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Background: Topical photodynamic therapy (PDT) is widely used to treat superficial nonmelanoma skin cancer and dysplasia, and is generally well tolerated. However, as with all treatments, adverse effects may occur and awareness may facilitate approaches to prevention and management., Objectives: To review the available evidence relating to the adverse effects of topical PDT, to help inform recommendations in updated clinical guidelines produced by the British Association of Dermatologists and British Photodermatology Group, and the efficacy of preventative and therapeutic approaches., Methods: This review summarizes the published evidence related to the adverse effects of topical PDT and attempts to interpret this evidence in the context of patient risk and management., Results: Pain and discomfort during PDT are acute adverse effects, which can be minimized through the use of modified and low-irradiance PDT regimens and do not therefore usually limit successful treatment delivery. Other adverse effects include the risk of contact allergy to photosensitizer prodrugs, although this is rare but should be kept in mind, particularly for patients who have received multiple PDT treatments to larger areas. There are no other significant documented longer-term risks and, to date, no evidence of cumulative toxicity or photocarcinogenic risk., Conclusions: Topical PDT is usually well tolerated, reinforcing the utility of this important therapeutic option in dermatology practice. The main acute adverse effect of pain can typically be minimized through preventative approaches of modified PDT regimens. Other adverse effects are uncommon and generally do not limit treatment delivery., (© 2018 British Association of Dermatologists.)

Background: Topical photodynamic therapy (PDT) is an established treatment option for low-risk basal cell carcinoma (BCC)., Objectives: To compare efficacy, cosmesis and tolerability of PDT for BCC with alternative treatments., Methods: MEDLINE, PubMed, Embase and CENTRAL databases were searched from inception until 1 September 2017. Included studies were randomized controlled trials (RCTs) of PDT for nodular (n) and superficial (s) BCC reporting at least one of the following outcomes: clearance at 3 months and sustained at 1 or 5 years; recurrence at ≥ 1 year; cosmesis; adverse events; tolerability., Results: From 2331 search results, 15 RCTs (2327 patients; 3509 BCCs) were included. PDT efficacy (5-year sustained clearance) was high but inferior to excisional surgery [nBCC pooled risk ratio (RR) 0·76; 95% confidence interval (CI) 0·63-0·91], and without re-treatment of partially responding lesions, was modestly inferior to imiquimod (sBCC: RR 0·81; 95% CI 0·70-0·95) and similar to fluorouracil (sBCC: RR 0·88; 95% CI 0·75-1·04). Five-year sustained clearance was inferior with conventional vs. fractionated PDT (sBCC: RR 0·76; 95% CI 0·68-0·84). PDT cosmesis was superior to surgery (sBCC: RR 1·68, 95% CI 1·32-2·14; nBCC: RR 1·82, 95% CI 1·19-2·80) and cryosurgery (BCC: RR 3·73, 95% CI 1·96-7·07), and without re-treatment of partially responding lesions was similar to imiquimod (sBCC: RR 1·01, 95% CI 0·85-1·19) and fluorouracil (sBCC: RR 1·04, 95% CI 0·88-1·24). Peak pain was higher but of shorter duration with PDT than topical treatments. Serious adverse reactions were rarer with PDT than imiquimod (sBCC: RR 0·05, 95% CI 0·00-0·84) and fluorouracil (sBCC: RR 0·11, 95% CI 0·01-2·04). Combination PDT regimens demonstrated reduced recurrence and improved cosmesis; however, results from these small studies were often nonsignificant., Conclusions: PDT is an effective treatment for low-risk BCC, with excellent cosmesis and safety. Imiquimod has higher efficacy than single-cycle PDT but more adverse effects. Highest efficacy is with excisional surgery. Fractionated and combination PDT options warrant further study., (© 2018 British Association of Dermatologists.)

Background: Animal studies report photodynamic therapy (PDT) to improve healing of excisional wounds; the mechanism is uncertain and equivalent human studies are lacking., Objectives: To explore the impact of methyl aminolaevulinate (MAL)-PDT on clinical and microscopic parameters of human cutaneous excisional wound healing, examining potential modulation through production of transforming growth factor (TGF)-β isoforms., Methods: In 27 healthy older men (60-77 years), a 4-mm punch biopsy wound was created in skin of the upper inner arm and treated with MAL-PDT three times over 5 days. An identical control wound to the contralateral arm was untreated and both wounds left to heal by secondary intention. Wounds were re-excised during the inflammatory phase (7 days, n = 10), matrix remodelling (3 weeks, n = 8) and cosmetic outcome/dermal structure (9 months, n = 9). Production of TGF-β1, TGF-β3 and matrix metalloproteinases (MMPs) was assessed by immunohistochemistry alongside microscopic measurement of wound size/area and clinical assessment of wound appearance., Results: MAL-PDT delayed re-epithelialization at 7 days, associated with increased inflammation. However, 3 weeks postwounding, treated wounds were smaller with higher production of MMP-1 (P = 0·01), MMP-9 (P = 0·04) and TGF-β3 (P = 0·03). TGF-β1 was lower than control at 7 days and higher at 3 weeks (both P = 0·03). At 9 months, MAL-PDT-treated wounds showed greater, more ordered deposition of collagen I, collagen III and elastin (all P < 0·05)., Conclusions: MAL-PDT increases MMP-1, MMP-9 and TGF-β3 production during matrix remodelling, ultimately producing scars with improved dermal matrix architecture., (© 2014 British Association of Dermatologists.)

Background: Topical 5-aminolaevulinic acid photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown., Objectives: To look for involvement of the proinflammatory mediators prostaglandin (PG)E2 and nitric oxide (NO) in topical PDT-induced erythema in human skin., Methods: A series of studies was performed in healthy volunteers (n = 35). Following definition of the erythemal time course and dose response to 5-ALA-PDT, duplicate 5-ALA dose series were iontophoresed into the skin of each ventral forearm and exposed to 100 J cm(-2) broadband red light. Within subject, arms were randomized to control, or treatment with the cyclooxygenase and NO synthase inhibitors indometacin and Nω -nitro-l-arginine methyl ester (l-NAME), respectively, and the impact on 5-ALA-PDT-induced erythema was quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT administration., Results: A 5-ALA dose-related delayed erythema occurred by 3 h (r = 0·97, P < 0·01), with erythema persisting to 48 h post-PDT. Topical indometacin applied immediately post-PDT reduced the slope of erythemal response at 3 h and 24 h (P < 0·05). Intradermal injection of l-NAME into 5-ALA-PDT-treated sites reduced the slope of response at 24 h post-PDT (P < 0·001), while significantly inhibiting erythema from 3 h to 48 h post-PDT (P < 0·01). Analysis of dermal microdialysate showed release of NO and PGE2 following treatment., Conclusions: Topical 5-ALA-PDT upregulates PGE2 and NO in human skin, where they play a significant role in the clinical inflammatory response. The potential relevance of these mediators to PDT in human cutaneous pathology warrants study., (© 2013 British Association of Dermatologists.)

Background: With increasing problems of antibiotic resistance, photodynamic therapy (PDT) is being developed as a novel antimicrobial treatment. Following light activation, cationic photosensitizer PPA904 [3,7-bis(N,N-dibutylamino) phenothiazin-5-ium bromide] kills a broad spectrum of bacteria in vitro and this has a variety of potential clinical applications., Objectives: To determine if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers can reduce bacterial load, and potentially lead to accelerated wound healing., Methods: Sixteen patients with chronic leg ulcers and 16 patients with diabetic foot ulcers (each eight active treatment/eight placebo) were recruited into a blinded, randomized, placebo-controlled, single-treatment, Phase IIa trial. All patients had ulcer duration > 3 months, bacterially colonized with > 10 colony-forming units cm . After quantitatively assessing pretreatment bacterial load via swabbing, PPA904 or placebo was applied topically to wounds for 15 min, followed immediately by 50 J cm of red light and the wound again sampled for quantitative microbiology. The wound area was measured for up to 3 months following treatment., Results: Treatment was well tolerated with no reports of pain or other safety issues. In contrast to placebo, patients on active treatment showed a reduction in bacterial load immediately post-treatment (P < 0·001). After 3 months, 50% (four of eight) of patients with actively treated chronic leg ulcer showed complete healing, compared with 12% (one of eight) of patients on placebo., Conclusions: This first controlled study of PDT in chronic wounds demonstrated significant reduction in bacterial load. An apparent trend towards wound healing was observed; further study of this aspect with larger patient numbers is indicated., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Topical photodynamic therapy (PDT) is a widely applied treatment for basal cell carcinoma (BCC). PDT-induced immunosuppression leading to reduced antitumour immune responses may be a factor in treatment failure., Objectives: To examine the impact of topical PDT on leucocyte trafficking following clinical treatment of BCC., Methods: Superficial BCCs in eight white caucasian patients were treated with methyl aminolaevulinate (MAL)-PDT. Biopsies for immunohistochemical assessment were taken from BCCs pre-PDT, 1 h and 24 h post-PDT and from untreated healthy skin., Results: Treatment of BCC with MAL-PDT produced a rapid neutrophil infiltration, commencing by 1 h and significantly increased at 24 h post-PDT (P < 0·05 compared with baseline). An associated increase in the number of blood vessels expressing E-selectin was observed at 1 h and 24 h post-PDT (both P < 0·05 compared with baseline). In contrast, the number of epidermal Langerhans cells fell sharply by 1 h post-PDT, and remained significantly reduced at 24 h post-PDT (both P < 0·05 compared with baseline)., Conclusions: Reduction of Langerhans cells during clinical treatment of BCC might potentially impact negatively on antitumour responses through reduced activation of tumour-specific effector cells. Investigation of modified PDT protocols with the aim to minimize immunosuppressive effects while maintaining antitumour efficacy is warranted., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Topical photodynamic therapy (PDT) elicits a therapeutic response in both skin cancer and immune-mediated skin disorders. While PDT induces direct cell death, host inflammatory and immune responses to PDT may contribute to the therapeutic effects., Objectives: To examine the impact of topical PDT on leucocyte trafficking and mediators of chemotaxis in healthy human skin., Methods: Aminolaevulinic acid (ALA)-PDT was performed on the buttock skin of seven healthy volunteers. Biopsies for immunohistochemical assessment were taken 1, 4 and 24 h post-PDT and from untreated contralateral buttock skin (baseline)., Results: A significant dermal neutrophilic infiltrate appeared early, peaking at 4 h (P < 0·01) and returning to near baseline by 24 h. Expression of E-selectin was significantly higher at 4 h (P < 0·05) and correlated strongly with neutrophil numbers (r = 0·93). Expression of intercellular adhesion molecule 1 was significantly elevated after 24 h (P < 0·05) with an apparent gradual increase in CD4+ T cells up to this time point. Notably, epidermal Langerhans cells were significantly reduced 24 h post-PDT compared with baseline (P < 0·01) and comprised a significantly larger proportion of cells with migratory rather than dendritic morphology (P < 0·05). The number of epidermal cells expressing tumour necrosis factor-α significantly increased at 4 h (P < 0·05) and remained elevated 24 h post-PDT, whereas no significant change in expression of interleukin (IL)-1β or IL-8 was seen., Conclusions: Reduction of Langerhans cells by topical PDT of human skin may play a significant role in PDT-induced local immunosuppression, potentially benefiting the treatment of immune-mediated skin disorders but negatively impacting on antitumour responses. Further exploration according to disease indication/treatment protocol is warranted., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Multicentre randomized controlled studies now demonstrate high efficacy of topical photodynamic therapy (PDT) for actinic keratoses, Bowen's disease (BD) and superficial basal cell carcinoma (BCC), and efficacy in thin nodular BCC, while confirming the superiority of cosmetic outcome over standard therapies. Long-term follow-up studies are also now available, indicating that PDT has recurrence rates equivalent to other standard therapies in BD and superficial BCC, but with lower sustained efficacy than surgery in nodular BCC. In contrast, current evidence does not support the use of topical PDT for squamous cell carcinoma. PDT can reduce the number of new lesions developing in patients at high risk of skin cancer and may have a role as a preventive therapy. Case reports and small series attest to the potential of PDT in a wide range of inflammatory/infective dermatoses, although recent studies indicate insufficient evidence to support its use in psoriasis. There is an accumulating evidence base for the use of PDT in acne, while detailed study of an optimized protocol is still required. In addition to high-quality treatment site cosmesis, several studies observe improvements in aspects of photoageing. Management of treatment-related pain/discomfort is a challenge in a minority of patients, and the modality is otherwise well tolerated. Long-term studies provide reassurance over the safety of repeated use of PDT.

Background: Methyl aminolaevulinate-photodynamic therapy (MAL-PDT) is an effective treatment in facial/scalp actinic keratosis (AK)., Objectives: The aims of this study were to compare efficacy, safety, cosmetic outcome and patient preference of MAL-PDT vs. cryotherapy in patients with AK at other locations., Methods: A multicentre, controlled, randomized, open, intraindividual, right-left comparison was performed. Patients with nonhyperkeratotic AK were treated once with MAL-PDT and cryotherapy on either side of the body. At week 12, lesions showing noncomplete response were retreated. The primary efficacy variable was the lesion response at week 24. Investigator's assessment of cosmetic outcome, patient's preference in terms of cosmetic outcome and a patient preference questionnaire were also analysed at week 24., Results: In total, of 121 patients with 1343 lesions (98% located on the extremities and the remainder on the trunk and neck) were included. Both treatments provided a high mean percentage reduction in lesion count at week 24 with significantly higher efficacy for cryotherapy: 78% for MAL-PDT and 88% for cryotherapy (P=0.002, per protocol population). Investigator's assessment of cosmetic outcome was significantly better for MAL-PDT than cryotherapy (P<0.001), 79% of lesions having an excellent cosmetic outcome with MAL-PDT vs. 56% with cryotherapy at week 24. The cosmetic outcome achieved by MAL-PDT compared with cryotherapy was also preferred by patients (50% vs. 22%, respectively, P<0.001), and 59% of patients would prefer to have any new lesions treated with MAL-PDT compared with 25% with cryotherapy (P<0.001). Both treatment regimens were safe and well tolerated., Conclusions: MAL-PDT showed inferior efficacy for treatment of non-face/scalp AK compared with cryotherapy. However, both treatments showed high efficacy, and MAL-PDT conveyed the advantages of better cosmesis and higher patient preference.

Background: Conventional treatment of basal cell carcinoma (BCC) causes morbidity and/or disfigurement in some patients because of the location (e.g. mid-face) and size of the lesion., Objectives: Following reports that such difficult-to-treat BCC lesions have been treated successfully with topical methyl aminolaevulinate (MAL) photodynamic therapy (PDT), a multicentre study was performed to determine the response of such BCC to MAL-PDT., Methods: An open, uncontrolled, prospective, multicentre study was conducted comprising patients with superficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfigurement and/or recurrence using conventional therapy. Patients were given one or two cycles within 3 months of topical MAL-PDT, each consisting of two treatments 1 week apart. Tumour response was assessed clinically at 3 months after the last PDT, with histological confirmation of all lesions in clinical remission. The cosmetic outcome was rated. Patients with a BCC in remission will be followed up for 5 years for recurrence, of which the 24-month follow-up is reported here. Ninety-four patients with 123 lesions were enrolled and treated with MAL-PDT at nine European primary care and referral university hospitals. An independent blinded study review board (SRB) retrospectively excluded nine patients and a total of 15 lesions from the efficacy analysis, for not having a difficult-to-treat BCC according to the protocol., Results: The lesion remission rate at 3 months was 92% (45 of 49) for superficial BCC, 87% (45 of 52) for nodular BCC, and 57% (four of seven) for mixed BCC, as assessed by clinical examination, and 85% (40 of 47), 75% (38 of 51), and 43% (three of seven), respectively, as assessed by histological examination and verified by the SRB. At 24 months after treatment, the overall lesion recurrence rate was 18% (12 of 66). The cosmetic outcome was graded as excellent or good by the investigators in 76% of the cases after 3 months follow-up, rising to 85% at 12 months follow-up, and 94% at 24 months follow-up., Conclusions: Topical MAL-PDT is effective in treating BCC at risk of complications and poor cosmetic outcome using conventional therapy. MAL-PDT preserves the skin and shows favourable cosmetic results.

Photodynamic therapy is a rapidly developing treatment modality in dermatology. A sensitizer drug is activated by light in the presence of oxygen. This results in the release of reactive oxygen species that damage the target tissue. The ideal features of a photosensitizer are that it should be highly selective for lesional tissue, activated by light of a sufficiently long wavelength for tissue penetration, and have a high photodynamic yield (i.e. production of singlet oxygen). A short time interval between administration and its maximal accumulation in tumour tissue, followed by rapid tissue clearance, are also desirable. First-generation sensitizers were complex chemical mixtures, needing parenteral administration and causing troublesome and prolonged photosensitivity. A range of second-generation sensitizers of different chemical families show several advantages including purity, longer activation wavelength and less prolonged photosensitivity, but effective topical formulations have not been developed. Currently, the most convenient and widely practised form of PDT for cutaneous disorders is the topical application of the pro-drug delta-aminolevulinic acid or its methylated ester, which are activated by light following metabolism to the endogenous sensitizer protoporphyrin IX.

Photodynamic therapy (PDT) has been reported to be useful in treating certain nonmelanoma skin cancers and a variety of benign skin conditions. We examined whether PDT might be effective in the treatment of disseminated superficial actinic porokeratosis. Three patients with classical disseminated superficial actinic porokeratosis had a small test area treated with topical aminolaevulinic acid PDT. Following the first treatment, the disorder cleared in the test area in one patient, but failed to respond in the other two patients. After subsequent treatment, the initial benefit seen in the first patient was not sustained, and no response was seen in the second patient, while the third patient was not retreated due to hyperpigmentation induced by the procedure. The results obtained in this small case series suggest that topical PDT is not a promising treatment for disseminated superficial actinic porokeratosis.

Topical photodynamic therapy (PDT) is effective in the treatment of certain non-melanoma skin cancers and is under evaluation in other dermatoses. Its development has been enhanced by a low rate of adverse events and good cosmesis. 5-Aminolaevulinic acid (ALA) is the main agent used, converted within cells into the photosensitizer protoporphyrin IX, with surface illumination then triggering the photodynamic reaction. Despite the relative simplicity of the technique, accurate dosimetry in PDT is complicated by multiple variables in drug formulation, delivery and duration of application, in addition to light-specific parameters. Several non-coherent and coherent light sources are effective in PDT. Optimal disease-specific irradiance, wavelength and total dose characteristics have yet to be established, and are compounded by difficulties comparing light sources. The carcinogenic risk of ALA-PDT appears to be low. Current evidence indicates topical PDT to be effective in actinic keratoses on the face and scalp, Bowen's disease and superficial basal cell carcinomas (BCCs). PDT may prove advantageous where size, site or number of lesions limits the efficacy and/or acceptability of conventional therapies. Topical ALA-PDT alone is a relatively poor option for both nodular BCCs and squamous cell carcinomas. Experience of the modality in other skin diseases remains limited; areas where there is potential benefit include viral warts, acne, psoriasis and cutaneous T-cell lymphoma. A recent British Photodermatology Group workshop considered published evidence on topical PDT in order to establish guidelines to promote the efficacy and safety of this increasingly practised treatment modality.

Background: Topical 5-aminolaevulinic acid (ALA) is widely used in photodynamic therapy (PDT) to generate protoporphyrin IX (PpIX) in the skin. However, other prodrugs may be more effective., Objectives: The pharmacokinetics of ALA- and ALA-n-pentylester-induced PpIX, together with the phototoxicity after PDT, were compared in human skin in vivo, using iontophoresis as a quantitative drug delivery system., Methods: A series of six increasing doses of equimolar prodrug solutions was iontophoresed into normal skin of the upper inner arms of 20 healthy subjects. The kinetics of PpIX metabolism in skin (n = 4) and the response to light exposure, performed at 4.5 h (n = 6) and 6 h (n = 10) after application, were assessed by skin surface PpIX fluorescence and postirradiation erythema., Results: ALA and ALA-n-pentylester showed a linear correlation between logarithm of dose and PpIX fluorescence (P < 0.005), and logarithm of dose and skin phototoxicity with irradiation at 4.5 h (P < 0.001 and P < 0.005, respectively) and 6 h (P < 0.05 and P < 0.0001, respectively) after iontophoresis. Higher phototoxicity was observed with ALA-n-pentylester than with ALA when sites were irradiated at 6 h, as indicated by the significantly lower theoretical threshold dose for erythema (P < 0.05) and the shift of the PpIX fluorescence/phototoxicity curve towards greater skin erythema at equal PpIX fluorescence levels. Depth of PpIX fluorescence in skin, as determined by fluorescence microscopy, was similar for both prodrugs, but a more homogeneous distribution of PpIX was seen with the more lipophilic ALA-n-pentylester., Conclusions: The observed greater phototoxicity of ALA-n-pentylester relative to ALA may be attributable to a more favourable PpIX localization in tissue and/or greater intrinsic toxicity.

Our novel approach was to compare the pharmacokinetics of 5-aminolevulinic acid (ALA), ALA-n-butyl and ALA-n-hexylester induced protoporphyrin IX (PpIX), together with the phototoxicity after photodynamic therapy (PDT) in human skin in vivo, using iontophoresis as a dose-control system. A series of four increasing doses of each compound was iontophoresed into healthy skin of 10 volunteers. The kinetics of PpIX metabolism (n = 4) and the response to PDT (n = 6) performed 5 h after iontophoresis, were assessed by surface PpIX fluorescence and post-irradiation erythema. Whilst ALA-induced PpIX peaked at 7.5 h, highest PpIX fluorescence induced by ALA-n-hexylester was observed at 3-6 h and no clear peak was seen with ALA-n-butylester. With ALA-n-hexylester, more PpIX was formed after 3 (P < 0.05) and 4.5 h, than with ALA or ALA-n-butylester. All compounds showed a linear correlation between logarithm of dose and PpIX fluorescence/phototoxicity at 5 h, with R-values ranging from 0.87 to 1. In addition, the ALA-n-hexylester showed the tendency to cause greater erythema than ALA and ALA-n-butylester. Fluorescence microscopy (n = 2) showed similar PpIX distributions and penetration depths for the three drugs, although both ALA esters led to a more homogeneous PpIX localization. Hence, ALA-n-hexylester appears to have slightly more favorable characteristics for PDT than ALA or ALA-n-butylester.

Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is increasingly employed for skin cancer, yet ALA dosing is crude. Using iontophoresis, we developed a rapid and quantifiable system for topical ALA delivery, with measurement of subsequent PpIX fluorescence and phototoxicity. ALA was iontophoresed from a 2% solution into upper inner arm skin of 13 healthy volunteers. Six doses of ALA were delivered with a series of charges varying from 3-120 milliCoulombs (mC); four additional doses were given with a charge of 60 mC. Five hours post-iontophoresis, sites were irradiated with broad-band yellow-red light, the series of six ALA doses receiving 100 J/cm2, while the four identical doses received 6.25, 12.5, 25, and 50 J/cm2, respectively. Resultant erythema was measured by reflectance spectroscopy. The time course of PpIX fluorescence was ALA-dose-dependent. With charge < or = 24 mC, PpIX fluorescence peaked at 3 h and returned to zero at 9-10 h, whereas charges > 24 mC had a sustained peak at 5-10 h, falling to zero by 24 h. Pre-irradiation, PpIX fluorescence correlated with ALA dose (r = 1.0). PpIX fluorescence fell immediately post-irradiation (p < 0.0001); recovery levels at 3 h correlated with ALA dose (p < 0.0001). Delayed erythema correlated with ALA dose and irradiation dose (p < 0.0001, p < 0.01, respectively). Both PpIX fluorescence intensity pre-irradiation and fall in PpIX fluorescence post-irradiation correlated with erythema (r = 0.98). Hence, PpIX synthesis is ALA-dose-dependent, and phototoxicity can be predicted from ALA dose, irradiation dose, and photobleaching of PpIX. This reproducible system allows accurate dosimetry in topical PDT and facilitates study of ALA metabolism.