Adverse effects of topical photodynamic therapy: a consensus review and approach to management.

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.

Conventional and combination topical photodynamic therapy for basal cell carcinoma: systematic review and meta-analysis.

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.

Predicted increased risk of squamous cell carcinoma induction associated with sunbed exposure habits.

BACKGROUND: Solar ultraviolet radiation (UVR) is recognized as the principal environmental cause of skin cancer. In particular, the risk of induction of squamous cell carcinoma (SCC) has been shown to increase with cumulative exposure to UVR. Models of risk of SCC induction have been developed but these do not include the use of sunbeds. OBJECTIVES: To explore the links between sunbed exposure and risk of SCC induction. METHODS: To this end, the values of published on-site UVR levels emitted from sunbeds were used to provide real measured sunbed exposure levels to inform the model. The model incorporated three conditions of exposure: day-to-day, holiday and sunbed exposure. The risks associated with different exposure scenarios were implemented in the model. Baseline exposure comprised day-to-day and holiday exposure. Relative risk (RR) was defined as the risk of SCC induction from (sunbed + baseline dose)/baseline dose. RESULTS: The RR of SCC induction from estimated median sunbed exposure output [176 standard erythemal dose (SED) per year; 20-35 years of age] in addition to median baseline sun exposure level (166 SED year + 85.5 SED per year holiday) was 1.9 (90% risk increase) up to 55 years of age. A higher sunbed exposure (302 SED per year; 20-35 years of age) produced an RR value of 2.8 (180% increase) at 55 years of age. CONCLUSIONS: This is the first time that a risk model for SCC of the skin has been developed that includes estimated sunbed doses derived from measured irradiance data. The model demonstrates that the additional risk associated with sunbed use may be significant, particularly when high-output, fast-tan sunbeds are used.

Impact assessment of energy-efficient lighting in patients with lupus erythematosus: a pilot study.

BACKGROUND: Patients with lupus erythematosus (LE) are often abnormally photosensitive. Ultraviolet (UV) exposure can not only induce cutaneous lesions but may also contribute to systemic flares and disease progression. Various forms of energy-efficient lighting have been shown to emit UV radiation. OBJECTIVES: To determine the effects of these emissions on individuals with LE. METHODS: This assessment investigated cutaneous responses to repeated exposures from three types of lighting: compact fluorescent lamp (CFL), light-emitting diode (LED) and energy-efficient halogen (EEH). The subjects were 15 patients with LE and a control group of five healthy volunteers. RESULTS: No cutaneous LE lesions were induced by any of the light sources. Delayed skin erythema was induced at the site of CFL irradiation in six of the 15 patients with LE and two of the five healthy subjects. Erythema was increased in severity and more persistent in patients with LE. One patient with LE produced a positive delayed erythema to the EEH. A single patient with LE produced immediate abnormal erythemal responses to the CFL, LED and EEH. Further investigation revealed that this patient also had solar urticaria. All other subjects had negative responses to LED exposure. CONCLUSIONS: Compact fluorescent lamps emit UV that can induce skin erythema in both individuals with LE and healthy individuals when situated in close proximity. However, this occurs to a greater extent and is more persistent in patients with LE. EEHs emit UVA that can induce erythema in patients with LE. LEDs provide a safer alternative light source without risk of UV exposure.

Treatment of superficial vascular lesions with the KTP 532-nm laser: experience with 647 patients.

Superficial vascular lesions are a common dermatological diagnosis but are often difficult to treat. Numerous lasers (especially the dye laser) and intense pulsed light sources have been used, but there have been very few reports on the effectiveness of the potassium-titanyl phosphate (KTP) laser. We have extensive experience of this modality at our institution, and the purpose of this survey is to report on the safety and efficacy of the KTP laser. Using an in-house database, we retrospectively collected data from patients who had undergone treatment with the KTP laser for superficial vascular lesions. Patients of Fitzpatrick skin type I-IV were included. Exclusion criteria were Fitzpatrick skin type V, patients with obvious suntan and those on potentially phototoxic medications or minocycline therapy. Diagnoses included discrete or matted telangiectasia, strawberry naevus, spider angioma, rosaceal erythema, rosaceal telangiectasia, telangiectatic naevus, angioma, combined rosaceal erythema/telangiectasia, port-wine stain, venous lake haemangioma and hereditary haemorrhagic telangiectasia. Patients underwent an initial test treatment and further treatment at 6-week intervals as required. Clinical photographs were taken pre- and post-treatment, and outcome was graded by patient and physician. Adverse effects were recorded including scarring, hypo- or hyperpigmentation, marked swelling, blistering, scabbing and bruising. Six hundred forty-seven patients with 13 diagnoses on 9 different body sites were recorded. Four hundred eighty-six were female, and the median age was 39.5 years. Of the lesions treated, 33.7 % (n = 218) were discrete telangiectases and 31.8 % (n = 206) were spider angiomas. A 92.7 % of lesions were on the face. Four hundred thirteen (77.6 %) patients who had outcomes recorded at 6 weeks were graded as "clearance" or "marked improvement". Only 38 (5.8 %) patients experienced adverse effects, all of which were minor; the main adverse effect was swelling. Unlike the dye laser, there was only one case of bruising out of 647 patients. This is the largest survey of patients to have undergone KTP laser treatment reported in the literature. Our results show that the KTP laser is a safe and effective modality for the treatment of superficial vascular lesions.

Review of an established UK home phototherapy service 1998-2011: improving access to a cost-effective treatment for chronic skin disease.

OBJECTIVES: To review the Tayside home phototherapy service, including numbers of patients treated, diagnoses and outcomes, side-effects and safety, cost-effectiveness and absolute costs. To consider why home or outpatient phototherapy is not available to all patients who might benefit and how this could be addressed. STUDY DESIGN: Observational and cost analysis. METHODS: Analysis of the Tayside home phototherapy database 1998 and 2011, home phototherapy patient questionnaires, outcome data, costs and a comparison with outpatient phototherapy. Review of literature and current national guidelines for phototherapy, traditional systemic and biologic therapies for psoriasis. RESULTS: 298 courses of home narrowband UVB (NB-UVB) phototherapy were undertaken by 212 patients between 1998 and 2011, five courses in 1998 increasing to 36 in 2011. The main diagnoses treated were psoriasis (72%), atopic dermatitis (8%), and desensitization of photodermatosis (7%). For psoriasis, 74.5% achieved clearance or minimal residual activity in a median of 30 exposures (range 10-60). The estimated costs to the hospital ranged from £229 to £314 per course (£307 to £422 per effective course for psoriasis), compared with £114 for out-patient therapy (£149 per effective course for psoriasis). The total cost to society (hospital and patient costs) is around £410 per course, compared to an estimated £550 for outpatient therapy for this group of patients. Treatment was well tolerated, erythema rates were similar to outpatient therapy, there were no complaints and the vast majority would choose home over outpatient phototherapy if required in the future. CONCLUSIONS: Hospital supervised home phototherapy appears as safe and effective as outpatient therapy and provides equality of access for patients who cannot attend for outpatient therapy. These patients may otherwise be inadequately treated or given more costly and higher risk systemic therapies, particularly for psoriasis. Commissioners and clinicians involved in dermatology services should provide accessible phototherapy for all patients who might benefit, utilizing home phototherapy where outpatient access is not possible.

Energy-saving lamps and their impact on photosensitive and normal individuals.

BACKGROUND: A preliminary investigation showed that ultraviolet radiation (UVR) emissions from compact fluorescent lamps (CFLs) can pose a risk to the skin of photosensitive individuals. OBJECTIVES: To carry out a larger-scale study, in patients with a range of photodermatoses, to assess this risk. To determine a safe alternative light source for photosensitive individuals. To investigate if CFL emissions have the potential to induce skin responses in normal individuals. METHODS: Two hundred patients were directly exposed to a single-envelope CFL as part of their routine management. Irradiation was carried out on the inner forearm with lamps positioned at 5 cm. Skin assessments were made immediately and 24 h postirradiation. Eleven of these patients were further tested to a double-envelope CFL. One hundred and one patients were tested to emissions from a light-emitting diode (LED). A study involving 20 healthy individuals was carried out with exposure to the single-envelope CFL. RESULTS: Skin erythema was induced by the single-envelope CFL in the following cases: 16 of 53 chronic actinic dermatitis, seven of 52 polymorphic light eruption, five of nine solar urticaria, one of two actinic prurigo, one of one erythropoietic protoporphyria and two of 20 healthy subjects. The double-envelope CFL eliminated or reduced the skin response in all 11 patients tested. The LED did not induce any UVR-provoked skin responses. CONCLUSIONS: UVR from CFLs can aggravate the skin of photosensitive and healthy individuals when situated in close proximity. Double-envelope lamps reduce this risk. LEDs offer a safer alternative light source that eliminates the risk of UVR-induced skin erythema.

Nine out of 10 sunbeds in England emit ultraviolet radiation levels that exceed current safety limits.

BACKGROUND: Exposure to ultraviolet (UV) radiation from sunlight is recognized as the principal cause of skin cancer. Moreover, sunbeds have been classified as carcinogenic by the International Agency for Research on Cancer. Despite this, there is a shortage of objective data on UV exposure levels in sunbeds in England. OBJECTIVES: We set out to measure UV emission levels in sunbeds at sites around England, and to compare these levels with both current standards and natural sunlight. METHODS: Between October 2010 and February 2011, UV spectra were measured on site from a total of 402 artificial tanning units in England. Measurement instrumentation was calibrated, traceable to the National Physical Laboratory. Compliance with the relevant British and European standard was determined, and a skin-cancer weighting factor was used to compare the carcinogenic potential of sunbeds with that of sunlight. RESULTS: For compliance with the European standard, erythemal-effective irradiance should not exceed 0·3 W m(-2). The values that we measured ranged between 0·10 and 1·32 W m(-2) with a mean of 0·56 ± 0·21 W m(-2) . Only 10% of sunbeds surveyed were within the recommended limit. Application of the skin-cancer weighting factor produced values that varied from 0·17 to 2·52 W m(-2) with a mean of 0·99 ± 0·41 W m(-2). The comparable value for Mediterranean noon day sun was 0·43 W m . CONCLUSIONS: Nine out of 10 sunbeds surveyed throughout England emitted levels of UV radiation that exceed the maximum levels contained within the European standard. Moreover, the skin cancer risk for comparable times of exposure was up to six times higher than that for Mediterranean sunlight. This situation is unacceptable and stricter control measures must be put in place.

Self-administration of hospital-based narrowband ultraviolet B (TL-01) phototherapy: a feasibility study in an outpatient setting.

BACKGROUND: Self-administration of narrowband (TL-01) ultraviolet (UV)B phototherapy by patients at home is a safe and effective mode of treatment. Could selected patients self-administer phototherapy in hospital? OBJECTIVES: To assess the feasibility of outpatient self-administration of UVB phototherapy as a potential service development. METHODS: A total of 20 patients with psoriasis (n = 15) and eczema (n = 5) (13 female, mean age 32 years, range 17-56 years) were included in this pilot project. Patients underwent a training programme over 2 days, which included a minimal erythemal dose test and supervised treatment, prior to commencing self-administration of phototherapy. Questionnaires were used to gather feedback from patients and staff. RESULTS: Treatment data were collected for 18 of the 20 patients. The mean number of exposures was 25 (range 3-45), and the mean cumulative dose was 16 J cm(-2) (range 0·23-41·27 J cm(-2) ). No unexpected adverse effects were noted. These results were similar to those of a sample group of outpatients who had nurse-administered UVB phototherapy, for whom the mean number of exposures was 24 (range 4-49) and the mean cumulative dose was 17 J cm(-2) (range 0·53-71·16 J cm(-2) ). Thirteen patients completed the questionnaires. All concluded that the training programme sufficiently prepared them for self-administering phototherapy, and 12 reported that they would be happy to self-administer treatment in the future. CONCLUSIONS: Self-administration of UVB phototherapy is practicable, safe and effective for most selected patients. This mode of treatment provides training and support for patients to gain more control over management of their skin disease, empowering them to take an active role in their treatment. Self-administration of UVB phototherapy by outpatients provides an intermediate level of care between nurse-administered hospital phototherapy and self-administered home phototherapy.

Phase IIa randomized, placebo-controlled study of antimicrobial photodynamic therapy in bacterially colonized, chronic leg ulcers and diabetic foot ulcers: a new approach to antimicrobial therapy.

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.

Analysis of energy saving lamps for use by photosensitive individuals.

Due to European legislation, the British government has begun the phase out of incandescent bulbs, to be replaced by energy-saving alternatives. The alternatives that are available on the market are Compact Fluorescent Lamps (CFL), Energy-Efficient Halogens (EEH) and Light Emitting Diodes (LED). Whilst previous research has shown that CFLs emit UVC, UVB and UVA, there is conflicting data available on whether double enveloped CFLs are a safer alternative to single enveloped CFLs for individuals suffering from photosensitivity. The emission spectra of 106 single enveloped CFLs and 65 double enveloped CFLs were measured. There were 17 different models of single enveloped CFLs, including lamps from 6 different manufacturers (ranging from 8-20 W) and 9 models of double enveloped CFLs from 6 different manufacturers (7-15 W). In addition, the emission spectra of 53 LEDs and 56 EEHs were also analysed. The LEDs consisted of 8 different models, from 3 manufacturers, spanning between 2.5 and 12 W. There were 11 models of EEH from 6 different manufacturers with wattages ranging from 28-70 W. In order to reduce sample bias, some bulbs were provided by the lighting industry federation and others were purchased randomly from local retailers. The results validate previous research in that considerable variation exists in the UV emitted from CFLs. This variation in UV levels is true, not only within different makes and models but also, surprisingly, within a box of 8 seemingly identical bulbs supplied by a single manufacturer. It was concluded that double enveloped CFLs do reduce the levels of UVC and UVB and therefore are a safer alternative for photosensitive individuals. However, as some double enveloped CFLs and EEHs do emit UVA at levels that provoke a reaction in the skin of UVA sensitive individuals, newly emerging LEDs that have minimal UV levels may provide a safer alternative.

Ultraviolet A1 phototherapy: a British Photodermatology Group workshop report.

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK.

A preliminary investigation into the effect of exposure of photosensitive individuals to light from compact fluorescent lamps.

BACKGROUND: Compact fluorescent lamps (CFLs) are due to replace common incandescent lamps over the next few years. There has been no investigation of the possible effect of this on patients with photosensitive disorders. OBJECTIVES: To determine the effect of exposure of photosensitive individuals to light from CFLs. METHODS: The spectral emission from a sample of CFLs was measured using a calibrated spectroradiometer. The erythemal response was determined in one normal individual and four photosensitive individuals by direct exposure of the skin to light from a CFL. The susceptibility of a wider group of photosensitive individuals was predicted based on the light dose known to elicit a reaction during phototesting at discrete ultraviolet (UV) wavelengths. RESULTS: CFLs emit UV radiation at wavelengths down to 254 nm. Prolonged exposure of a normal individual's skin produced erythema. However, an exposure of only 2.5 min at 5 cm elicited marked erythema in one of the abnormally photosensitive patients. CONCLUSIONS: CFLs could be a source of harmful UV radiation to photosensitive individuals. Patients with chronic actinic dermatitis are thought to be at greatest risk. The use of a protective envelope is recommended.

An open pilot study of ambulatory photodynamic therapy using a wearable low-irradiance organic light-emitting diode light source in the treatment of nonmelanoma skin cancer.

BACKGROUND: Photodynamic therapy (PDT) is a popular treatment for nonmelanoma skin cancer with clearance rates of between 70% and 100%. Although reported to have a superior cosmetic outcome, the inconvenience of hospital visits and discomfort during therapy are considered drawbacks. OBJECTIVES: To present an open pilot study of a low-irradiance, potentially disposable, lightweight, organic light-emitting diode (OLED), which is an area-emitting light source (2 cm diameter), suitable for ambulatory PDT. METHODS: Twelve patients with Bowen's disease (eight) and superficial basal cell carcinoma (four) < 2 cm in diameter were recruited into the study following histological confirmation of the diagnosis. Two treatments (45-60 J cm(-2) red light, 550-750 nm, peak 620 nm, irradiance 5 mW cm(-2)) were administered 1 month apart following application of aminolaevulinic acid for 4 h. RESULTS: At the 12-month follow-up, seven of the 12 patients remained clear, with four of the nonresponders demonstrating peripheral margin failure. Patients were scored for pain during and immediately after treatment using the numerical rating scale (NRS; 1-10). All 12 subjects scored pain as < 2 using the NRS (median score 1). In contrast, a similar cohort of 50 consecutive patients from our routine PDT clinic (Aktilite inorganic LED source; 75 J cm(-2), irradiance 80 mW cm(-2)) scored a median of 6 on the NRS. CONCLUSIONS: Pain and inconvenience are practical barriers to the use of conventional PDT. This pilot study suggests that OLED-PDT is less painful than conventional PDT with the added advantage of being lightweight, and therefore has the potential for more convenient 'home PDT'. These results need to be validated in larger studies.