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.

A review of photodiagnostic investigations over 26 years: experience of the National Scottish Photobiology Service (1989-2015).

Background The Scottish Photobiology Service is the national referral pathway for patients with cutaneous photosensitivity diseases in Scotland. We reviewed the pattern of diagnosis of photosensitivity diseases and investigations performed between 1989 and 2015. Methods and Results Data were collected from the Photodiagnostic Database, annual reports and paper records. The total number of patients assessed each year was stable over the period studied (median 242 [range 231-266]), with most being new patients (median 69 [range 62-73]%). Monochromator phototesting was the most utilised investigation, although the use of provocation testing and photopatch testing has increased. The most common diagnosis was polymorphic light eruption, and there was a trend to increasing diagnosis of photoaggravated atopic eczema. Conclusions The pattern of diagnosis of photosensitivity diseases remains fairly stable in Scotland and we wish to emphasise the importance of this Scottish specialist service for patients with photosensitivity diseases and referrers.

Modelling topical photodynamic therapy treatment including the continuous production of Protoporphyrin IX.

Most existing theoretical models of photodynamic therapy (PDT) assume a uniform initial distribution of the photosensitive molecule, Protoporphyrin IX (PpIX). This is an adequate assumption when the prodrug is systematically administered; however for topical PDT this is no longer a valid assumption. Topical application and subsequent diffusion of the prodrug results in an inhomogeneous distribution of PpIX, especially after short incubation times, prior to light illumination. In this work a theoretical simulation of PDT where the PpIX distribution depends on the incubation time and the treatment modality is described. Three steps of the PpIX production are considered. The first is the distribution of the topically applied prodrug, the second in the conversion from the prodrug to PpIX and the third is the light distribution which affects the PpIX distribution through photobleaching. The light distribution is modelled using a Monte Carlo radiation transfer model and indicates treatment depths of around 2 mm during daylight PDT and approximately 3 mm during conventional PDT. The results suggest that treatment depths are not only limited by the light penetration but also by the PpIX distribution.

Monte Carlo modelling of photodynamic therapy treatments comparing clustered three dimensional tumour structures with homogeneous tissue structures.

We explore the effects of three dimensional (3D) tumour structures on depth dependent fluence rates, photodynamic doses (PDD) and fluorescence images through Monte Carlo radiation transfer modelling of photodynamic therapy. The aim with this work was to compare the commonly used uniform tumour densities with non-uniform densities to determine the importance of including 3D models in theoretical investigations. It was found that fractal 3D models resulted in deeper penetration on average of therapeutic radiation and higher PDD. An increase in effective treatment depth of 1 mm was observed for one of the investigated fractal structures, when comparing to the equivalent smooth model. Wide field fluorescence images were simulated, revealing information about the relationship between tumour structure and the appearance of the fluorescence intensity. Our models indicate that the 3D tumour structure strongly affects the spatial distribution of therapeutic light, the PDD and the wide field appearance of surface fluorescence images.

Monte Carlo modelling of daylight activated photodynamic therapy.

The treatment of superficial skin lesions via daylight activated photodynamic therapy (PDT) has been explored theoretically with three dimensional (3D) Monte Carlo radiation transfer simulations. For similar parameters and conditions, daylight activated PDT was compared to conventional PDT using a commercially available light source. Under reasonable assumptions for the optical properties of the tissue, protoporphyrin IX (PpIX) concentration and a treatment dose of 75 J cm(-2), it was found that during a clear summer day an effective treatment depth of over 2 mm can be achieved after 30 min of daylight illumination at a latitude of 56 degrees North. The same light dose would require 2.5 h of daylight illumination during an overcast summer day where a treatment depth of about 2 mm can be achieved. For conventional PDT the developed model suggests that 15 min of illumination is required to deliver a light dose of 75 J cm(-2), which would result in an effective treatment depth of about 3 mm. The model developed here allows for the determination of photo-toxicity in skin tissue as a function of depth for different weather conditions as well as for conventional light sources. Our theoretical investigation supports clinical studies and shows that daylight activated PDT has the potential for treating superficial skin lesions during different weather conditions.

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.

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.

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.

Porphyrin profile in four human cell lines after supplementation with 5-aminolaevulinic acid and its methyl ester.

Multiple factors can affect the synthesis of the prodrugs aminolaevulinic acid and its methyl ester to protoporphyrin. These may ultimately influence the efficacy of ALA-induced porphyrin as a photosensitiser for photodynamic therapy or fluorescence diagnosis. This study demonstrates the variation in total amount of porphyrin produced and cellular porphyrins synthesised in four different human cell lines after supplementation with these prodrugs. A non-invasive optical biopsy system was able to detect spectral changes associated with the more carboxylated porphyrins accumulating in oesophageal (OE19) and bladder (HT1197) carcinoma cells, and to a lesser extent neuroblastoma (SH-SY5Y) cells after a 24h incubation with the prodrugs. If the porphyrin profile changes during disease progression, or between normal and cancerous cells clinically, then the demonstrated non-invasive spectral analysis may be exploitable in distinguishing between normal, dysplastic and tumour tissue. Finally, the OE19 cell line was insensitive to photo-inactivation under the experimental conditions used, despite accumulating more porphyrin than the other cells lines.

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.

Oral 5-aminolevulinic acid induced Photodynamic Diagnostic Ureterorenoscopy--does the blood pressure require monitoring?

BACKGROUND: Photodynamic Diagnosis has been proven to improve detection of superficial bladder cancer and improve visualisation of resection margins. The use of 5-aminolevulinic acid as the photosensitising agent has been associated with side effects, specifically hypotension. We aimed to evaluate the effect of oral 5-ALA on the blood pressure in a group of patient who underwent Photodynamic Diagnostic Ureterorenoscopy. METHODS: We carried out an observational study on all patients who underwent PDD-Ureterorenoscopy with oral 5-ALA between July 2009 and September 2011. Pre-administration, hourly post-administration and hourly post-operative blood pressures were noted. Mean arterial blood pressure and the threshold for cerebral ischaemia were calculated as well. RESULTS: The study includes thirty-eight procedures which involved twenty-four patients with a mean age of 74 (SD±16.95). Hypotension was defined as <80% of the systolic or diastolic baseline blood pressure. Twenty patients were hypotensive pre-operatively after the ingestion of 5-ALA while 21 patients were hypotensive post-operatively. Three patients crossed their MAP threshold pre-operatively and were symptomatic. Fast infusion of intravenous fluids improved their symptoms. CONCLUSION: Hypotension is a common occurrence after the ingestion of 5-ALA. Patients undergoing PDD Ureterorenoscopy should have their blood pressure monitored closely after the ingestion of 5-ALA.

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.