Photodynamic Therapy () Basics and clinical applications D. Roseeuw, S. T kint Department of Dermatology UZBrussel - VUB
GOAL of : selective destruction of targeted abnormal cells Light O 2 Photosensitiser ROS O O 2 O 2 2 O 2 It requires the presence of 3 components to form Reactive Oxygen Species 2
Upon activation of photosensitiser with the light of specific spectra it transmits the energy to the oxygen Light Photosensitiser excited state O Type-II-reaction Localisation-dependent cellular damage (i.e. plasma membrane, lysosomes, mitochondria) Photosensitiser energetic ground state Cytotoxicity Modulation of cellular function 3
Photodynamic therapy requires the presence of 3 components to form Reactive Oxygen Species LIGHT PHOTO - SENSITISER ROS O 2 O 2 O 2 O2 O 2 4
Photo-sensitiser N H 2 O C H 3 O Methyl aminolevulinate (MAL) O O 5-Aminolevulinate (ALA) N H 2 O H O 5
Metabolic pathway ALA Porphobilinogen Porphobilinogen deaminase MAL Intermediates Haem Ferrochetalase Protoporphyrin IX 6
Metvix specificity Application of Metvix leads to formation of porphyrins specifically at the lesion site. 7
Metvix penetration 8 Metvix leads to formation of porphyrins at full lesion depth (here 1.2 mm) without affecting underlying tissue.
Electromagnetic spectrum X-ray UV 400 nm 700 nm Infrared Microwaves UV C UV B2 UV B1 UV A2 UV A1 220 280 300 320 340 400 nm 9
Wavelength and skin penetration Porphyrin absorption spectrum nm Stratum corneum Epidermis Dermis Subcutis 10
Light sources Conventional light sources Lasers Incandescent lamps High pressure/low pressure arc lamps (Light Emission Device) LED LEDL Diode lasers Pulsed dye lasers 11
LED lamps l LED lamps: red light of 635 nm for deep penetration l Compact l No calibration needed l Easy to operate, to position and to store l Mobile l Built-in fan (cooler) l Total illumination time: long 12
Treatment procedure 1. Lesion preparation Curette to remove loose scales and crust Avoid distressing surrounding skin 13
Treatment procedure 2. MAL application Apply Metvix about 1 mm thick Including 5 10 mm normal surrounding skin Cover with occlusive dressing Leave for 3 hours 14
Treatment procedure 3. Illumination Wash off Metvix cream with saline Illuminate with red light (630 nm) Distance = 5-8 cm 15
Treatment procedure AK treatment Standard 1 session AZ-VUB 2 sessions,1 week apart BCC treatment 2 sessions, one week apart 2 sessions, 1-2 weeks apart 16
and Pain Common problem, variable, unpredictable and limiting factor. AK > Bowen > BCC Head > trunk > extremities Large > small lesions Men > women Pale complex phototype I > phototype IV Inflammatory reaction > pain patients Scoring: Visual analogue scale : VAS 0 10 17
and Pain Pathophysiology: not well known Pain in -40% - 60% Photoreaction causes pain throught free nn fibers in epidermis direct pain through photoreaction 2 types (depolarisation) indirect pain through inflammation (prostaglandins bradykinine) ALA > MAL { in normal skin in AK (1 studie) 18
and Pain Management 1) Cooling - raises pain threshold -> skin temp to 20 C -> 30% pain reduction - 50% do not react on cooling - cooling fans spray water cold air 2) Oral analgetics Time to be efficient Paracetamol Melarnizol Na (metanizol) Tramadol Benzodiazepine 35 min 60 min 90 min 19
and Pain Management 3) Block anesthesia (xylocaine type) {! Genital: spinal block hand? 4) Tumescent anesthesia 5) Infiltration: 0,5% (Xylocaine + adr.) 6) EMLA and tetracaine gel: of no help 20
Clinical experience Actinic keratosis 21
Aims of clinical programme Document safety and efficacy of MAL in treatment of AK Compare with most common therapies Efficacy and safety Cosmetic outcome Patient satisfaction 22
Placebo-controlled vs cryotherapy: Used as indicated in non-hyperkeratotic AKs on face and scalp MAL when repeated after one week is more effective than cryotherapy % lesions with complete response at 3 months (Freeman M. et al; J Dermatol Treat 2003;14:258-62 N=204 pts MAL Cryotherapy Placebo 120 23 % complete response 100 80 60 40 20 0 88 89 23 Overall Thin lesions Moderate lesions Lesions on face Lesions on scalp
AK: Clinical result Actinic keratosis before treatment* Actinic keratosis after Metvix- (two treatment cycles) treatment*, after 3 months * Pariser DM et al; J Am Acad Dermatol 2003; 48(2): 227-232 24
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MAL- in Actinic Keratosis 26
Cosmetic Outcome (Investigator) in AK Percent 100 80 60 40 20 0 83 14 2 6 43 51 Australia: Fractionated and single freeze-thaw cryotherapy Metvix Cryotherapy Fair Good Excellent * Pariser DM et al; J Am Acad Dermatol 2003; 48(2): 227-232 27
Patient preference: actinic keratosis Pooled data, Phase III studies: Patients prefer MAL to previously received treatments 80 80 80 60 60 60 40 40 40 20 20 20 0 vs cryotherapy N=102 0 vs 5-FU N=21 0 vs surgery N=37 best Cryotherapy best 5-FU best Surgery best * Pariser DM et al; J Am Acad Dermatol 2003; 48(2): 227-232 28
Indications Indications Thin/non-hyperkeratotic and non-pigmented AKs on face and scalp + contraindications Hypersensitivity to MAL or any of the excipients sbcc and/or nbcc unsuitable for other therapies Morpheaform BCC Porphyria 29
Other indications Diagnostic tool Rejuvenation Acne Rosacea Infections: - mycoses - MRSA 30
Photodynamic diagnosis: PDD Fluorescence guided biopsy Detection clinical invasion Tumor margin Control of efficacy of treatment Development of special devices with high selectivity for tumor tissue (NMSC) 31
Extramammary Paget s Disease (EMPD) Rare intraepithelial neoplasm arising in apocrine glandbearing skin In situ vs. invasive disease 2 Types Primary cutaneous Secondary: underlying neoplasm internal malignancy 32
Standard treatment in situ EMPD Surgery with intraoperative margin control Wide Local Excision (WLE) Mohs Micrographic Surgery (MMS) high recurrence rate (31-61 %) & significant morbidity & discomfort 33
Case report Woman of years old In situ peri-anal EMPD No associated malignancies History of Crohn s disease Pre-surgical clinical aspect 34
Case report Pre-and peri-operative margin delineation with MAL+ woodlight 99,8 % sensitivity; 98 % specificity in vulvary EMPD Obstet. Gynaecol. 1991: 77-156-9, Misas JE et al 35
Case report Post-surgical MAL Fluorescence Imaging Surgical WLE with VY-plasty : no complete removal! Treatment with : Topical MAL under occlusion 4 hrs and visible red light (200 J/cm²) at 2 week interval sessions 36
Case report: results Clinical Aspect after 3 MAL sessions 37
Case report: results Complete clinical & histological response rate after 4 sessions Adverse events: pain VAS 4 Cosmetic outcome: no scarring 38
Conclusions: role of PDD and for in situ EMPD PDD or FD is effective in detecting in situ neoplastic skin. Tumor fluorescence mapping is a useful method for border delineation and can be used to control disease clearance in the upperlayers of the skin. Multimodal approach with MMS & adjuvant treatment to improve the cure rate with minimal tissue destruction More research has to be done to optimize treatment variability's and to evaluate the long term follow-up 39
and Infection Mycoses: Porphyrins metabolized by dermatophytes to protoporphyrin IX fungicide effect at lower dosis than needed on keratinocytes no genotoxic or mutagenic activity no resistance till now Tested on CA and T. Rubrum 40 Conclusion : effective not first line treatment
and Side- effects (N = 3000) erythema 90% (1-2 weeks) + burning or itching + swelling Scaling 80% treatment: emollients crusting 26% pustulation 2% sterile damage to follicular wall treatment: - 2 weeks humid dressing - benzoyl peroxide - anxiety erosions 0,5% - healing time 6 weeks with wound dressings - irritation and anger hyper/hypopigmentation: 2% infection bacterial or viral (herpes) < 0,5% 41
Summary Effective in both sbcc and AK Selective accumulation in lesions : can be used for delineation of lesions and other epidermal diseases (infections) Non-invasive Minimal scarring Fast healing Excellent cosmetic outcome High patient satisfaction Minimal side effects, except pain! 42
THANK YOU 43