical PDT. In 5-ALA-PDT, fluency rates higher than 50mW/cm(2) may affect oxygen availability, and rates over 150mW/cm(2) may induce hyperthermic injury.(6,7) The optimal light dose is likely to be disease specific, with high tumour-killing doses (50–200J/cm(2)) and lower doses for inflammatory disorders (10–20J/cm(2)). Orenstein et al have reported that hyperthermia may contribute to tissue damage and pain.(8) Water-filtered infrared-A light (wIR-A; Hydrosun) apparently causes less pain and discomfort during illumination (own unpublished observation).

Adverse effects
Discomfort and pain during illumination of the lesions are the major problem during ALA-PDT. The intensity of discomfort is different from patient to patient; most patients tolerate the treatment without analgesia. Pain starts almost immediately after the beginning of the illumination and occasionally persists for hours after treatment. Analgesics, local anaesthetics or a cooling fan can be used to at least partially prevent the pain. After PDT the patients develop erythema, oedema, erosions and crusts. The healing period takes two to four weeks and the clinical outcome is excellent in most cases. Occasionally, hyper- and/or hypopigmentation or scarring can be seen in the treated areas.

Indications for topical PDT

Actinic keratosis
Actinic keratoses (AKs) are premalignant, sun-induced skin lesions. AKs can give rise to spinocellular carcinomas, especially in immunosuppressed patients. Treatment is aimed at preventing malignant progression. In several open studies of ALA-PDT the clearance rates ranged from 71% to 100% after a single treatment.(6) Stefandiou et al reported a complete response rate of 87.5% at 26–48 months post-treatment.(9) Response rates for lesions of the head and neck (93%) appear to be better than those for the forearms and hands (51%).(6) PDT is at least as effective as 5-fluorouracil(10) or cryotherapy,(11) and has the advantage of a better cosmetic outcome.

Bowen’s disease
PDT of Bowen’s disease (squamous cell carcinoma in situ) has been assessed in several open pilot or case series and randomised comparative studies (reviewed).(6) The response rate of a single ALA-PDT is 86%, rising to 93% after a second or third treatment. The recurrence rates during a follow-up period of 3–36 months ranged from 0% to 40% (average 12%).(6) The efficacy of PDT is at least comparable to that of cryotherapy,(12) or 5-fluorouracil,(13) with fewer adverse reactions. Thus far, there are no studies comparing ALA-PDT with radiotherapy, surgery or curettage.(6)

Basal cell carcinoma
Basal cell carcinomas (BCCs) are cutaneous malignancies. Three different types of BCCs are known: superficial, morphoeiform and nodular BCC.

Current evidence suggests that topical 5-ALA-PDT is an effective therapy in superficial, <2mm BCCs, with a response rate of 81–100%. The clearance rates of nodular BCCs are poorer, ranging from 10% to 71%.(14) Pigmented BCCs and morphoeiform BCCs are poor responders. ALA-PDT was found to be as effective as cryotherapy in cases of superficial BCCs, but shows advantages including shorter healing time, improved cosmetic outcome and fewer adverse reactions.(15) Long-term follow-up studies, however, have not been published as yet.

Squamous cell carcinoma
Because of the risk of local recurrence even after excision and with their tendency to metastasise, squamous cell carcinomas (SCCs) have thus far only been treated with PDT in a small number of studies. Calazavara-Pinton et al reported a complete response rate of 92% in superficial SCCs and of 67% in nodular SCCs judged by visual inspection. Histological analysis at one month and at 24–36 months after treatment showed a response rate of 83.3% (superficial SCCs) and 33% (nodular SCCs), respectively.(14) Fritsch et al achieved a clearance rate of 79% in superficial SCCs.(16) In summary, PDT is effective in superficial SCCs (<2mm). Long-term studies on the recurrence rate are needed.

Other indications
The results of clinical studies of ALA-PDT for warts, acne, psoriasis and cutaneous T-cell lymphoma have recently been reviewed by Ibbotson.(17)

Stender et al achieved clearance rates of viral warts in 56–100%. He demonstrated superior efficacy of repetitive PDT compared with cryotherapy and placebo-PDT.(18–21) A major side-effect of this treatment is pain.

The rationale for the use of PDT in the treatment of acne is based on the knowledge that Propionibacterium acnes contain endogenous porphyrins, in particular coproporphyrin III.(17) Therefore visible light and blue light phototherapy is effective. Itoh et al reported benefit for several months after low-dose, single-course ALA-PDT.(22) However, side-effects of 5-ALA-PDT use in acne were considerable, including pain, crust formation, erythema and hyper-pigmentation.

5-ALA was observed to accumulate in psoriasis plaques.(23) Multiple treatments of 5-ALA-PDT lead to an improved clinical outcome, but pain and an unpredictable response are limiting factors.(24)

In small case series encouraging results after 5-ALA-PDT have been reported in actinic cheilitis,(25) lichen sclerosus,(26) and scleroderma.(27) Case reports of successful 5-ALA-PDT applications include epidermodysplasia verruciformis,(28) and lichen planus.(29)

Conclusions and outlook
PDT using 5-ALA has emerged as a widely used alternative to traditional treatments such as cryotherapy, curettage and excision for a number of common indications in dermatology. Standardised, approved formulations of 5-ALA, like methyl-ALA, and controlled studies with these preparations, are a welcome progress in the PDT field. New developments in illumination technology are also expected to contribute to improvements of PDT.

Acknowledgements
The authors would like to thank the Dr med hc E Braun Foundation, Basel, Switzerland, for grant support, and J Weis, Bern, for reading the manuscript.

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