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DOI: 10.1111/j.1610-0387.2010.07343.x

CME

Photodynamic therapy in dermatology Julia M. Steinbauer, Stephan Schreml, Elisabeth A. Kohl, Sigrid Karrer, Michael Landthaler, Rolf-Markus Szeimies Department of Dermatology, University Clinic of Regensburg, Germany

JDDG; 2010 • 8

Submitted: 5. 11. 2009 | Accepted: 25. 11. 2009

Section Editor Prof. Dr. Jan C. Simon, Leipzig

Keywords

Summary

• • • •

Photodynamic therapy (PDT) is a modern therapy modality, based upon the application of a photosensitizing agent like aminolevulinic acid, a physiological precursor of porphyrins, onto the tissue followed by illumination with light of the visible wavelength spectrum. During this oxygen-dependent reaction, reactive oxygen species (ROS) are generated that have immunomodulatory or cytotoxic effects. PDT shows excellent cosmetic results especially for its key indication in dermatology – the treatment of non-melanoma skin cancer. The associated pain and the low tissue penetration are the most frequent limiting factors of PDT. We review basic principles and recent developments in photosensitizers and light sources. Key oncological and non-oncological indications are presented as well.

photodynamic therapy non-melanoma skin cancer 5-aminolevulinic acid non-oncological indications

In the photodynamic reaction oxygen species are formed from the ubiquitously present oxygen in tissue; these are responsible for the subsequent immunomodulatory and cytotoxic cellular effects.

Introduction The natural precursor in heme biosynthesis, 5-aminolevulinic acid (5-ALA) is formed in the mitochondrium from succinyl CoA and glycine. This synthesis is normally regulated by a feedback mechanism, so that only in the event of exogenous supply of ALA are prophyrins, especially protoporphyrin IX (PPIX), rapidly produced. Due to the relatively slow insertion of an iron atom into PPIX catalyzed by the enzyme ferrochelatase and thus formation of the red blood pigment heme, PPIX accumulates and sensitizes the cell quite selectively. This is particularly the case in tumor cells, as these accumulate PPIX due to their increased need for heme proteins and a relative intracellular iron deficiency. Neighboring cells of mesenchymal origin (e. g. fibroblasts) do not demonstrate this behavior, so that the ratio between the tumor and surrounding normal tissue is particularly high. Upon irradiation with light of a suitable wavelength a photodynamic reaction takes place in the affected cells. During this reactive oxygen species (ROS) are produced from the oxygen ubiquitously present in tissue; these are responsible for the subsequent immunomodulatory and cytotoxic cellular effects. This oxygen-dependent effect of the porphyrins is utilized in a modern form of light therapy, photodynamic therapy (PDT), that has already become routinely established in dermatology, urology, gastroenterology and ophthalmology. The term was coined by von Tappeiner (1847–1927), director of the pharmacological institute of the Ludwig Maximilian University in Munich, who already in 1900 published the first papers on “the effect of fluorescent substances on infusions”. In the following years, further studies and the first therapeutic experiments especially with dyes in the treatment of tumors, tuberculosis and syphilis mainly performed by von Tappeiner and coworkers appeared. Starting in the 1920s especially porphyrins were studied with regard to their photosensitizing and tumor-localizing effects, until in 1966 photodynamic therapy was first employed for breast cancer. In 1990

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Figure 1: Selective accumulation of protoporphyrin IX (PPIX) in metabolically active cells after exogenous application of 5-ALA or MAL (PBG: porphobilinogen; URO: uroporphyrinogen; COPRO: coproporphyrinogen).

Kennedy introduced ALA as a sensitizer for the treatment of dermatological diseases – mainly superficial tumors and their precursors [1] (Figure 1).

In dermatology ALA and MAL are favored as photosensitizers due to the selectivity for metabolically active cells, their availability as pure substances and their relative short halflife in tissue after topical application.

The combination of MAL (Metvix® or Metvixia® in France and the USA) and red light has in the meantime been licensed worldwide for the treatment of actinic keratoses; in Europe it is also approved for the treatment of superficial and nodular basal cell carcinomas and Bowen disease [2].

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Photosensitizers (Table 1) The use of ALA or its methyl ester (MAL) has become established more quickly in dermatology in comparison to other potential sensitizers such as hematoporphyrin derivative (HpD, Photofrin®). Unlike the compound mixture HpD, ALA and MAL are available as pure individual substances that accumulate selectively on both proliferating tumor cells of epithelial origin as well as in metabolically active benign lesions. In contrast to HpD, which must be administered systemically, The PPIX produced by ALA or MAL remains in the skin only for about 24 hours; posttherapeutic light protection is therefore required only for this time. HpD accumulates for up to 6–8 weeks in the skin. Patients are extremely photosensitive and during this time must strictly avoid the sun and in the initial phase even indirect light exposure, as otherwise severe photothoxic reactions result. Classical UV protection is hardly effective, as porphyrins also significantly absorb light in the visible range. ALA- or MAL-PDT is principally suitable for non-melanoma skin cancers such as actinic keratoses (AK), basal cell carcinomas (BCC) and Bowen disease (BD) and for non-oncological indications such as acne or viral warts. The combination of MAL (Metvix® or Metvixia® in France and the USA) and red light has in the meantime been licensed worldwide for the treatment of actinic keratoses; in Europe it is also approved for the treatment of superficial and nodular basal cell carcinomas and Bowen disease [2]. Experimentally it could be shown both in animal models and after sensitization of AK and BCC, that MAL displays stronger accumulation in tumor tissue with regard to selectivity. The base, in particular, of the ALA preparation appears to have a decisive effect on penetration capacity and the subsequent PPIX production [3]. In the meantime new galenical developments have become available to compensate for poor penetration. Thus after application of an ALA preparation (Levulan Kerastick®, approved in the USA) produced directly before use by breaking and mixing two glass ampules (one with ALA crystals and the other with an alcoholic solution as vehicle), evaporation of the alcohol leads to a relatively high concentration of ALA on the skin resulting in increased penetration. In the meantime two new ALA preparations are available in Europe which are also close to approval. The first is an ALA nanoemulsion (BF-200 ALA, Biofrontera AG, Leverkusen, Germany) for which good results in the clinical phalse III trial exist. A self-adhesive patch containing ALA (Alacare®

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Table 1: Overview of the composition of currently employed formulations. Extratemporaneous ALA formulations

20 % aminolevulinate hydrochloride, e. g. in Ungt. emulsificans aquosum

Metvix® or Metvixia®, Galderma, Düsseldorf, Germany

16 % ALA methyl ester

Levulan Kerastick®, DUSA, USA

20 % ALA hydrochloride

BF-200 ALA, Biofrontera AG, Leverkusen, Germany

ALA nanoemulsion

®

PD P 506 A, Alacare , Intendis GmbH, Berlin, Germany

ALA in tape base

or Effala®, Intendis GmbH, Berlin, German) was found to be significantly more effective than placebo-PDT or cryotherapy in a series of multicenter studies [4] (Table 1). Light sources The absorption spectrum of porphyrin molecules usually possesses several maxima (405 nm [UV to blue], 505 nm [blue], 540 nm [green], 580 nm [yellow] and 635 nm [red]). When using red light with the maximum tissue penetration depth of 2–3 mm (maximum tumor thickness up to which sufficient light quanta penetrate into tissue to produce reactive oxygen species [ROS]), current studies reveal no significant differences with regard to efficacy between various lamp systems at uniform equivalent dose. Suitable light sources include incoherent broadband light sources, the long-pulsed dye laser, LED systems (light-emitting diodes) or flash lamps [5]. For the treatment of in part highly different disorders various therapeutic regimen exist. For the therapy of inflammatory, infectious or cosmetic indications low light and sensitizer doses (lower concentration, shorter exposure) with more frequent cycles are used. The goal here are immunomodulatory effects, usually mediated by proinflammatory cytokines (low-dose PDT) [6]. For non-melanoma skin cancers, on the other hand, the goal is selective tumor cell destruction, be it due to necrosis or induction of apoptotic processes. For this one or two treatment cycles (at an interval of 7–10 days) with significantly higher light and photosensitizer doses are the rule (high-dose PDT). During irradiation energy is transferred to the intracellular porphyrin molecule (tetrapyrrole ring system with conjugated double bonds). The energy level of the molecule is elevated. Energy can be emitted directly by the emission of light quanta of a longer wavelength (fluorescence), which can be utilized for tumor margin determination in fluorescence diagnostics. Further, after an internal conversion, energy can be transmitted to cellular oxygen, that can alter its energy level to become singlet oxygen. This is highly reactive and can interact with numerous further substrates, form reactive oxygen species that act in oxidative fashion and irreversibly damage cell organelles and membrane structures. In this process the porphyrin molecule itself is also destroyed (consumed); the process is termed “photobleaching” and is important with respect to limiting the effect of irradiation (an overdose of light is not possible as the amount of photosensitizer limits the duration of the PDT effect). The oxygen concentration is also of importance: hypoxic tissue cannot be treated well with PDT. These facts already led years ago to efforts to optimize effectiveness of the treatment by elevating the oxygen partial pressure during irradiation. In interaction with the well-known high amount of iron ions in tumor cells, significantly more ROS are generated in hyperbaric oxygen conditions, resulting in greater cell damage [7]. The efficacy of hyperbaric PDT with regard to tumor tissue has been proven in many studies, but the increased treatment effect is, as mentioned above, due to compensation of hypoxic states – be they pre-existing or induced by the irradiation [8].: Hjelde et al. studied 3 malignant cell lines under normal and increasing oxygen partial pressure and found no significant alterations in the tumor cell burden after the series of irradiations [9].

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With use of red light with a maximum tissue penetration depth of 2–3 mm and uniform equivalence dose incoherent broadband light sources, longpulsed dye lasers, LED systems or flash lamps can be used with equal efficacy.

During irradiation the energy level of the porphyrin is elevated, which subsequently leads either to the emission of light quanta (fluorescence diagnostic) or to the production of reactive oxygen species that can irreversibly damage cell organelles and membrane structures (photodynamic therapy).

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Table 2: Indications for PDT. Oncological

Inflammatory

Infectious

Cosmetic

Actinic keratoses

Acne

Verrucae vulgares

Photochemorejuvenation

Superficial BCC

Psoriasis

Condylomata acuminata

Bowen disease

Darier disease

Cutaneous leishmaniasis

Cutaneous lymphomas

Lichen planus

Epidermotropic metastases

Rosacea

Kaposi sarcoma

Figure 2: Patient with actinic keratoses on the forehead (a); Presentation 6 months after PDT using MAL (b).

In analogy to treatment in radiooncology fractioning of irradiation appears as a possible therapy modification. Recently a study on PDT of AK and BD demonstrated a significantly better remission rate for fractioned irradiation. In comparison to a single irradiation with an intensity of 100 J/cm2, after two sequential irradiations with 50 J/cm2 at an interval of 2 hours significantly less tumor tissue was detected by fluorescence diagnostics or biopsy after 24 weeks. In contrast to this another working group found significantly better results with regard to reduction of tumor burden in surgically treated patients in a comparison of fractioned PDT with surgical excision of nodular BCC. At the present time current studies do not allow for a final recommendation with regard to fractioning of irradiation.

In the treatment of actinic keratoses with MAL-PDT remission rates of 69–91 % are achieved.

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Indications (Table 2) Non-melanoma skin cancers Actinic keratoses and Bowen disease Cutaneous precancerous lesions that initially display a flat, horizontal growth pattern have been the focus of intense experimental and clinical use of PDT for more than 10 years. With PDT remission rates of 69–91 % are achieved [10]. A comparative study on 119 patients and 1501 lesions demonstrated PDT healing rates of 86.9 % vs. 76.2 % for cryotherapy. Further, in comparison to topical imiquimod treatment a greater response especially of KIN II lesions (a healing rate of 57–89 % after 6 months after PDT vs. 37.03 % after 5 % IMIQ) was observed. By combination of PDT with topical 5 % imiquimod recently the number of actinic keratoses on one side of the face was reduced by 89.9 % (versus 74.5 % on the side of the face treated solely with PDT). In the treatment of histologically confirmed Bowen disease PDT led to a complete remission rate of 80 % in comparison to 67 % for cryotherapy and 39 % for the use of 5-FU (Figures 2, 3). Classical treatment alternatives such as curettage, cryotherapy or excision cannot guarantee the same cosmetic results, particularly on sun-exposed – and therefore

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Figure 3: Patient with histologically proven Bowen disease on the right shin (a); Presentation after a single PDT using 5-ALA (20 % cream, duration of application: 6 h, illumination with red light: 120 J/cm²) (b).

Table 3: Current status of studies on various formulations. Author

ALA formulation Patients Clearance rate of AK

Hauschild et al. 2009

5-ALA tape Pd P 506 A

Morton et al. 2006 Fai et al. 2009

BF-200-ALA nanoemusion MAL MAL

449

82–89 %

122

96 %

119 210

89.1 % 79 %

visible – locations such as the face or décolleté. Furthermore, PDT is more controllable by the physician than for example the use of a complex applicable ointment (under occlusion etc.) by the patient himself. Treatment success of PDT thus does not depend on the compliance of the patient. Moreover, high-risk groups for the development of skin neoplasia such as the chronically immunosuppressed profit particularly from PDT. Organ graft recipients receiving preventive photodynamic therapy developed markedly less precancerous lesions after 3 months than in an untreated control area (65 vs. 103) in a comparative study – an effect that was no longer significant after 27 months. Also in transplant patients a two-time MAL-PDT at an interval of one week achieved a remission rate of 89 % at sites with biopsy-proven Bowen disease. In comparison to 11 % in skin areas treated with 5- FU twice daily for three weeks [11] (Table 3). Actinic cheilitis Carcinomas of the vermillion border of the lip have a markedly higher tendency to metastasize than squamous cell carcinomas on the skin. Therefore, to prevent malignant degeneration actinic cheilitides have to be treated radically with vermillionectomy, CO2 or Erbium:YAG laser therapy often with unfavorable cosmetic results. The good therapeutic efficacy and tolerability of photodynamic treatment of actinic cheilitis have been verified repeatedly. In a prospective, randomized study Freeman et al. compared a two-time MAL irradiation at an interval of one week to classical cryotherapy with regard to efficacy and patient satisfaction. A remission rate of 91 % was seen for PDT versus 68 % for cryotherapy and 30 % for placebo therapy with a significantly superior cosmetic result and higher patient satisfaction. For precancerous lesions of the vermillion border of the lip, PDT once again represents an effective, cosmetically advantageous, modern form of therapy.

The advantages of PDT are the excellent cosmetic results, especially in the treatment of extensive field cancerization, the good controllability by the physician and good efficacy in the immunosuppressed.

The therapeutic efficacy for actinic cheilitis, which requires early consistent therapy, is well-proven.

Basal cell carcinoma (BCC) An increasingly earlier age of manifestation has been observed for BCC in recent decades, underscoring the need for optimal cosmetic therapy results. In a study

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Table 4: Studies on the treatment of lymphomas.

For the treatment of superficial BCC, PDT offers comparable results in comparison to excision and cryotherapy with a superior cosmetic outcome. For nodular BCC with a thickness of several millimeters, surgical excision remains the method of choice.

Current studies reveal extremely satisfying results with biopsy-proven complete remission of cutaneous lymphomas.

Author

Indication

Patients Complete remissions

Hegyi et al. 2008

Mycosis fungoides

1

1

Recio et al. 2008

Mycosis fungoides

2

2

Morton et al. 2006 Mycosis fungoides

5

4

Zane et al. 2006

3

3

B-cell lymphoma

presented at the EADV conference in Vienna, Austria, in 2007 84.8 % of patients treated with PDT for superficial basal cell carcinomas rated the cosmetic result as good or very good in contrast to 50.6 % after simple excision with comparable remission rates (87.4 % for MAL-PDT vs. 89.4 % for simple excision after 3 months). The healing rates of crytotherapy are matched by PDT of superficial BCC (97 % of 102 BCC after MAL-PDT vs. 95 % of 98 BCC after cryotherapy) [12]. For the treatment of this histological subgroup PDT represents a therapy option of equal value. Solid tumors, however, that can easily be several millimeters thick, limit the use of PDT greatly. Therefore, surgical excision – especially micrographic surgery – remains method of choice here as for the treatment of tumors in the vicinity of fascial, embryonic fusion lines. In the meantime even for nodular BCC two-time MALPDT has achieved complete remission rates of 91 % with better cosmetic results after 3 months – values that do not differ significantly from surgical excision (98 %). After 24 months 5 recurrences were observed in the group of patients treated with PDT (vs. 1 recurrence after surgery). Further studies with long-term follow-up of BCC come to the conclusion that PDT with regard to the 5-year recurrence rate is equivalent to invasive procedures – in this case cryotherapy – for superficial BCC (recurrence rate of 22 % for MAL-PDT vs. 20 % for cryotherapy). In comparison to simple excision for nodular BCC the recurrence rate was 14 % after MAL-PDT in comparison to 4 % after surgery, so that here a recommendation should usually be made for excision. Cutaneous lymphomas Within the heterogeneous group of cutaneous lymphomas there is a great need for well tolerable treatment alternatives in face of the frequent and in part serious side effects of established therapy modalities such as potent topical steroids, radiation therapy, interferon treatment or chemotherapy. Current studies reveal extremely satisfying results with biopsy-proven complete remission of cutaneous lymphomas. Of five patients with therapy-refractory unilesional plaque stage mycosis fungoides four patients demonstrated complete remission after weekly irradiations until healing of the lesions with a follow-up of 12 to 34 months. Moreover, in a pilot study Mori et al. treated 5 patients with cutaneous B-cell lymphomas successfully [13]. It is obvious that studies up to now have been performed on very small collectives [14]. Multicenter studies with adequate case numbers are still lacking (Table 4), which is why a general therapy recommendation cannot be made. Further, PDT will remain limited to the treatment of few circumscribed lesions. In contrast to PUVA therapy, for example, a full body treatment is unjustifiable due to the resulting generalized inflammatory reaction. In lymphoma treatment PDT will probably play only a therapy-supporting, morbistatic or palliative role even in the future. Non-oncologic indications Tumor cell necrosis and apoptosis are desirable in the oncological indications described above. With modification of the therapy protocols immunomodulatory mechanisms of PDT become active. By lowering the light and sensitizer doses and increasing the number of treatment cycles, the quantity of local Langerhans cells, for example, is reduced [15], the production of transcription factors is induced or keratinocyte proliferation is inhibited. Especially inflammatory skin diseases such as acne, viral warts, morphea and even cutaneous leishmaniasis profit from this mechanism.

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Acne In the meantime photodynamic treatment of acne has been studied well. Numerous studies point to a strong antiinflammatory effect of PDT on inflammatory lesions as they are especially found in papulopustular acne and acne conglobata. This is based probably both on direct damage to Propionibacterium acnes and sebaceous glands as well as a keratolytic effect on the epithelium. The use of an incoherent light source in several treatment cycles at intervals of 2–4 weeks is superior to other forms of light therapy but is in part accompanied by significant side effects such as erythema, desquamation and pigmentary disturbances. Due to more frequent discontinuation of therapy, current guidelines do not deviate from established topical and systemic therapy modalities. A recent study suggests shorter incubation times with higher specificity by means of intralesional injection of the sensitizer. At present there are efforts to reduce severity and frequency of side effects, which is an urgent demand before standardized use in light of the benign nature of acne. Viral infections New possible indications for PDT encompass the broad field of viral skin infections. Here HPV-associated diseases such as common and genital warts stand in the foreground. In the meantime HPV-independent infections such as molluscum contagiosum and herpes simplex are being treated successfully [17]. PDT releases cytotoxic radicals in virally infected cells, which induce selective necrosis and apoptosis of the keratinocytes. Especially for common warts that often occur at mechanically burdened sites, scar-free healing is a great advantage. Before treatment consistent keratolysis must be performed which can be time-consuming. This and again the pain during irradiation are hardly tolerated especially by children, who constitute the majority of the potential patient collective. This continues to greatly limit the indication for common warts. Recently, in China ALA-PDT of condylomata acuminata was compared with the established CO2 laser therapy in 65 patients. Two sequential treatments led to a remission rate of 100 %, the recurrence rate in patients treated with PDT was 6.7 %, markedly lower than in the control group with 19.1 %, all this with significantly fewer side effects. The problem in this situation lies in the low depth of penetration of the sensitizer and light which prevents sufficient treatment of highly exophytic warts. A further indication was follow-up treatment of subclinical lesions remaining after CO2 laser therapy to prevent the known high recurrence rate. For this 175 patients with genital condylomata acuminata in a randomized, double-blind study received an adjuvant ALA-PDT or placebo PDT. After 12 weeks a recurrence rate of 50 % was seen after ALA- and 52.7 % after placebo PDT; a significant reduction in the frequency of recurrence could not be achieved [18]. Intraurethral condylomas and cervical intraepithelial neoplasia, on the other hand, were recently treated in part very efficiently with PDT with remission rates between 50 and 95 %. Especially the difficult treatment of intracavitary mucous membrane lesions would profit greatly from controlled studies with large case numbers.

In therapy of acne the antiinflammatory effect is proven beyond doubt. The high rate of side effects prevents standardized use at present.

PDT releases cytotoxic radicals in virally infected cells, which induce selective necrosis and apoptosis of the keratinocytes.

The low depth of penetration of sensitizer and light prevent a sufficient photodynamic treatment of exophytic condylomata acuminata.

Cutaneous leishmaniasis For tropical nations this widespread infectious disease constitutes a great problem especially due to a lack of reliable therapy options. For PDT in a study on 60 patients higher treatment response than for the topical application of paromomycin (remission rates of 93.5 % vs. 41.2 %) was demonstrated. After topical PDT a marked reduction of the parasite burden and macrophage number and highly elevated interleukin-6 levels in the infected tissue were found [19]. The hardly meaningful side effects include slight burning, erythema and reversible hypo- and hyperpigmentation. PDT cannot at present be recommended in an unrestricted fashion for clinical routine, because – as is often the case – sufficient data are lacking (Figure 4). Aesthetic-dermatologic indications Finally, in recent years PDT has entered the field of aesthetic dermatology and photorejuvenation. Initially, visible reduction of small wrinkles and the evening out of pigment anomalies in the vicinity of actinic keratoses after their treatment

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Figure 4: Patient with cutaneous leishmaniasis of the nose (a); Presentation after 5 treatments with ALA-PDT in weekly intervals (b).

Probably by increasing collagen neosynthesis PDT can improve superficial wrinkles, roughness and skin density.

PDT has in the meantime been established in the treatment of nonmelanoma skin cancers. Particularly with regard to depth of penetration and pain possibilities for further development exist. Then PDT will probably expand its spectrum even for nononcological applications.

stood in the foreground. Subsequent studies revealed marked positive effects on sun-damaged and aged skin even histologically. In the meantime the use of PDT in the aesthetic field has been a target of research. In split-face studies both in combination with established treatment methods such as fractional resurfacing with the Fraxel laser as well as after monotherapy improvement of superficial wrinkles, roughness and skin density could be achieved. The exact mechanism of action is unknown, collagen synthesis appears to profit most from photodynamic treatment [21]. Further, immunohistochemical markers point to an increase in epidermal proliferation. A further aesthetic target for PDT are idiopathic alopecias, inadequately treatable to date. A Japanese research group in a recent study applied a topical formulation with ALA and iron ions once daily for 21 days onto shaven mice. Under normal room lighting hair growth increased significantly without a simultaneous proliferation of epithelial keratinocytes or fibroblasts, while the mechanism of action here is also unknown [22]. This application is conceivable for all alopecia forms independent of the number of epidermal mesenchymal cells and will surely be in the focus of future cosmetic-aesthetic research. Conclusions and outlook Particularly as a treatment for non-melanoma skin cancers, clinical routine without PDT can hardly be imagined. Nevertheless, intensive work is being done to remove limitations that at present especially include poor access to deep lesions and the painfulness of treatment. Recently, many promising techniques have been studied and developed further to increase tissue penetration of ALA. By means of microneedle puncture in connection with a bioadhesive tape, pretreatment with etretinate, a derivative of vitamin A acid, or inclusion of a new chelating agent (CP 94) in increasing concentrations in the topical formulation, accumulation of ALA in healthy and tumor tissue could be increased significantly [23]. The often intense and difficult to treat irradiation pain is again one main factor that limits PDT especially for nononcological diagnoses such as acne or vulgar warts with many treatment alternatives. Recently good results were achieved for field cancerization of the forehead and scalp, a constellation that is known for the resulting pain of treatment, with nerve blockade without compromising clinical results. Should future developments make pain as significant side effect more controllable while retaining good efficacy and excellent cosmetic outcome, the applications of PDT even for inflammatory or aesthetic indications will expand greatly. Conflict of interest Prof. Szeimies has received grants for participation in clinical trials from Abbott, Biofrontera AG, Galderma, 3M, meda Pharma, PhotoCure ASA, photonamic, Schering-Plough and Wyeth; has received honoraria for participation in advisory boards from Galderma, Intendis, and Peplin; has received honoraria as a speaker for Almirall-Hermal, Galderma, Intendis and photonamic.