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.

Sunscreen photopatch testing: a series of 157 children.

BACKGROUND: Photoprotection including sunscreen use in children is encouraged by health campaigns. While sunscreen chemicals are common causes of photoallergic (PA) contact reactions in adults, limited data are available in children. OBJECTIVES: To assess the frequency of PA and contact allergy (CA) to sunscreens in children aged < 18 years undergoing investigation for suspected photosensitivity. METHODS: Retrospective analysis of data on children who underwent photopatch testing to a standard series of nine ultraviolet (UV) filters and to sunscreen products in a single photoinvestigation centre (2000-11). Duplicate series of UV filters and the children's own sunscreen products were applied to the back, with readings taken at sample removal, and at 24 and 48 h after 5 J cm(-2) UVA exposure of one series. RESULTS: The analysis comprised 157 children (aged 3-17 years, 69 male and 88 female). In total 10 children (6·4%) showed positive photopatch responses to UV filters and/or their sunscreen products (4·5% to UV filters, 5·7% to their sunscreen products). The responsible UV filters most often identified were benzophenone-3 and octyl methoxycinnamate. Additionally, CA reactions were observed in nine children (5·7%), with 16 children (10·2%) showing PA and/or CA to UV filters and/or sunscreen products. CONCLUSIONS: This is the largest series of photopatch testing reported in children, and shows that both sunscreen PA and CA are quite frequent in those undergoing photoinvestigation. Photopatch testing should be considered in children presenting with features of photosensitivity.

Voriconazole-induced photosensitivity: photobiological assessment of a case series of 12 patients.

BACKGROUND: Voriconazole, a broad-spectrum triazole antifungal agent increasingly used to treat aspergillosis, has been linked with acute photosensitivity and skin carcinogenesis. The action spectrum of the photosensitivity is unknown, while an indirect retinol effect secondary to the antifungal's impact on CYP450 enzymes has been proposed to contribute to the underlying mechanism. OBJECTIVES: To perform a detailed photobiological assessment of the photosensitivity presenting in a series of 12 patients treated with voriconazole. METHODS: Minimal erythemal dose thresholds (MED) to narrow wavebands of ultraviolet (UV) A, UVB and visible light were determined. Provocation testing was performed to broadband UVA (310-400 nm) and to solar-simulated radiation (SSR) (290-400 nm). Patients underwent routine photopatch testing and laboratory investigations including serum vitamin A (retinol). RESULTS: Patients (eight men, four women; median age 54years, range 40-63) experienced moderate-severe cutaneous erythema (n = 12), burning pain (n=5), itching (n=3), scaling (n=5), vesiculation (n=5) and oedema (n=1) following sunlight exposure; increased lentigines (n=4) and actinic cheilitis (n = 4) were also observed. While the majority (n=8) of patients showed normal MED thresholds to monochromator phototesting to UVB, UVA and visible light, a low MED to UVA was observed in four patients. Repeated provocation testing with broadband UVA and SSR provoked an abnormal erythema in eight and 10 patients, respectively. Serum retinol levels were mildly elevated in two patients but normal in the majority. CONCLUSION: UVA sensitivity is the predominant finding in acute voriconazole-induced photosensitivity. We found little evidence of elevated circulating retinol as the causal factor. Patients with voriconazole-induced photosensitivity require education in appropriate UVA protective measures in addition to consideration of skin surveillance for malignant sequelae.

Systemic photoprotection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-α-MSH.

BACKGROUND: Solar urticaria is a rare photosensitivity disorder demonstrating a range of action spectra, which can inflict a very large impact on life quality despite available treatments. Melanin broadly reduces skin penetration by ultraviolet-visible wavelengths, thus increased melanization may protect in solar urticaria. OBJECTIVES: To examine quantitatively for impact of the potent α-melanocyte stimulating hormone analogue afamelanotide ([Nle(4)-D-Phe(7)]-α-MSH, Scenesse(®); Clinuvel Pharmaceuticals Ltd, Melbourne, Vic., Australia) on the solar urticaria response and skin melanization. METHODS: Five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in winter time. Melanin density was assessed spectrophotometrically from day 0 to day 60. Detailed monochromated light testing to geometric dose series (increment ) of wavelengths 300-600 nm was performed at 0, 30 and 60 days, with assessment of weal and flare area and minimum urticarial dose (MUD). Data were analysed by repeated-measures anova. RESULTS: Mean melanin density increased by day 7, peaked at day 15 and remained elevated at day 60 (P=0·03, 0·01, 0·02 vs. baseline, respectively). Baseline phototesting revealed action spectra of 320-400 (n=1), 320-500 (n=2), 300-600 (n=1) and 370-500 nm (n=1), and on afamelanotide mean rises in MUD of 1-12 and 1-3 dose increments were seen at the individual wavelengths tested, at 30 and 60 days, respectively. A significant fall in weal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P=0·049 vs. baseline), accompanied by greater than twofold overall increase in MUD (P=0·058 vs. baseline). CONCLUSIONS: Melanization following afamelanotide is accompanied by reduction in solar urticaria response across a broad spectrum of wavelengths. Further study is warranted to assess clinical benefit under ambient conditions in summer.

Pharmacokinetic and therapeutic outcome in melanoma cells, of the administration of symmetric and asymmetric cationic photosensitizers.

The response of melanoma cell lines to a range of novel cationic photosensitizers based on either a protoporphyrin or a mesotetra(4-carboxylphenyl)porphine molecule, has been examined. The drugs varied in terms of either their symmetry or their side chain configuration. The effect of these variables on drug uptake and photodynamic cell kill were tested. The absorption wavelengths for the drugs were measured and a shift to the red was seen in the presence of cells. Drug uptake was measured and the cationic sensitizers had a relatively high uptake when compared to anionic HpD. The efficiency of the drugs in causing cell kill was expressed in terms of clonogenic cell survival. The asymmetric photosensitizers were more efficient in destroying mouse and human melanoma cells than the clinically used anionic HpD, which was in turn more efficient than the symmetric sensitizers tested.

Novel asymmetric photosensitizers: an in vitro study.

A series of compounds based on an asymmetrical protoporphyrin molecule have been examined. The paired groups of sensitizers differed in terms of the presence or absence of a permanent positive charge, in the alkyl side chain length and in having either a primary or secondary amine substituent. The effects of these variables on drug uptake, partition coefficient and photodynamic cell kill were tested. Drug uptake and partition coefficient were shown to be correlated. Differences in gross uptake were found within paired groups of sensitizers although cell-associated uptake alone did not correlate with clonogenic cell survival. Of the compounds tested it was the sensitizers with alkyl side chains, rather than the permanently positively charged compounds, which resulted in the greatest degree of clonogenic cell kill.

Photodynamic therapy of ovarian tumours and normal cells using 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin.

The photosensitizing ability of the second generation photosensitizer 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin (m-TCMPC), a derivative of m-THPC, was tested on both three-dimensional multicellular spheroids of varying sizes and on monolayer cultures. These experiments were carried out on two spheroid-forming cell lines, A2780 (a human ovarian adenocarcinoma) and CHO (Chinese hamster ovarian cells). For both cell lines, photodynamic therapy (sensitizer plus visible light) treatments were carried out. The chlorin m-TCMPC was shown to have considerable promise as a photosensitizing agent. Cell kill was achieved for all situations tested, i.e. monolayer, 100, 500 and 750 microm spheroids. In addition no significant dark toxicity was observed.

Singlet oxygen and superoxide characteristics of a series of novel asymmetric photosensitizers.

The singlet oxygen quantum yields and superoxide quantum yields for a series of novel compounds based on an asymmetrical protoporphyrin molecule have been examined. Electron spin resonance was used to measure superoxide yield and time resolved luminescence for singlet oxygen. A comparison between these results and previously published cell survival data was carried out. A broad association was found between singlet oxygen quantum yield and clonogenic cell kill.

DNA damage and repair in Gorlin syndrome and normal fibroblasts after aminolevulinic acid photodynamic therapy: a comet assay study.

Using normal, untransformed, human fibroblasts, the effectiveness of aminolevulinic (ALA)-mediated photodynamic therapy (PDT) was investigated in terms of both clonogenic survival and DNA damage. The response of normal fibroblasts was then compared with Gorlin syndrome-derived fibroblasts (basal cell nevus syndrome [BCNS]). In terms of clonogenic survival, no significant differences were observed between the two groups of cells. Using the alkaline comet assay, initial DNA damage after PDT was measured. Some DNA damage was detected at higher doses, but this was fully repaired within 24 h of treatment. The BCNS-derived cells showed levels of initial damage that did not differ significantly from normal lines.

Comparative analysis of foetal calf and human low density lipoprotein: relevance for pharmacodynamics of photosensitizers.

The effects of differences in lipoprotein content on the distribution of the novel hydrophobic photosensitizer n-butyl-3-[18-(2-butylcarbamoyl-ethyl)-3,7,12,17-tetramethyl-18,13-divinyl-22,24-dihydro-porphin-2-yl]propionamide (PP-N-3) and haematoporphyrin ester (HpE), a relatively hydrophilic photosensitizer, in human (HS) and foetal calf sera (FCS), were investigated. The binding characteristics of human and foetal calf low-density lipoprotein (LDL) were characterised using a human fibroblast line (Vag 12). The uptake into cells of HpE and PP-N-3 was also examined. A comparison of the lipoprotein content, composition and receptor-binding characteristics of foetal calf and human serum was also carried out. LDL content was measured directly using sequential ultracentrifugation to isolate LDL. In our study, we found haematoporphyrin ester to bind to human very low-density lipoprotein (VLDL), LDL and high-density lipoprotein (HDL) in the ratio 2:31:65. In the case of PP-N-3 this ratio was 56:10:33. As VLDL was not detected in foetal calf serum, only binding to LDL and HDL was observed. Using the sequential ultracentrifugation technique, foetal calf serum was found to contain LDL which in turn did bind to human LDL receptors. The uptake of PP-N-3 and HpE in the presence of low density lipoprotein from foetal calf serum (FC-LDL) was not significantly different to values observed in the presence of human serum low density lipoprotein (HS-LDL).

Vascular function and tissue injury in murine skin following hyperthermia and photodynamic therapy, alone and in combination.

The murine tail has been used as a model for injury to skin when hyperthermia (HT) and photodynamic therapy (PDT) using haematoporphyrin derivative, are used in combination. Skin injury by either agent alone was quantitated by the probability of tail necrosis as a function of dose of agent. 'Tolerance' doses of each modality were given and changes in skin vascular function were measured by the rate of clearance of 133Xenon. This was promptly inhibited but restored to normal by 7 days. The absolute numbers of hypodermal vessels of different sizes were measured in tail cross-sections and capillary numbers were found to be greatly reduced between 1 and 7 days, and restored to normal by 21-28 days. When a tolerance dose of PDT was followed at 1, 7, 21 and 28 days by test doses of HT, or vice versa, marked enhancements in probability of necrosis were observed when the interval was 1 or 7 days (Enhancement ratio (ER)PDT-HT = 1.5 and ERHT-PDT = 1.8). Prolonging the interval between modalities to 21-28 days spared the tissue (ERHT-PDT/21 DAYS = 1.1; ERPDT-HT/28 DAYS = 1.0). Close temporal apposition of PDT and HT, such as has been advocated to improve tumour control, may also increase injury to normal tissue through vascular effects common to both.

In vivo expression of the collagen-related heat shock protein HSP47, following hyperthermia or photodynamic therapy.

Heat shock protein 47 (HSP 47), a molecule expressed constitutively in cells that synthesise collagen, is involved in collagen type I biosynthesis, and after insult acts as a stress response molecule to sequester abnormal procollagen. Photodynamic therapy (PDT) is claimed not to result in extensive collagen damage, such as that which can occur after other laser treatments, e.g. hyperthermia (HT) or coagulation, thereby conferring on PDT a potential therapeutic advantage. In previous studies on mouse fibroblasts in vitro we demonstrated HSP47 elevation in the first hours after the application of conditions known to damage collagen, and an absence of HSP47 elevation following PDT with two well-established photosensitisers, haematoporphyrin ester (HpE) and meta-tetrahydroxyphenylchlorin (mTHPC). The present study examines HSP47 metabolism in murine skin following (1) HT, (2) PDT with HpE and (3) PDT with riboflavin (RB). Riboflavin was examined because of reports of collagen injury induced by its photoactivation. All three stresses were applied at grossly equitoxic, 'tolerance' doses. Three months after these doses, linear extensometry revealed the skin to have fibrotic characteristics after HT and RB PDT, but not after HpE PDT. HSP47 expression levels were analysed at transcriptional (Northern) and translational (Western) levels at early time intervals up to 24 h after the treatment application, starting immediately after the treatment for mRNA and 6 h post-treatment for protein. Highly significant upregulation of HSP47 was detected following HT, and PDT with RB. PDT mediated by HpE did not have any impact on HSP47 levels. These results were thus consistent with those from in vitro work and support the hypothesis of early elevation of HSP47 expression only by modalities affecting collagen or its precursors.

Comparison of the cellular molecular stress responses after treatments used in bladder cancer.

OBJECTIVE: To investigate the molecular stress responses related to the quality of recovery of normal tissue after various treatments for bladder cancer, i.e. hyperthermia, ionizing radiation, mitomycin-C and 5-aminolaevulinic acid photodynamic therapy (ALA-PDT). MATERIALS AND METHODS: The study focused particularly on intracellular fibroblast levels of heat-shock protein-47 (HSP47) and HSP72, which are associated with collagen metabolism and the development of tolerance to repeated treatment, respectively. Iso-effective treatment doses (50% clonogenic cell survival) of each method were delivered to a 3T6 murine fibroblast model. Intracellular extracts were analysed at 3, 6, 9, 12 and 24 h after treatment, using Western blot analysis to compare the levels of HSP47 and HSP72. Time-matched treatment and control groups were quantified by comparison with actin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression using appropriate software. RESULTS: There were various changes in levels of HSP expression with treatment method; HSP47 levels were significantly higher after hyperthermia and radiation but not with mitomycin-C or ALA-PDT. HSP72 levels were significantly higher with all methods except ALA-PDT. CONCLUSIONS: Hyperthermia and ionizing radiation are associated with early increases in levels of HSP47 (a marker of collagen metabolism), in contrast to ALA-PDT and mitomycin-C. These findings are compatible with clinical findings where fibrosis/scarring is common with the first two but not the last two methods. In addition, all methods except ALA-PDT are associated with an increase in HSP 72 (a protein associated with cellular tolerance) and this may help to explain, at a cellular level, why resistance to repeated ALA-PDT treatments does not seem to occur.