Transcript
REVIEW
Photodynamic therapy in dermatology: state-of-the-art Philipp Babilas, Stephan Schreml, Michael Landthaler & Rolf-Markus Szeimies Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
Summary Key words: aminolevulinic acid; inflammation; methyl aminolevulinate; photodynamic therapy; skin cancer
Correspondence: Philipp Babilas, M.D., Department of Dermatology, University Hospital Regensburg, Franz-Josef-StraussAllee 11, 93053 Regensburg, Germany. Tel: 149 941 944 9605 Fax: 149 941 944 9532 e-mail:
[email protected]
Photodynamic therapy (PDT) has become an established treatment modality for dermatooncologic conditions like actinic keratosis, Bowen’s disease, in situ squamous cell carcinoma and superficial basal cell carcinoma. There is also great promise of PDT for many non-neoplastic dermatological diseases like localized scleroderma, acne vulgaris, granuloma anulare and leishmaniasis. Aesthetic indications like photo-aged skin or sebaceous gland hyperplasia complete the range of applications. Major advantages of PDT are the low level of invasiveness and the excellent cosmetic results. Here, we review the principal mechanism of action, the current developments in the field of photosensitizers and light sources, practical aspects of topical PDT and therapeutical applications in oncologic as well as non-oncologic indications.
Accepted for publication: 3 March 2010
Conflicts of interest: None declared.
H
ermann von Tappeiner, director of the Institute of Pharmacology at the University of Munich, coined the term ‘photodynamic reaction’ already 100 years ago. According to the observations of one of his doctoral students, Oscar Raab, the reaction was characterized as an oxygen-dependent tissue reaction following photosensitization and irradiation with light (1, 2). Oscar Raab could show in his experiments that the organic photosensitizer acridine orange was lethal for paramecia in the presence of daylight (2). The toxicity of acridin orange on protozoae was not only dependent on the concentration of the dye but also on the intensity of illumination. In cooperation with the dermatologist Jesionek, von Tappeiner successfully treated patients suffering from lupus vulgaris, stage II syphilis and superficial skin cancer with topical eosin red solution (1–5%) (1). In 1911 Hausmann reported photodynamic effects on mice injected with hematoporphyrin. The treated mice exhibited extensive edema and erythema after light exposure. As early as 1942, the German researchers Auler and Banzer observed the specific uptake and retention of hematoporphyrin in tumors with subsequent higher fluorescence in the cancerous tissue as compared with the surrounding tissue. Following irradiation with a powerful quartz lamp they also histologically demonstrated the induction of necrosis (1). Thereafter, photodynamic therapy (PDT) passed out of mind until Thomas Dougherty initiated a renaissance in the mid seventies when treating patients with cutaneous and subcutaneous tumors after an 118
injection of the photosensitizer dihematoporphyrin followed by red light irradiation using a laser. The majority of the treated tumors showed either complete or partial remission (1, 3, 4). Today, it is precisely known that PDT requires the simultaneous presence of a photosensitizer, light energy and oxygen inside the diseased tissue. The photosensitizer accumulates in the target cells and absorbs light of a certain wavelength. The energy is transferred to oxygen and highly reactive oxygen species (ROS) – mainly singlet oxygen – are generated. Treating with appropriate light doses, ROS directly lead to cell and tissue damage by inducing necrosis and apoptosis and indirectly stimulate the production of inflammatory mediators. Following lower light doses when treating inflammatory dermatoses, immunomodulatory effects are induced. In the past decades, PDT gained worldwide popularity, first as an experimental therapy for a variety of human cancers. Mainly porphyrins, chlorine derivatives or phthalocyanines have been studied so far for primary or adjuvant cancer therapy (5). However, for dermatological purposes, only hematoporphyrin derivatives like porfimer sodium or protoporphyrin IX (PpIX)-inducing precursors like 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) are of a practical concern. As systemic photosensitizing drugs induce a prolonged phototoxicity (5), topical photosensitizers are preferred for the use in dermatology. Meanwhile, several formulations containing drugs like ALA or MAL have reached approval status for epithelial cancers or their precursors
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throughout the world and there is a growing interest in the use of PDT, not only for non-melanoma skin cancer (NMSC) but also for other skin tumors like lymphoma or for tumor surveillance in transplant patients as well as for non-oncological indications (6–9).
Photosensitizers At the beginning of the last century, eosin red or erythrosine were the first dyes used by Georges Dreyer (Copenhagen, Denmark) and Albert Jesionek (Munich, Germany) as topical ‘photosensitizers’ to treat conditions like syphilis, lupus vulgaris, pityriasis versicolor, psoriasis, molluscum contagiosum or skin cancer (1). However, due to recurrence and severe side effects (pain, unspecific deep tissue necrosis), these experiments were abandoned. Since 1908, the tumor-localizing effects of porphyrins were studied. In the late 1970s, hematoporphyrin derivative (HPD)-based PDT for the treatment of skin cancer came up again (1, 3, 4). The main problem in the use of HPD like porfimer sodium (Photofrin, Axcan PharmaTM, Birmingham, AL, USA) is the prolonged skin photosensitization, which may last for several weeks (10). A topical application is impossible as the rather big molecules (tetrapyrrol rings) do not penetrate sufficiently into the skin. Therefore, the introduction of the porphyrin precursor ALA by Kennedy and colleagues in 1990 was a significant milestone in the development of PDT in dermatology as the small molecules easily penetrate into the epidermis due to their low molecular weight (1, 11). In the United States, ALA hydrochloride (Levulans Kerastick, DUSA Pharmaceuticals Inc., Wilmington, MA, USA), is approved for PDT of actinic keratoses (AK) in combination with blue light (12). The ALA-based photosensitizers are not photoactive by themselves, but show a preferential intracellular accumulation inside the altered cells constituting the diseased tissue. Subsequently, they are metabolized in the heme biosynthesis to photosensitizing porphyrins rather selectively inside these cells (1, 13). If no surface illumination is given, the porphyrins are metabolized to the photodynamically inactive heme within 24–48 h. The prerequisites of good tissue penetration and selective accumulation in tumor tissue are fulfilled perfectly with the hydrophilic molecule ALA. However, when using ALA as a photosensitizer, tumor thickness should not exceed 2–3 mm in order to induce sufficient necrosis of deep tumor tissue portions upon illumination. An alternative is the methyl ester of ALA, the methyl-5amino-4-oxopentanoate, MAL. The maximum intracellular concentration of protoporphyrin IX is reached earlier, which allows for a shorter incubation time (MAL: 3 h vs. ALA: 4–6 h) (14). Christiansen et al. (15) reported on the fluorescence profile of ALA in a cream formulation (20%) as compared with liposomal encapsulated ALA (0.5% and 1.0%). Peak fluorescence was reached after 2 h using the liposomal form and 8 h after application no luminescence was detectable. The duration of luminescence represents the duration of the iatrogenic photosensitivity after PDT. ALA cream showed an increase of luminescence up to 8 h. The mean luminescence was equivalent in both groups. Therefore, the use of a liposomal form allows for
a reduced ALA concentration as the penetration is significantly better using this vehicle. Further studies regarding liposomal or nanocolloidal ALA compositions are ongoing. For using MAL in clinical practice, the requirement of a mechanical curettage before application of the photosensitizing drug is cumbersome. New modalities have been introduced recently (16). In three clinical studies, the liberation of ALA from a patch matrix (PD P 506 A, Photonamic GmbH, Wedel, Germany) was investigated. No side effects or phototoxic reactions were reported. In a multicenter phase II trial, 149 patients with 520 AK (grade I/II) were treated with the ALA patch PDT. Curettage was omitted. The patches were applied for 0.5, 1, 2 or 4 h. The highest remission rate (86%) 8 weeks after therapy was achieved in the group with a 4 h incubation time. Side effects were comparable to those after standard PDT. In a further series of studies, ALA patch PDT was compared with cryotherapy in a multicenter trial with 346 patients with 4–8 AK each. Following a 4 h incubation period, illumination was performed using a light-emitting diode (LED) light source (630 nm). The comparative treatment was cryotherapy with liquid nitrogen. Although designed as a non-inferiority study, both on lesion- or patient-based outcome after 3 months, PDT was superior to cryotherapy [89% vs. 77% complete clearance (lesionbased); 67% vs. 52% (patient-based)]. Moreover, these results were achieved despite the fact that no lesion preparation (i.e. slight curettage before patch application) was performed (16). Meso-tetrahydroxyphenylchlorine (mTHPC) or benzoporphyrin derivative monoacid A ring (Verteporfin) are other photosensitizers that have been applied systemically for the treatment of basal cell carcinoma (BCC) and Bowen’s disease (17, 18). In contrast to HPD, these second-generation photosensitizers show only limited cutaneous phototoxicity. Both drugs are already registered for head and neck cancers or agerelated macular degeneration, but it remains unclear whether a registration for dermatological purposes will follow.
Light sources Following bioconversion of the precursors to photosensitizing porphyrins, the latter can be activated by light of an appropriate wavelength. The porphyrins or related photosensitizers with a tetrapyrrolic structure exhibit a very typical absorption spectrum with the highest peak at approximately 405 nm, the so-called Soret-band. Besides, several Q-bands exist, the last having an absorption peak at 635 nm. Although the peak is much smaller than that at 405 nm, this wavelength is preferentially used for irradiation because light in the red spectrum shows the best tissue penetration (19, 20). However, blue light is approved in the United States in the combination with ALA hydrochloride (Levulans Kerastick) for photodynamic treatment of nonhyperkeratotic AK (12, 21). In addition, white light sources or green light sources also exist for PDT. However, it has been demonstrated in a comparative trial that light of shorter wavelengths is less effective in the treatment of Bowen’s disease at a theoretically equivalent dose. Therefore, only the use of red light is recommended for PDT of NMSC (22, 23). With red light,
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NMSC up to a thickness of 2–3 mm can be treated; thicker lesions require multiple treatments or tissue preparation (debulking) before PDT (24–26). For irradiation in PDT, lasers and incoherent light sources have been used (27–30). Pulsed laser light sources matching one of the Q-bands at 585 nm have been evaluated with equal results as compared with an incoherent light source in the treatment of AK (29). An advantage of lasers is the shorter exposition time as compared with incoherent light sources. Although not ideally matching the porphyrin absorption spectrum, the use of a long pulsed dye laser at 595 nm appears to be effective in the treatment of AK, too (31). However, incoherent light-sources exhibit fundamentally different irradiation characteristics as compared with lasers. As coherence is lost within less than a millimeter of penetration into skin, this property is not mandatory for PDT (30). The high versatility of intense pulsed light (IPL) has made these incoherent light sources to a favored device for PDT. The emission spectrum of IPL devices ranges from 500 to 1300 nm. With the aid of convertible cut-off filters, the IPL device can easily be adapted to the desired wavelengths. Recently, several authors have reported successful treatments of acne vulgaris (32–34), AK (35, 36), photoaged skin (37–39) and sebaceous gland hyperplasia (40) with IPL devices for PDT. Babilas et al. (41) compared the effectiveness of a gas discharge lamp with an LED system in vitro and in vivo. Human epidermal keratinocytes (HEK) were incubated for 24 h with ALA (100, 200, 300, 400 or 500 mmol/l) and irradiated consecutively using either an incoherent halogen lamp (lem = 580–700 nm, 24 J/ cm2, 40 mW/cm2) or an LED system (lem = 633 3 nm; 3, 6, 12 or 24 J/cm2, 40 mW/cm2). For the in vivo experiments, the authors performed topical ALA-PDT on 40 patients with AK (n = 584) in a symmetrical dissemination suitable for two-side comparison. After incubation with ALA (20% in cream base), irradiation was performed with the incoherent lamp (160 mW/ cm2; 100 J/cm2) on one side and the LED system (80 mW/cm2; 40 J/cm2) on the opposite side followed by re-evaluation up to 6 months. The authors reported no significant differences between the LED system (3, 6, 12 or 24 J/cm2) versus the incoherent light source (24 J/cm2) regarding cytotoxicity in vitro. The complete remission rate yielded in the in vivo investigation was also not significantly different 6 weeks (P = 0.95), 3 months (P = 0.75) and 6 months (P = 0.61) following therapy. Six weeks following therapy, complete remission rates of 84.3% (LED system) and 82.8% (incoherent lamp) were achieved. There were also no significant difference between both light sources regarding pain during illumination (P = 0.68) and patient satisfaction (P = 1.00) as well as cosmetic outcome (P = 1.00) following therapy. Therefore, the authors were able to demonstrate the efficacy of a LED system for ALA-PDT both in vitro and in vivo. Using the LED system, lower light doses were sufficient, as these devices emit only a narrow band of wavelengths that perfectly match the absorption spectrum of porphyrins. The wavelengths unnecessary for the phototoxic reaction, which only contribute to heat effects are omitted. In another work the same group evaluated the painfulness and effectiveness of an IPL device in a prospective, randomized and controlled split-face study (42). 120
They conducted topical MAL-PDT in 25 patients with AK (n = 238) that were suitable for two-side comparison. After incubation with MAL, they performed irradiation with a LED (50 mW/cm2; 37 J/cm2) versus IPL (80 J/cm2; 610–950 nm filtered hand piece) followed by re-evaluation up to 3 months. They reported a significantly lower painfulness during and after therapy using the IPL [t(df = 24) = 4.42, P o 0.001]. The overall infiltration and keratoses score 3 months after treatment were reported not to be significantly different [0.86 0.71 (LED system) vs. 1.05 0.74 (IPL device)]. Patient satisfaction following both treatment modalities did not significantly vary during the 3 months follow-up according to their data. The authors concluded, that IPL use for MAL-PDT is an efficient alternative for the treatment of AK because of comparable results in complete remission and cosmetic outcome. Moreover, IPLPDT appears to cause significantly less pain. In a further work of the same group, the authors evaluated the efficacy, painfulness, patient satisfaction and cosmetic result of LED-based PDT in a prospective, randomized and controlled split-face study (43). They conducted topical ALA-PDT in 17 patients with AK (n = 131) in a symmetrical dissemination suitable for a two-side comparison. After incubation with MAL (16%), irradiation was performed with the incoherent lamp (160 mW/cm2; 100 J/cm2, PDT 1200L, Waldmann Medizintechnik, Villingen-Schwenningen, Germany) on one side and a LED system (120 mW/cm2; 40 J/ cm2, LEDA, WaveLight AG, Erlangen, Germany) on the opposite side followed by re-evaluation up to 6 months. They reported no significant difference between the infiltration and keratoses scores in both treatment regimes (P = 0.812) 6 months following treatment. The remission rate was 78.5% (LED system) versus 80.3% (incoherent lamp). The authors reported no significant difference between both light sources regarding the painfulness during therapy (P = 0.988) and patient satisfaction (P = 1.00). Currently, the gold standard in topical PDT are incoherent light sources, either lamps (e.g. PDT 1200 l, Waldmann Medizintechnik) or LEDs (e.g. AktiliteTM, Galderma, Albysur-Ch´eran, France; Omnilux PDTTM, Phototherapeutics, Altrincham, UK), which match the absorption maxima of the ALA- or MAL-induced porphyrins and accomplish the simultaneous irradiation of larger areas (19, 23, 44–46). For tissue destruction when treating malignant tumors, a light dose – using broad-spectrum red light (580–700 nm) – of 100–150 J/cm2 (100–200 mW/cm2) is chosen. For the more narrow emission spectra of the LED systems (bandwidth approximately 30 nm), the values are significantly lower (37–50 J/cm2). The light intensity should not exceed 200 mW/cm2 to avoid hyperthermic effects (19, 44). For inflammatory dermatoses, a light dose of 10–40 J/cm2 and a light intensity of 50–70 mW/cm2 are sufficient (broadspectrum red light, usually multiple treatments). During irradiation, both the patient and clinic staff should be wearing protective goggles in order to avoid the risk of eye damage (47).
Mechanism of action In the presence of oxygen, the activation of a photosensitizer by light of the appropriate wavelength leads to the generation of
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ROS, in particular singlet oxygen. Depending on the amount and localization in the target tissue, these ROS modify either cellular functions or induce cell death by necrosis or apoptosis (9, 12, 13). There is a need for heme and related molecules in fast proliferating, relatively iron-deficient tumor cells of epithelial origin. Therefore, intracellular uptake of heme-precursors like ALA or MAL is eased, thus resulting in a preferential sensitization of these cells. The same applies for target cells constituting inflammatory dermatoses. Therefore, tissue damage is mostly restricted to the sensitized cells almost leaving the surrounding tissue unaffected – especially cells of mesenchymal origin like fibroblasts – resulting in an excellent cosmetic result (22). Until now, there have been only two reports of malignant melanoma following PDT in the literature. Wolf et al. (48) reported on a de novo melanoma in the treatment area following multiple PDT of solar keratoses and superficial squamous cell carcinomas (SCCs) over 4 years. The authors discussed the development of the melanoma as an incidental event. We report on a patient who developed a melanoma at the site of a suspected Bowen’s lesion on the right cheek after PDT treatment (49). Bowen’s disease was only clinically diagnosed, but no biopsy was taken to confirm the diagnosis. In this case, it could not definitely be proven whether PDT led to de novo melanoma or rather promoted the progression of a pre-existing melanoma or whether the melanoma occurred incidentally at the treatment site (49). Moreover, in a recent study, even long-term topical application of ALA and subsequent irradiation with blue light in a hairless mouse model did not induce skin tumors (50). Stender et al. (51) even showed a delay in photoinduced carcinogenesis in mice following repetitive treatments with ALA–PDT.
Practical aspects of topical PDT As it could be shown that hyperkeratosis is the reason for a poor response to PDT of AK localized on the hands (13), keratolysis should be performed in hyperkeratotic lesions before incubation with the aid of a gentle abrasion or a non-bleeding curettage (26, 46, 47, 52). Overnight incubation with an ointment for easy mechanical removal might also work. ALA preparations are mostly applied to the lesions with little overlap to the surrounding tissue for 4–6 h before irradiation under occlusion and in addition with a light protective dressing or clothing (13). For the licensed MAL formulation (Metvixs, Galderma), a shorter incubation time of 3 h is sufficient due to preferential uptake and higher selectivity (53, 54). Here, the entire area is covered with an occlusive foil to allow for better penetration. Lesion preparation is mandatory when using the photosensitizer MAL. The most important side effects of PDT are stinging pain and a burning sensation. Even if they are usually restricted to the time span of irradiation and a couple of hours thereafter (22), they often limit patient compliance. Especially if an extented irradiation field is selected, administration of analgesics is often necessary (55). Pain perception can also be alleviated by concurrent cold air analgesia, which improves the tolerability of
ALA/MAL-PDT (56). Application of topical analgesics like eutectic mixtures of lidocaine/prilocaine before irradiation is not recommended because their high pH might chemically inactivate the photosensitizer. In addition, it could be shown that the topical application of Emlas (AstraZeneca, Wedel, Germany) induced a local vasoconstriction, what might reduce the pO2 -dependent effect of PDT (57). Recently, it was shown that MAL-PDT is less painful as compared with ALA-PDT. In the respective study, 69 patients with AK in field cancerization were treated and asked for their sense of pain on a visual analog scale (1–10). If reaching 10 (worst imaginable pain), the study was discontinued. Fifty-four percent of the patients treated with ALA-PDT as compared with 14% of patients treated with MAL-PDT reached this critical value. These results are confirmed by another work on AK distributed in field cancerization (58). It is discussed whether ALA in contrary to MAL is transported in the endings of the peripheral nerves via GABA-receptors (59). Independent of the photosensitizer used, a pain medication is mandatory for field cancerization especially on face and scalp (60). The complementary application of cold air (e.g. Cryo 6 derma, Zimmer Medizinsysteme, Neu-Ulm, Germany) can further reduce the sense of pain. Green light is less painful than red light, which can be explained by the lower penetration depth (1–2 mm) (61). Babilas et al. (43) could show that the use of an IPL induces significantly less pain as compared with a LED but reaches comparable remission rates. Another study pointed out that pain is the most frequent (92%) side effect of PDT. However, in only 2% of treatments, the therapy was discontinued due to pain (62). A central prognostic factor is the dimension of the affected skin area. Cooling was reported as being most effective for pain reduction. Other frequent side effects are edema and erythema (89%) that persist 4–7 days and they are reported to be a minor problem for the patients. The development of pustules is reported by 6% of patients and is often a source of great uncertainty. In nearly all cases, the pustules are sterile. Following tumor treatment, a dry necrosis sharply restricted to the tumor-bearing areas frequently develops over days. After 10–21 days, formed crusts come off and usually complete re-epithelialization is observed. During this phase, most patients only report slight discomfort. Because of significantly lower doses of both light and photosensitizer in ‘low-dose-PDT’ when treating inflammatory dermatoses, little or no side effects are observed although multiple treatments are necessary. Based on the restriction of photosensitization to cells of epithelial origin – which does not sensitize fibroblasts or dermal fibers – usually no scarring or ulceration is observed clinically (13, 22, 25). Pigmentary changes are also rare and only temporary. Irreversible alopecia has not yet been observed in treated patients. However, due to the concomitant sensitization of the pilosebaceous units, this effect should be taken into account when treating hair-bearing areas (13, 22). Besides contraindications for patients with a known history of porphyrias or allergic reactions to active ingredients of the applied sensitizers, no other severe limitations to perform ALA/ MAL-PDT are known (63). PDT can be repeated several times and
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even in areas with prior exposure to ionizing irradiation, PDT is possible (64).
Therapeutic applications – oncologic indications Regarding oncologic indications, AK, nodular or superficial BCC and – since 2006 – Bowen’s disease are approved indications for MAL. Approval for ALA was given by the FDA for the combination with blue light in the treatment of AK and most recently (2009) the ALA patch was approved in combination with red light for the treatment of AK in Europe.
AK AK evolve in UV-exposed areas and are the most frequent precancerous lesion of the skin. They often impose in a widespread pattern, often necessitating field cancerization. The treatment of AK is mandatory as they have the potential to develop into invasive SCC. In addition to PDT, there exist a number of registered chemical and/or immunological treatment options for the treatment of AK 5-fluorouracil (5-FU, Podophyllin, Imiquimod, Diclofenac, PDT) (65). The choice of the suitable treatment depends on numerous factors, one of which is the number and localization of the lesions that have to be treated. For therapy of single lesions, surgical or physical treatment options like cryotherapy, laser ablation or surgery might be favorable. In contrast, PDT may be the first choice for the therapy of multiple lesions, in particular for AK on the scalp and face or in cases of basal cell nevus syndrome (12). A great advantage of PDT as compared with chemical and/or immunological treatment options is the fact that the patient himself does not have to take care of the treatment over weeks, which is a great compliance-related problem. The efficacy of ALA-PDT has been observed so far in multiple studies and is recommended in numerous consensus works or therapy guidelines of different national and international dermatologic societies (66, 67). In a European multicenter randomized prospective study, MAL-PDT was compared with cryosurgery in the treatment of AK. A total of 193 patients (95%) with 699 lesions completed the trial. Patients received either a single treatment with MAL-PDT (repeated after 1 week in 8% of cases) or a double freeze–thaw course of liquid nitrogen cryosurgery. MAL was applied for 3 h after slight lesion preparation, followed by illumination with broad-spectrum red light (75 J/ cm2). The follow-up visit was performed 3 months after treatment. The efficacy for MAL-PDT (single application) was 69% versus 75% for cryosurgery, yet there was no significant difference. Thin lesions on the scalp had the highest response rates (80% and 82% for PDT and cryosurgery). Cosmetic outcome, as judged by the investigator, was superior for MALPDT (96% vs. 81%) (54). Another comparable trial was conducted in Australia. In this study MAL-PDT was used in two treatment sessions with a 1-week interval. PDT was compared with a single course of cryosurgery or placebo in 204 patients. Lesion response was also 122
assessed after 3 months. A significantly higher complete remission rate with MAL-PDT was observed (91%) versus 68% with cryosurgery and 30% with placebo. The cosmetic outcome was rated excellent in 81% of MAL-PDT patients versus 51% treated with cryosurgery (68). A multicenter, randomized, double-blind and placebocontrolled study with two MAL-PDT cycles was performed in 80 patients with AK in the United States. PDT treatment parameters were similar to the above-mentioned trials. Assessment after 3 months revealed a complete remission in 89% for MAL-PDT versus 38% for placebo. An excellent or good cosmetic outcome was reported in 4 90% of MAL-treated patients (69). In their recent prospective, randomized, double-blind and placebo-controlled study, Dragieva et al. (8)focused on MAL-PDT in the treatment of AK (n = 129) in 17 transplant recipients. As transplant recipients have an increased propensity to develop multiple AK, which demonstrate an increased transformation rate into invasive SCC, an effective treatment is imperative. Sixteen weeks following illumination with red light (incoherent light source, 75 J/cm2, 80 mW/cm2) they observed complete remission in 13 out of 17 patients. They concluded that MALPDT is a safe and effective treatment for AK in transplant recipients, which may reduce the risk of transformation of AK to SCC. Recently, a randomized, placebo-controlled and unevenparallel-group trial was published investigating ALA-PDT for AK. In 243 patients, clinical response, based on lesion clearing, was assessed at weeks 8 and 12. Patients were randomized to receive either the vehicle or ALA (Levulans Kerastick), followed within 14–18 h by illumination with visible blue light (BLU-Us, DUSA, Wilmington, USA, low-pressure fluorescent lamps). Complete response rates for ALA-PDT patients or vehicle with Z75% clearance rate at weeks 8 and 12 were 77% and 89%, respectively. In the placebo group, clearing rates were 18% and 13%. The 12-week clearance rates included 30% of patients who received a second ALA-PDT course. Moderate-to-severe discomfort during illumination was reported by at least 90% of patients. However, in only 3% of patients therapy had to be discontinued (21). To lower the amount of side effects of ALA-PDT, shorter incubation periods (1–3 h), pre-treatment using 40% urea (to enhance ALA penetration) and the use of topical 3% lidocaine hydrochloride (to decrease discomfort) were evaluated. One and 5 months after therapy (18 patients with at least four nonhypertrophic AK) lesions were reduced up to 90% in the target area. There was neither a difference between the three incubation times, nor did pre-treatment with urea or lidocaine have an influence on the therapeutical outcome (55). In a randomized multicenter trial using a side-by-side design, Morton et al. (70) compared the effectiveness of MAL-PDT with cryotherapy. They treated 119 patients with 1501 lesions. Twenty-four weeks after treatment, both groups showed no significant difference in terms of remission rates (MAL-PDT: 89.1%, cryotherapy: 86.1%). Patients as well as investigators favored PDT due to a significantly better cosmetic result. In a recently published randomized, double-blinded, prospective
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split-face study, Moloney and Collins (58) compared MAL- and ALA-PDT in 16 patients. Effectiveness of both treatments was not significantly different. However, MAL-PDT turned out to be less painful. In United States, ALA is approved only in combination with blue light for the treatment of AK. In a multicenter phase IV trial, 110 patients with 748 lesions were treated with a 20% ALA formulation (Levulans Kerastick). One month after therapy, 76% of lesions showed a complete remission and 2 months after therapy 72% did. The recurrence rate 1 year after therapy was 19% (21). In organ transplant recipients (n = 27), the potential of PDT to prevent the appearance of epithelial tumors was investigated. The patients showed AK, BCC and viral warts. A randomized area was treated with MAL-PDT (lem = 570–670 nm, light dose: 75 J/ cm2) and compared with an untreated area. All patients had been immunosuppressed for over 3 years. The median time until appearance of a new lesion was significantly longer in the treatment group as compared with the control group (9.6 vs. 6.8 months). Twelve months following treatment 62% of the treated areas did not show any lesion as compared with 35% of the control areas. Thus, PDT appears to have a preventive character in terms of epithelial neoplasias (71). Moreover, in a prospective, randomized, double-blinded and placebocontrolled study, Piacquadio et al. (21) investigated the effectiveness of MAL-PDT for the treatment of AK (n = 129) in organ transplant recipients. In 13 of 17 patients, a complete remission was reported 4 months after treatment. BCC Various studies concerning ALA/MAL-PDT for BCC have been performed over the years (5, 13, 25, 26, 71–74). The weighted average complete clearance rates calculated from 12 studies (follow-up periods: 3–36 months) were 87% for superficial BCC (n = 826) and 53% for nodular BCC (n = 208) (5, 22). Available compiled data from other trials have shown an average of 87% for superficial BCC, and 71% for nodular BCC (12). In order to ameliorate poor outcome after PDT of thicker BCC lesions, Thissen et al. (26) treated nodular BCC (23 patients, 24 lesions) once with ALA-PDT (incoherent red light; 100 mW/ cm2, 120 J/cm2) 3 weeks after debulking of the BCC. The former tumor areas were excised 3 months later and histopathologically evaluated for residual tumor. Twenty-two (92%) of the lesions showed complete remission, both clinically and histologically. In a prospective phase III trial comparing ALA-PDT with cryosurgery, Wang et al. (74) included 88 superficial and nodular BCC. Only one lesion per recruited individual was included in the trial. A 20% ALA/water-in-oil cream was applied for 6 h under an occlusive dressing, followed by irradiation with a laser at 635 nm (80 mW/cm2, 60 J/cm2). In the cryosurgery arm, lesions were treated with liquid nitrogen using the open spray technique with two freeze–thaw cycles for 25–30 s each. After 3 months, punch biopsies were performed and revealed a recurrence rate of 25% in the PDT group and 15% in the cryosurgery group. However, the clinical recurrence rates
were only 5% for ALA-PDT and 13% for cryosurgery. The discrepancy between the clinical appearance of the treated lesion and the actual status in histology is problematic, as tumor recurrence can be masked. In the PDT-treated group, a better cosmetic outcome and a shorter healing time was documented. Another work reported the recurrence rates after 2 years following the treatment of superficial BCC with PDT versus cryotherapy as 22% for PDT and 19% for cryotherapy (75). In a review of Lehmann, the recurrence rates at the 5-year follow-up were quoted as identical for PDT (74%) and cryotherapy (74%) (76). Sole`r and colleagues (25) studied the long-term effects of MAL-PDT (59 patients, 350 BCC). Nodular tumors were curetted before MAL-PDT (160 mg/g) was applied for 24 or 3 h before irradiation with a broadband halogen light source (50–200 J/ cm2). Patients were followed for 2–4 years (mean 35 months). Overall cure rate was 79%, and cosmetic outcome was excellent or good in 98% of the completely responding lesions. In a recent open, uncontrolled, prospective, multicenter trial, both patients with superficial and/or nodular BCC who were at risk of complications (poor cosmetic outcome, disfigurement and/or recurrence) when using conventional therapy were studied. Ninety-four patients were treated with a single cycle of MAL-PDT involving two treatment sessions 1 week apart, and followed-up at 3 months, at which time non-responders were retreated. The clinical lesion remission rate after 3 months was 92% for superficial BCC and 87% for nodular BCC. Histological cure rates at this time point were 85% for superficial BCC and 75% for nodular BCC. At 2 years after treatment, the overall lesion recurrence rate was 18% (72). In a comparative trial in Australia, MAL-PDT for nodular BCC was compared with a placebo. Lesions from 66 patients were treated in two sessions of either placebo or MAL-PDT in a randomized, double-blind, controlled study. In case there was no complete response 3 months after initial treatment, lesions were excised. After 6 months, complete remission rate was 73% for MAL-PDT compared with 21% for placebo (53). In another European multicenter, open, randomized trial, MAL-PDT for nodular BCC was compared with surgery. A total of 101 patients were included and received either PDT twice, 7 days apart (75 J/cm2 red light) or surgical excision. The primary endpoint of this trial was the clinically assessed lesion clearance at 3 months after treatment, besides cosmetic outcome. The 3 months cure rate was similar with MAL-PDT or surgery (91% vs. 98%), the 2 years recurrence rate was 10% with MAL and 2% with surgery. The cosmetic result was rated good/excellent in 85% of the patients receiving PDT versus 33% with surgery (73). ALA-PDT can be used also for adjuvant therapy in combination with Moh’s micrographic surgery, as reported by Kuijpers et al. (77). In four patients, who had Moh’s micrographic surgery for extensive BCC, the central infiltrating tumor part was excised before ALA-PDT. After re-epithelialization, ALA-PDT of the surrounding tumor rims (2–5 cm) bearing remaining superficial tumor parts was performed. This led to a complete remission of the tumors with excellent clinical and cosmetical results (follow-up period up to 27 months) (77).
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In a multicenter, randomized, controlled, open study, Szeimies et al. (78) compared MAL-PDT (two sessions, 1 week apart, repeated 3 months later if incomplete clinical response) with simple excision surgery of superficial BCC (196 patients, on average 1.4 lesions each). Primary endpoints were efficacy and cosmetic outcome over a 1-year period. Mean lesion count reduction at 3 months was 92.2% with MAL-PDT versus 99.2% with surgery, confirming the non-inferiority hypothesis (95% confidence interval: –12.1, –1.9). A total of 92.2% lesions showed complete remission at 3 months with MAL-PDT versus 99.2% with surgery. At 12 months, 9.3% lesions recurred with MAL-PDT and none with surgery. Cosmetic outcome was statistically superior for MAL-PDT at all time points. At 12 months, 94.1% lesions treated with MAL-PDT had an excellent or good cosmetic outcome according to the investigator compared with 59.8% with surgery. This difference was confirmed with a self-assessment of the patients. The proportion of excellent cosmetic outcome markedly improved over time with MAL-PDT in contrast to surgery. However, the surgical standard treatment of superficial BCC is curettage and this procedure would likely lead to significantly better cosmetic results as compared with simple excision surgery. However, even if all clinical studies qualify PDT as an effective treatment of BCC, Moh’s micrographic surgery shows generally higher cure rates as compared with PDT. Besides, the relatively short follow-up of most of the performed studies has to be considered. Mandatory indications for surgical treatment are histological subtypes like pigmented or morpheic BCC, BCC located in the area of the facial embryonic fusion clefts as well as all BCC thicker than 3 mm if no debulking procedure is performed before PDT. Bowen’s disease and initial SCC Bowen’s disease is approved for MAL-PDT since 2006 and is – as a planar epithelial precancerous lesion – highly suitable for PDT. In a recent study by Salim et al. (79), ALA-PDT was compared with topical 5-FU in the treatment of Bowen’s disease. In this bicenter, randomized, phase III trial, 40 patients with one to three lesions of histologically proven Bowen’s disease untreated previously (40 patients, 66 lesions) received either PDT (n = 33) or 5-FU (n = 33). ALA 20% in an oil/water-emulsion was applied 4 h before illumination with an incoherent light source (Paterson lamp, Phototherapeutics, lem = 630 15 nm; 50–90 mW/cm2, 100 J/cm2). Treatment with 5-FU was once daily in week 1 and then twice daily during weeks 2–4. At the first follow-up at week 6, both ALA-PDT and 5-FU application were repeated, if required. Twenty-nine of 33 lesions (88%) treated with PDT showed complete response, versus 67% after 5-FU (22 of 33). After 1 year of follow-up, further recurrences reduced the complete clinical clearance rates to 82% and 42%, respectively (79). In another recently published, placebocontrolled randomized multicenter study, Morton et al. (80) compared the effectiveness of MAL-PDT with cryotherapy and 5-FU in the treatment of histologically confirmed in situ SCC (225 patients, 295 lesions, lesion size 6–40 mm) at 3 and 12 months 124
after the last treatment. MAL-PDT or matching placebo cream PDT (n = 17), cryotherapy (n = 82) or topical fluorouracil (5% cream; n = 30) was performed. MAL or placebo cream was applied for 3 h before illumination with broadband red light (75 J/cm2, 570–670 nm). Treatment was repeated 1 week later. Cryotherapy was performed using liquid nitrogen spray. 5-FU was applied for 1 month. Lesions with a partial response at 3 months were re-treated. The primary endpoint was a clinically verified complete response of lesions and the cosmetic outcome on a four-point rating scale. The authors reported that at 1 year, the estimated sustained lesion complete response rate with MALPDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01–3.12; P = 0.047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78–3.45; P = 0.19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with MAL-PDT versus 66% with cryotherapy and 76% with 5-FU, and was maintained for 1 year. The authors concluded that MAL-PDT is an effective treatment option for in situ SCC, with excellent cosmetic outcome.
Therapeutic applications – non-oncologic indications In contrast to PDT of tumors, when cellular destruction is the main goal of the therapy, in PDT of inflammatory skin conditions, the modulation of functions on the cellular and subcellular level plays the pivotal role. We know, that Langerhans cells are temporary suppressed in their activity, which leads to a minor immunosuppression (81). Besides, AP-1, NfkB and subsequently different cytokines are induced, which influences inflammatory cells within the epidermis and the dermis as well as fibroblasts (82, 83). The therapeutic protocols differ significantly to that used for the treatment of tumors. Lower doses of both light and photosensitizer are used in ‘low-dose-PDT’ for the treatment of inflammatory skin conditions. However, multiple treatments are necessary to achieve the desired therapeutic effects with little or no side effects. So far, the best results for PDT in inflammatory skin conditions have been achieved with ALA. Even if there are numerous publications reporting a remarkable therapeutical benefit following PDT of e.g. acne vulgaris, localized scleroderma, psoriasis or genital warts, there is a need of controlled clinical trials for the different indications (84–87). However, it is very likely that PDT will also be of great value for a choice of non-oncologic indications.
Psoriasis vulgaris The data provided in the literature for the treatment of P. vulgaris are controversial. It could be shown that ALA is capable of penetrating the parakeratotic stratum corneum in the area of a psoriatic plaque and accumulating selectively in the diseased tissue (88, 89). Boehncke et al. (90) compared the efficacy of ALA-PDT with a conventional topical treatment using dithranol in a half-side trial on three patients. The lesions were incubated
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with a 10% ALA-ointment for 5 h followed by an irradiation with an incoherent light source (600–700 nm, 70 mW/cm2, 25 J/ cm2). This treatment was performed once weekly for 3 weeks, the plaques on the other side received anthralin on a daily base. The time to reach complete remission of psoriatic plaques was similar in both treatment settings. In a recent study performed by Collins et al. (91), 22 patients with psoriasis were treated with ALA-PDT. After application of a 20% ALA preparation for 4 h, the plaques were illuminated using incoherent light (400–650 nm, 300 mW/cm2, 2–16 J/cm2). In 7 of the 22 patients some of the treated plaques healed. In a further study, the same group studied the effect of multiple treatments with ALA-PDT (92). Ten patients with chronic plaque-stage psoriasis have been treated up to three times a week for a maximum of 12 treatments. A 20% ALA emulsion was applied for 4 h, afterwards, the plaques were irradiated with a broadband light source (15 mW/cm2, 8 J/ cm2). In eight patients, clinical success was achieved. However, all patients complained of pain during the irradiation process. Beatti et al. (93) reported a lack of efficacy and tolerability of topical PDT for psoriasis in comparison with narrowband UVB phototherapy. Furthermore, Radakovic-Fijan et al. (94) performed a randomized, intrapatient comparison study on topical ALA-PDT in psoriatic patients and documented that not only an unsatisfactory clinical response but also a frequent occurrence of pain during and after irradiation was observed. They concluded topical ALA-PDT to be an inadequate treatment option for psoriasis. The pain appears to be dose dependent of both photosensitizer and light and it lasts up to 2 days after therapy. Therefore, it is important to study whether both light dose and drug concentration can be lowered following the concept of a ‘low-dose-PDT’ to reduce pain without lowering the efficacy of PDT. In another work, this group performed a prospective randomized, double-blind phase I/II intrapatient comparison study on topical ALA PDT in 12 patients with chronic plaquetype psoriasis. In each patient, three psoriatic plaques were randomly treated with a light dose of 20 J/cm2 and 0.1%, 1% or 5% ALA. Treatment was conducted twice a week until complete clearance or for a maximum of 12 irradiations. Therapeutic efficacy was assessed by the weekly determination of the psoriasis severity index (PSI). The authors reported that the mean percentage improvement was 37.5%, 45.6% and 51.2% in the 0.1%, 1% and 5% ALA groups. However, due to severe burning and pain sensation, irradiation had to be interrupted several times. The authors concluded, that topical ALA-PDT did not prove to be an appropriate treatment option for plaque-type psoriasis due to disappointing clinical efficacy, the timeconsuming treatment procedure and its unfavorable adverse event profile (95). Another side effect reported in the literature is Koebnerization (96). One patient receiving PDT with ALA for the treatment of AK and initial SCC developed psoriatic lesions on her lower leg 2 days after PDT. The impact of PDT on psoriatic lesions is not yet fully clear used because the therapeutic protocols used differ significantly and so far no controlled clinical trials with high numbers of
patients are available. Anyway, some investigations also show that the number of treatments to gain therapeutic success appears to be lower in comparison to PUVA therapy.
Human papilloma viruses (HPV)-induced skin diseases Vulgar warts on hands and feet, plain warts or genital warts (condylomata acuminata, CA) are common skin diseases induced by HPV (97). Even after surgical removal or application of cytotoxic drugs, a high rate of recurrences can be observed. Because the fast-proliferating cells in viral acanthomas accumulate, ALA induced PpIX selectively (98, 99) and because ALA-PDT has virucidal properties (100), PDT is introduced as a possible alternative treatment modality.
Vulgar warts Kennedy et al. (11) did not achieve success in the treatment of vulgar warts with ALA-PDT in their study published 1990. Correspondingly, Amman et al. (101) could not report on a successful topical ALA-PDT in the treatment of recalcitrant vulgar warts. Only in one out of six patients, a complete remission was achieved within 2 months after PDT (101). The reason for the treatment failures was probably the less effective cutaneous penetration of ALA due to the prominent hyperkeratosis in vulgar warts. Smetana et al. (100) tried to increase the effectivity of ALA-PDT by adding the penetration enhancers ethylenediamine–tetraacetic-acid (EDTA, 2%) and dimethylsulfoxide (DMSO, 2%). With this formulation, they were able to successfully treat widespread vulgar warts in a patient who received a kidney transplant. Within a follow-up period of 2 years, no recurrence was observed. Stender et al. (102) conducted a comparative trial in 30 patients with recalcitrant warts. After incubation with a 20% ALA cream for 5 h, irradiation was performed using a slide protector with different wavelengths and a total light dose of 40 J/cm. Before ALA-PDT, keratolysis of the warts was performed (102). Following PDT with white light, which was performed three times, complete remission was significantly higher (73%) than after PDT performed three times with blue light (28%) or red light (42%) or with the use of cryotherapy as a comparative treatment modality (20%). Within the follow-up period of 12 months, no further recurrences were observed. This study was then followed by a double-blinded, randomized trial by the same working group in 45 patients, which consolidated the results of the first pilot-trial (87). In this trial, it could also be proven that ALA-PDT is successful in the treatment of recalcitrant warts of the hand and the soles of the feet. Irradiation was performed with an incoherent light source (Waldmann PDT 1200 l, 590–700 nm, 50 mW/cm2, 70 J/cm2). The procedure was repeated twice, after 1 and 2 weeks. In case the warts were still present after 7 weeks, another therapeutic cycle (three treatments in weekly increments) was performed. The patients were advised to debride their warts before PDT. The trial resulted in a complete remission of warts in 56% of cases in the ALA-PDT-treated group
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in comparison to 42% in the placebo group. A major side effect of this treatment was pain (87). Fabbrocini et al. (103) performed another placebo-controlled trial on 64 plantar warts treated with 20% ALA after keratolysis. Fifty-one warts treated solely with the emollient served as controls. Irradiation was performed with an incoherent light source (400–700 nm, 50 J/cm2); it was repeated depending on the results up to three times per week within a period of 3 weeks. Two months after therapy 75% of the warts treated with ALAPDT showed complete remission, whereas only 22.8% of the warts treated with placebo showed complete remission. These results show that ALA-PDT in combination with a sufficient keratolysis is a successful alternative in the treatment of recalcitrant warts. Again, the main drawback is pain during irradiation, which probably will hinder a broad use of PDT, especially in children. Genital warts Most of the destructive therapeutic modalities for anogenital CA like electrodesiccation or vaporization using a CO2 laser only lead to a destruction of the visible part of the warts, whereas subclinical lesions will not be treated effectively causing the high recurrence rate. ALA-PDT could be of great interest for this indication, especially due to the selective destruction of subclinical virus-shedding areas, helping to reduce the high recurrence rate. Because a selective enrichment of PpIX in warts is the main prerequisite for the therapeutic efficacy, Fehr et al. (98) studied the luminescence of PpIX after topical application of ALA in vulvar CA in 22 patients. Three to 6 h after the application of ALA, a homogeneous distribution of PpIX was observed in the epidermis. After 24 h, luminescence was only observed in the region of the granular layer. Similar results were reported by Ross et al. (99). They were able to show a selective accumulation of PpXI in CA after a topical application of ALA. Already 2 h following application, highest selectivity compared with the surrounding normal skin was achieved. In a pilot study, seven patients with anogenital warts were treated with a cream containing 20% ALA in combination with lidocaine hydrochloride. The incubation time was 14 h. After this time period a local anesthetic was applied for 2 h. Afterwards, the area was irradiated with an argon ion-pumped dye laser (630 nm, 75–150 mW/cm2, 100 J/cm2). Four out of seven patients treated with ALA-PDT showed a complete remission (104). The most important goal in the treatment of CA is the reduction of the high recurrence rate using conventional treatment modalities. The combination of classical ablative treatments and PDT (which contributes to a selective destruction of subclinical virusshedding areas) may be of value. However, in a recent trial, prePDT vaporization of CA using a CO2 laser was studied in terms of improved efficacy. CO2 laser ablation was followed by ALA-PDT in a phase III, prospective, randomized, bicenter double-blind study to prevent the recurrence of CA. Patients (n = 175) with CA received CO2 laser vaporization plus adjuvant ALA-PDT (n = 84) or adjuvant placebo-PDT (n = 91). A 20% ALA or placebo 126
ointment was applied to the CA area 4–6 h before CO2 laser vaporization, followed by illumination with red light (600–740 nm, 100 mW/cm2, 100 J/cm2). The cumulative recurrence rate 12 weeks after treatment was 50.0% in the ALAPDT group, versus 52.7% in the placebo-PDT group (P = 0.72). No significant difference between the groups was detected with regard to recurrence rates up to 12 months after treatment. No major complications were observed. Although adjuvant ALA-PDT of CA after CO2 laser ablation was well tolerated, no significant difference with regard to recurrence rates was observed as compared with CO2 laser vaporization alone (105). Acne vulgaris PDT in the treatment of acne is based on the fact that Propionibacterium acnes contains endogenous porphyrins, in particular coproporphyrin III (84). Therefore, visible as well as blue light phototherapy is effective. Hongcharu et al. (106) treated 22 patients with acne vulgaris on the back in an open, prospective trial with ALA-PDT. Eleven patients received a single treatment, the other 11 patients were treated four times. Twenty percent ALA was applied under occlusion for 3 h, afterwards the area was irradiated with red light (550–700 nm, 150 J/cm2). The phototoxic reaction after ALA-PDT was restricted selectively to areas containing sebaceous glands. The function of the sebaceous glands was altered and the numbers of bacteria in the follicles was also reduced. Histopathology showed an acute cytotoxic damage of the sebaceous glands. Clinically, a significant improvement of the inflammatory acne lesions was observed after ALA-PDT and the effect was sustained for 4 20 weeks after multiple PDT sessions. Although ALA-PDT was very effective in the treatment of acne, severe side effects were observed: pain, erythema, edema, transient hyperpigmentation, sometimes even blistering, purpura or an acute acneiform rash. These results were in accordance with those published by Itoh et al. (85). Twenty-three patients with acne vulgaris resistant to standard therapy in the face were treated with ALA-PDT. An emulsion containing 20% ALA was applied for 4 h and irradiated with polychromatic light from a halogen lamp (600–700 nm, 17 mW/cm2, 13 J/cm2). In all patients, acne improved and the development of new acne spots was reduced up to 6 months thereafter. Considerable side effects were pain, edema, crust formation, erythema and hyperpigmentation (85). Pollock et al. (107) showed a statistically significant reduction in inflammatory acne lesions after three courses of ALA-PDT performed within 3 weeks. However, as they documented no statistically significant reduction in P. acnes, they suggested an alternative mode of action for ALA-PDT in acne. Wiegell and Wulf (108) evaluated the efficacy and tolerability of MAL-PDT in patients with moderate-to-severe facial acne vulgaris in a randomized, controlled and investigator-blinded trial. The treatment group (n = 21) received two MAL-PDT treatments, 2 weeks apart. Fifteen patients were assigned to the control group. Both groups were evaluated 4, 8 and 12 weeks after treatment. Efficacy evaluation included changes from baseline in numbers of noninflammatory and inflammatory
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lesions, in global acne severity grade and clinical improvement as assessed by the patient and the dermatologist. Pain scores during treatment and local adverse effects were also evaluated. The authors reported that 12 weeks after treatment, the treatment group showed a 68% reduction from baseline in inflammatory lesions versus no change in the control group (P = 0.0023). There was no reduction in the number of noninflammatory lesions after treatment. All patients experienced moderate-tosevere pain during treatment and developed severe erythema, pustular eruptions and epithelial exfoliation. Seven patients did not receive the second treatment due to adverse effects. The authors concluded that MAL-PDT is an efficient treatment for inflammatory acne, but that the use of this treatment option is limited due to severe pain and severe adverse effects (108). H¨orfelt et al. (109) investigated the efficacy and tolerability of MAL-PDT in patients (n = 30) with moderate-to-severe acne in a blinded, prospective, randomized and placebo-controlled multicenter study. Each side of each patient’s face was randomly assigned to treatment with MAL or placebo cream. A second treatment was performed 2 weeks later. Patients assessed the intensity of pain on a VAS. Inflammatory and noninflammatory acne lesions were counted at baseline, 4 and 10 weeks after the last PDT treatment. The authors reported a significantly higher reduction in the total inflammatory lesion count with MAL-PDT compared with placebo PDT at week 12 [median reduction 54% (95% CI) 35–64%) vs. 20% (95% CI 8–50%)]. However, MALPDT was associated with more pain than placebo PDT. The authors concluded, that MAL-PDT is effective in the treatment of moderate to severe inflammatory facial acne. These investigations indicate that PDT is very potent in the treatment of acne vulgaris. However, with most of the present protocols, the massive side effects do not qualify PDT for a routine-based use in acne vulgaris. Perhaps, lower doses of both light and photosensitizer combined with a higher number of treatments may improve the efficacy and lower the rate of side effects. Morphea and lichen sclerosus Morphea is a chronic inflammatory reaction of the skin, which results after an inflammatory reaction in a circumscribed sclerosis of the skin. Although the prognosis of morphea is mostly favorable, widespread lesions may lead to contractions of joints and immobilization. Although PUVA or bath-PUVA therapy as well as high-dose UVA1 are effective in the treatment of morphea, the limited penetration depth of UV light as well as the long-term side effects of UV therapy (carcinogenic potential, photoinduced skin aging) should be considered. In a clinical study, 10 patients with morphea, who did not respond to bathPUVA, penicillin-infusions and local therapies were treated with topical ALA-PDT. After the application of 3% ALA-gel for 6 h, irradiation was performed with an incoherent light source (PDT 1200 L, 40 mW/cm2, 10 J/cm2). This treatment was repeated once or twice weekly for 3–6 months (86). The mean number of therapies was 26 8 (SD). Morphea was judged before, during and after therapy using a durometer (110) or a clinical score
(111). In every patient, both scores were reduced significantly at the end of therapy. Slight burning sensation or mild pruritus in the treated area were reported as side effects. Even after 2 years no further progression and recurrence was observed. However, in some patients, new morphea lesions developed at sides that had not been treated with PDT. The effectivity of ALA-PDT was also reported for lichen sclerosus (112). Twelve women with lichen sclerosus and severe pruritus were treated with a 20% ALA formulation, followed by irradiation with light from an argon ion-pumped dye laser (635 nm, 70 mW/cm2, 80 J/cm2). In case the pruritus did not resolve after the first treatment, the patients were retreated within 1–3 weeks after the first therapy. PDT was tolerated well and even 6–8 weeks after the last session pruritus improved in 10 out of 12 patients (112). Cosmetic indications A general advantage of PDT, which is consistent throughout all clinical studies, is the excellent cosmetic result. Numerous studies attest even an improvement in the aesthetic appearance of the treated areas. The use of PDT with the sole aim to improve different cosmetic aspects of the skin, especially of the sun damaged or premature skin, is obvious. For aesthetic PDT, IPL, blue light, incoherent red light and pulsed diode lasers are the light sources of main interest (113). Touma et al. (55) investigated the effects of ALA-PDT in patients (n = 18) with AK and moderate sun-damaged skin in the face. ALA was incubated for 1, 2 or 3 h followed by an irradiation with blue light (10 J/cm2). The variation of incubation times did not yield different effects. After one as well as 5 months following therapy, there was not only a significant reduction in AKs but also a significant improvement of several photodamage parameters. The authors concluded that ALA-PDT is safe and effective for AK treatment as well as for improving photodamage. Babilas et al. (41) investigated the cosmetic outcome in a prospective, randomized, controlled split-face study (25 patients, 238 AK) and sun-damaged skin using two different light devices. After incubation with MAL, irradiation was performed with either a LED (50 mW/cm2; 37 J/cm2) or an IPL device (80 J/cm2, 610–950 nm filtered hand piece), followed by re-evaluation up to 3 months. Cosmetic outcome of the treated but perilesional area was evaluated before and up to 3 months following treatment using a rating (four-level) for wrinkling, hyperpigmentation, hypopigmentation, hair coat, redness and desquamation. The sum of the score value was calculated. In addition, the overall aesthetic results were evaluated by both the patient as well as the physicians (two independent and blinded investigators) on a score from 1 (very bad) to 10 (excellent). According to their results, the patients [5.52 2.06 (both treatment sites before PDT) vs. 7.76 1.39 (IPL site 3 months following PDT), and 7.92 1.29 (LED site 3 months following PDT] as well as the investigators [6.64 1.79 (both treatment sites before PDT) vs. 8.20 1.06 (IPL site 3 months following PDT) and 8.16 0.97 (LED site 3 months following PDT)] assessed a significant improvement of aesthetic appearance due
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to treatment, which was irrespective of the light device used. In another study, the combination of ALA-PDT using an IPL device led to an excellent cosmetic result in 17 patients with diffuse sundamaged skin. Side effects like hypopigmentation and scars were not observed (114). Gold et al. (115) evaluated short-contact (30 to 60 min) ALA-PDT using IPL versus the use of IPL alone in sixteen patients in a side-by-side design. Three treatments were given at monthly intervals and patients were followed-up at 1 and 3 months after the final treatment. The authors reported on a higher improvement in the ALA-PDT-IPL side than in the IPL alone side for all facets of photodamage, crow’s feet appearance (55% vs. 29.5%), tactile skin roughness (55% vs. 29.5%), mottled hyperpigmentation (60.3% vs. 37.2%) and telangiectasias (84.6% vs. 53.8%). The clearance rate of AK lesions was also higher using ALA-PDT-IPL (78% vs. 53.6%). They concluded that short-contact ALA-PDT-IPL induces a greater improvement in photodamaged skin and a higher clearance rate of AK lesions than IPL alone, thereby confirming the usefulness of ALA-PDT in photorejuvenation. Corresponding results were published by Dover et al. (38) who performed a prospective, randomized, controlled and split-face study. The patients (n = 20) received series of three split-face treatments 3 weeks apart. Half of the face was pretreated with ALA followed by IPL treatment while the other half was treated with IPL alone. Two additional full-face treatments (with IPL alone) were then delivered 3 weeks apart. Assessment of global photodamage, fine lines, mottled pigmentation, tactile roughness and sallowness (on a scale of 0–4) was performed by a blinded investigator before each treatment and 1 month after the final treatment. Patients were also asked to compare their results with pretreatment photographs. The authors reported that pretreatment with ALA resulted in more improvement in the global score for photoaging (80% of subjects vs. 45% of subjects) and mottled pigmentation (95% of subjects vs. 60% of subjects) than IPL treatment alone. While there was a noticeable improvement over baseline scores with respect to tactile roughness and sallowness, pretreatment with ALA did not appears to enhance the results of the IPL treatment. The final investigator cosmetic evaluations and subject satisfaction scores were significantly better for the ALA-pretreated side. The authors concluded that the adjunctive use of ALA in the treatment of facial photoaging with IPL is highly favorable in terms of improving global photodamage, mottled pigmentation and fine lines, without a significant increase in adverse effects (38). Leishmaniasis A recently published placebo-controlled randomized study (116) compared the effectiveness of PDT to topically applied Paromomycin in patients (n = 60) with cutaneous leishmaniasis. The patients were randomly assigned to three treatment groups (n = 20 each). Group 1 was treated with weekly topical PDT. Groups 2 and 3 received twice-daily topical paromomycin and placebo, respectively. The duration of treatment was 1 month for all groups. Patients were followed-up for 2 months after the end of treatment. The authors reported that 57 patients with 128
95 lesions completed the study. At the end of the study, complete improvement was seen in 29 of 31 (93.5%), 14 of 34 (41.2%) and four of 30 lesions (13.3%) in groups 1, 2 and 3, respectively. At the same time point, 100%, 64.7% and 20% of the lesions had parasitological cure in groups 1, 2 and 3, respectively. The authors concluded, that topical PDT can be used safely as a rapid and highly effective treatment alternative for cutaneous leishmaniasis (116). Enk et al. (117)performed ALA-PDT twice on 11 patients with 32 cutaneous leishmaniasis lesions and reported a lack of any parasites in 31 out of 32 lesions and the average reduction in size was 67% following ALA-PDT. Cosmetic results were excellent and there was no recurrence within 6 months. Further case reports document the successful use of PDT in cutaneous leishmaniasis (118, 119). Regarding the mechanism of action it is proposed that PpIX leads to the generation of singlet oxygen, which induces the destruction of the parasite’s coat, oxidates bacterial lipids and proteins (120).
Conclusion PDT in dermatology is approved for the treatment of superficial BCC, AK and meanwhile for Bowen’s disease in many countries all over the world also. Numerous publications could demonstrate the effectiveness of PDT also for the treatment of other cutaneous malignancies and non-oncologic indications (10). However, controlled clinical trials are required to clarify whether PDT of non-oncologic indications can demonstrate superiority over existing, approved therapeutic modalities. The proven advantages of PDT include the simultaneous treatment of multiple tumors and incipient lesions, relatively short healing times, good patient tolerance and an excellent cosmetic outcome. PDT also shows great promise for tumor control in immunosuppressed patients (i.e. transplant recipients). Costeffectiveness analyses indicate that topical PDT is probably no more expensive than conventional therapy plus the advantage of less frequent side effects (22). In all, PDT appears to be a valuable treatment strategy in dermatology with exceptional cosmetical results.
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