欧洲皮肤病学论坛-局部光动力疗法指南

doi:10.1684/ejd.2015.2570TherapyEur J Dermatol 2015;25(4):296-311Colin MORTON 1Rolf-Markus SZEIMIES 2Alexis SIDOROFF 3Ann-Marie WENNBERG 4Nicole BASSET-SEGUIN 5PiergiacomoCALZA V ARA-PINTON 6Yolanda GILABERTE 7Günther HOFBAUER 8Robert HUNGER9Sigrid KARRER 10Percy LEHMANN 11Stefano PIASERICO 12Claas ULRICH 13Lasse BRAATHEN 9,on behalf of the European Dermatology Forum1Department of Dermatology,Stirling Community Hospital,Stirling,FK82AU,UK2Department of Dermatology &Allergology,Knappschaftskrankenhaus Recklinghausen,Recklinghausen,Germany3Department of Dermatology and Venereology,Medical University Innsbruck,Austria4Department of Dermatology,Sahlgrenska University Hospital,Gothenburg,Sweden5Department of Dermatology,Hôpital Saint Louis,Paris,France6Department of Dermatology,Spedali Civili,Brescia,Italy 7Department of Dermatology,Hospital San Jorge,Huesca,Spain8Department of Dermatology,Zurich University Hospital,Zürich,Switzerland9Department of Dermatology Bern,Bern,Switzerland10Department of Dermatology,University Hospital Regensburg,Regensburg,Germany11Department of Dermatology,HELIOS Klinikum Wuppertal,Germany12Unit of Dermatology,Department of Medicine,University of Padova,Italy 13Skin Cancer Centre,Hautklinik der Charitie,Berlin,GermanyReprints:C.Morton <colin.morton@>Article accepted on 15/3/2015European Dermatology Forum Guidelines on topical photodynamic therapyTopical photodynamic therapy (PDT)is a widely approved therapy for actinic keratoses,squamous cell carcinoma in-situ ,superficial and cer-tain thin basal cell carcinomas.Recurrence rates are typically equivalent to existing therapies,although inferior to surgery for nodular basal cell carcinoma.PDT can be used both as a lesional or as a field therapy and has the potential to delay/reduce the development of new lesions.PDT has also been studied for its place in the treatment of,as well as its poten-tial to prevent,superficial skin cancers in immune-suppressed patients,although sustained clearance rates are lower than for immunocompetent individuals.Many additional indications have been evaluated,including photo-rejuvenation and inflammatory and infective dermatoses.This S2guideline considers all current and emerging indications for the use of topical photodynamic therapy in Dermatology,prepared by the PDT subgroup of the European Dermatology Forum guidelines committee.It presents consensual expert recommendations reflecting current pub-lished evidence.An unabridged version of this guideline is available online at:/edf/index.php/edf-guidelines.Key words:5-aminolaevulinic acid,dermatology,guidelines,methyl aminolaevulinate,non-melanoma skin cancer,photodynamic therapyI n addition to undertaking a systematic literaturereview,these guidelines include evidence reviewed in therapy specific guidelines published in2007[1],2008 [2]and2013[3,4]and disease-specific EDF guidelines on actinic keratosis(2011[5])and basal cell carcinoma(2012 [6]).Photodynamic therapy involves the activation of a photo-sensitizing drug by visible light to produce reactive oxygen species within target cells,resulting in their destruction [7,8].In dermatological indications,PDT is usually per-formed by topical application of precursors of the haeme biosynthetic pathway,in particular5-aminolaevulinic acid (5-ALA)or its ester,methyl aminolaevulinate(MAL),con-verted within target cells into photo-active porphyrins, especially protoporphyrin IX(PpIX).After an incubation period,light of an appropriate wavelength activates the pho-tosensitizer promoting the photodynamic reaction.Before light illumination,it is possible to detect skin surfacefluo-rescence,assisting detection and delineation of both visible and incipient lesions.Three agents are currently licensed for use in Europe:Methyl aminolaevulinate(160mg/g)(MAL) Metvix®/Metvixia®(Galderma,Paris,France)is used along with red light to treat non-hyperkeratotic actinic keratosis(AK),squamous cell carcinoma in-situ(SCC in-situ/Bowen’s disease),superficial and nodular basal cell carcinomas(sBCC,nBCC),although approvals vary between countries.A patch containing5-ALA(Alacare®(Galderma-Spirig AG,Egerkingen,Switzerland))is approved for mild AK in a single treatment in combination with red light.Furthermore for AK,a nanoemulsion (Ameluz®(Biofrontera AG,Leverkusen,Germany))is licensed for PDT in combination with red light for the treatment of mild and moderate AK.A20%formulation of5-ALA,Levulan(DUSA Pharmaceuticals,USA),is approved in N.America and certain other countries for AK,in a protocol that uses blue light.Treatment is generally well tolerated but discomfort/pain is common during PDT.Alterations in the way PDT is delivered,including the use of daylight or shorter photo-sensitizer application times,are associated with decreased discomfort.PhotosensitizersALA is hydrophilic whilst MAL is more lipophilic,and hence MAL may penetrate more deeply,although compar-ison studies have failed to show a difference in response [9–11].A nanoemulsion of ALA was recently compared with MAL,with a higher clearance of AK of78%vs.64% 12weeks after the last treatment[12].PDT using a self-adhesive,5-ALA patch,has been shown to be superior to cryotherapy for mild and moderate thickness AK[13]. Enhancing penetration of a photosensitizer may increase treatment efficacy but currently there is no approval for a penetration enhancer or iontophoresis.Elevating skin tem-perature during ALA application may improve efficacy as PpIX production is a temperature-dependant process[14]. In nodular BCC of up to2mm thickness,a3-hour applica-tion of160mg/g MAL showed the highest selectivity for tumour and is licensed for two treatments one week apart for BCC[15].It is also licensed as a double treatment for SCC in-situ(Bowen’s disease),but in AK one initial treatment is recommended,with non-responders receiving a second treatment at three months.The20%ALA formulation used with the Blu-U TM system is licensed for a drug light inter-val of18-24hours but shorter intervals of around1hour are widely practised[16].A shorter incubation time of1 hour with MAL for AK is also an option,given that in a comparison of1h vs.3h,overall lesion response rates were 76%vs.85%respectively[17].Additional topically applied photosensitizers have been assessed,including indocyanine green,compared with indole-3-acetic acid,for acne with both agents equally effective[18].Topical hypericin has been studied in several indications with relatively disappointing results[19,20]. Similarly,topical silicon phthalocyanine PDT has been demonstrated to trigger apoptosis in various cutaneous neo-plasms[21].PDT using the cationic photosensitizer3,7-bis (N,N-dibutylamino)phenothiazin-5-ium bromide reduced the bacterial load in chronic wounds with a trend towards wound healing in a recent trial[22].Light sources and dosimetryA range of light sources can be used for PDT,includingfil-tered xenon arc and metal halide lamps,fluorescent lamps and light emitting diodes(LED)and even rge fields can be treated using narrowband LED devices e.g. the Aktilite128(Galderma,Paris,France),BF-Rhodo LED (Biofrontera,Leverkusen,Germany)and Omnilux PDT (Phototherapeutics,London,UK),each with an output that matches the630/635nm activation peak of PpIX whilst excluding the extraneous wavelengths present in broad-band sources e.g.PhotoDyn750/505(Hydrosun,Germany) and Waldmann PDT1200L(Waldmann,Germany),permit-ting shorter irradiation times.Filtered intense pulsed lights (IPLs)have been successfully used in PDT although they emit different spectra,resulting in a need to derive specific protocols to achieve identical radiant exposures[23].There is evidence of higher response rates with narrow spectrum sources,with patient clearance rates of85%and68%for BF-200ALA-PDT or MAL-PDT respectively,compared with72%and61%when broad-spectrum devices were used [12,24].Most light sources for PDT use the630nm absorption peak in the red region,in order to improve tissue penetration, although a bluefluorescent lamp(peak emission417nm) is recommended in Levulan-PDT.Dosimetry for emerging inflammatory/infective dermatoses is not yet standardized although high and low dose protocols are described for acne [25].Discontinuous illumination(fractionation)may improve the efficacy of PDT by permitting tissue re-oxygenation during‘dark’periods.Studies support the superiority of fractionation in ALA-PDT for sBCC,but not in SCC in-situ [26,27].Overall clearance of95%after a2-year follow-up has been reported in a large series of552lesions(AK,SCC in-situ,sBCC,nBCC)following ALA-PDT using two light fractions of20and80J/cm2at4and6hours[28].Supe-rior clearance of AK treated by fractionated ALA-PDT (using the same protocol)at3months of96%compared with89%for lesions treated to standard protocol(2treat-ments7days apart)with12-month clearance rates both onlyslightly lower at94%and85%respectively[29].An alter-native protocol of two doses of75J/cm2at4and5hours was associated with an initial94%clearance rate for nBCC but with a failure rate of30%by3years[30].Differences in localization between the agents,with an altered response of endothelial cells to ALA and MAL-PDT noted in-vivo, may explain why no similar efficacy improvement has yet been observed with fractionated MAL-PDT[31]. Daylight can also be used as the light source for PDT with application of MAL for0.5hour,followed by exposure to daylight for up to2.5hours[32].Daylight MAL-PDT is as effective as conventional treatment for AK,with the advan-tage of only minimal pain.No inferiority was observed by reducing the daylight exposure to1.5hours although the response was greater for thinner AK[33,34].Daylight-PDT has recently been assessed for treating BCC[35]. Patients can wear a portable LED device,permitting ambu-latory PDT to reduce the need for hospital attendance[36]. Efficacy has been reported in three studies with the largest achieving84%lesion clearance,predominantly sBCC and SCC in-situ,1year following2treatments,one week apart, with minimal pain[36–38].Dosimetry in PDT is defined by photosensitizer dose,drug-light interval,wavelength/band,irradiance andfluence of light.Total effectivefluence,taking into account irradi-ance,optical transmission through tissue and absorption by photosensitizer,has been proposed as a method for more accurate dosimetry but,in practice,light dosage can only be estimated from the energyfluence[39].Lesion preparationProtocols for PDT in Europe conventionally recommend some form of lesion preparation to enhance photosensitiz-ing agent absorption and light penetration.Studies using the ALA plaster for mild and moderate thickness AK did not require prior preparation,with results consistent with stan-dard protocols[13,14].Some practitioners have observed reduced efficacy if lesions are not debrided prior to PDT [14,17],while others have not noted increased drug uptake following lesion preparation of SCC in-situ and BCC[41]. Lesion preparation is probably more important when treat-ing nodular BCC by PDT with recommended practice to gently remove overlying crust with a curette/scalpel in a manner insufficient to cause pain,and thus not requiring local anaesthesia.Some practitioners perform a more for-mal lesion debulking days/weeks prior to PDT,with92% of BCC clearing following a single session of ALA-PDT in one study[42].In a small comparison study of PDT (ALA and MAL),with or without debulking immediately pre-photosensitizer application,residual nodular BCC was more often observed in BCCs that were not debulked[10]. Additional techniques of skin preparation have been reported,including microneedling,skin vaporization with CO2laser,or ablative fractional resurfacing prior to PDT [43–46].Practitioners typically cover treatment sites with light occlusive dressings,on the presumption that full expo-sure to ambient light during the incubation period will lead to increased activation of PpIX superficially,reducing the opportunity for deeper photosensitizer penetration before photoactivation.PDT with occlusion is standard practice in MAL-PDT of AK,SCC in-situ and BCC but is not per-formed when using Levulan PDT for facial AK.The most recent studies of daylight PDT also do not require initial occlusion[34].Treatment protocolsStandard PDTRecommended protocols in Europe for ALA-PDT and MAL-PDT using currently licensed photosensitizing agents for non-melanoma skin cancer indications involve the appli-cation of the topical photosensitizing agent for3-4hours, depending on agent,with occlusion,to be followed by illu-mination most often using a narrowband red LED light source(∼630nm,light dose of37J/cm2).Daylight PDTDaylight PDT is performed with initial widespread appli-cation of an organic sunscreen followed approximately15 minutes later by lesion preparation,then MAL cream is applied to the treatment area,without occlusion.After30 minutes application,patients are exposed to daylight for 1.5-2.0hours when treating AK[34,47].Ambulatory PDTThe light emitting‘plaster’is applied to the lesion after routine preparation and cream application and the device automatically switches on after the incubation period to deliver a total dose of75J/cm2at7mW/cm2[38].Another approach under trial is the integration of an opticalfibre in aflexible textile structure coupled to a portable laser light source adjustable to the appropriate wavelengths[48].Fluorescent diagnosisThe detection of skin surfacefluorescence following appli-cation of ALA or MAL,using a Wood’s lamp or CCD camera system,may assist in lesion definition as well as in identifying persistent/recurrent disease that may not be clinically obvious[49].Fluorescence imaging has given inconsistent results when used to determine tumour boundaries to improve surgical efficacy during Mohs micro-graphic surgery and has not been shown to be substantially superior to simple clinical assessment of tumour margins [50,51].Measurement offluorescence during MAL-PDT has shown the extent of photobleaching but not the total initial pro-toporphyrin IXfluorescence,to be predictive of lesion clearance[52].In another study,fluorescence diagnosis in intraepidermal neoplasias was unable to discriminate between lesions or proliferative activity,with hyperkerato-sis an important determinant offluorescence intensity[53]. Intensity of pain is associated withfluorescence intensity and may help identify patients more likely to require active pain management[54].Current indicationsActinic keratoses(Strength of Recommendation A,Quality of Evidence1)PDT has been widely studied for thin and moderate thick-ness AK on the face and scalp with clearance rates of licensed products of81-92%three months after treatment to current protocols[12,13,24,55–57].One-year lesion clearance rates of78%and63-79%have been reported fol-lowing ALA-PDT(up to2treatments)and patch ALA-PDT (single treatment)respectively[40,58].An initial double treatment of MAL-PDT,7days apart, does not confer advantage in clearing thin AK,although fewer moderate thickness lesions clear on a single ini-tial treatment[56].The response rate improved after a repeat treatment at3months,when required.A random-ized intra-individual study of1501face/scalp AK in119 patients used this protocol to compare MAL-PDT with cryotherapy[57].After the initial cycle of treatments, PDT resulted in higher cure rate than cryotherapy(87% vs.76%),but with equivalent outcome after non-responders were retreated(89%vs.86%).ALA-PDT using a20%formulation and blue light cleared 75%or more of all lesions in77%patients using14-18hour ALA application[55].Following a second treatment,where required,the clearance rate increased to89%at week12. ALA-PDT using BF-200nanoemulsion was superior to MAL for thin and moderate thickness AK,with clearance of90%vs.83%of lesions12weeks after one or two PDT treatments[12].Another randomized study observed over-all clearance of81%of lesions following BF-200ALA PDT compared with a22%placebo response.Superior patient and lesion clearance rates were noted in those illu-minated by a narrowband red LED source(96%and99% respectively)compared with broadband light[24].Similar recurrence rates were observed following BF200ALA-PDT and MAL-PDT of22%and25%respectively at12 months[59].ALA-PDT using the self-adhesive patch cleared82%-89% of mild or moderate AK,superior to cryotherapy(77%) [13].Twelve months after the single treatment,patch ALA-PDT remained superior to cryotherapy[40].MAL-PDT using daylight is as effective in clearing AK but is less painful than conventional PDT,with a lesion reduction after a single treatment of79%compared with 71%,respectively[32].Daylight exposure of1.5hours is as effective as the2.5hours but lesion response is highest for thin lesions(76%)compared with61%and49%for mod-erate and thick AK[33,34].A study assessing the impact of latitude identified that daylight PDT can be performed throughout summer and until mid-September in Reykjavik and Oslo,late October in Copenhagen and Regensburg, mid-November in Turin and all year in Israel[60].A study comparing MAL-PDT with cryotherapy for AK on the extremities demonstrated inferior efficacy with PDT, with clearance of78%of lesions at6months compared with 88%for cryotherapy[61].However,in a right/left compari-son study with imiquimod,ALA-PDT cleared significantly more moderate thickness AK lesions(58%vs.37%)and equivalent numbers of thin AK on the hands/forearms(72% lesions)[62].Actinic cheilitis has also been treated by PDT,with26/40 patients clear at3months following ALA-PDT,although with histological evidence of recurrence in9patients by18 months[63].MAL-PDT cleared cheilitis in7/15although histological clearance was evident in only4[64].In a recent retrospective analysis,27/43patients with actinic cheilitis cleared with response maintained after4.2±5.9 months[65].Sequential MAL-PDT then imiquimod5% cream achieved a histological cure of73%in a study of30 patients,suggesting an improved outcome using combina-tion treatment[66].Therapy guidelines identify PDT as effective both as a lesion andfield-directed treatment and suggest PDT has a role where AK are multiple/clustered and at sites of poor healing[67,68].In a randomized comparison of patient tolerance to MAL-PDT and topical imiquimod for multi-ple face/scalp AK,a high level of satisfaction was observed with both therapies,with PDT slightly superior[69].Squamous cell carcinoma in-situ(Bowen’s disease)/Invasive SCCSquamous cell carcinoma in-situ(Strength of Recommendation A,Quality of Evidence1)Invasive SCC(Strength of Recommendation D,Quality of Evidence11-iii).Lesion clearance rates of88-100%are reported for SCC in-situ3months after one or two cycles of MAL-PDT,with68-89%of treated lesions remaining clear over17-50months[70–74].MAL-PDT using a broadband red light was compared with cryotherapy or topical5-fluorouracil(5-FU)in a study with 225patients[70].The3month lesion clearance rates were similar with all regimens(93%for MAL-PDT,86%for cryotherapy,83%for5-FU)but PDT gave superior cos-metic results.Sustained lesion clearance rates for the three therapies were similar after2years with68%of lesions cleared following PDT,60%after cryotherapy and59% after5-FU[71].A similar3-month efficacy of88%was observed following MAL-PDT for41SCC in situ,using the narrowband red LED sources now in routine use,with sustained clearance at24months of71%[72].Further open studies of51and43lesions treated by MAL-PDT observed 76%and89%sustained clearance after17and50months, respectively[73,74].MAL-PDT cleared22/23lesions over3cm,with only3 recurrences over a1year follow-up[75].ALA-PDT cleared 35/40of large(>2cm)lesions and44/45patches in10 patients with three or more SCC in situ,although with four lesions recurring in each group over1year[76].ALA-PDT using two penetration enhancers achieved an initial90%clearance of19SCC in situ but with only53% clear at5years[77].ALA-PDT has been compared with cryotherapy and with5-FU[78,79].PDT proved superior in efficacy and adverse events in comparison with5-FU,as well as being less painful compared with cryotherapy. Body site does not appear to impact efficacy of PDT with protoporphyrin IX accumulation identical in SCC in situ located on acral and non-acral sites[80].PDT has been reported to clear digital,subungual and nipple Bowen’s dis-ease and where it arises in a setting of poor healing[81–87]. PDT may offer an alternative for treating penile intraep-ithelial neoplasia,with one large series,using ALA-andMAL-PDT in10patients noted clearance in7,but later recurrence in4[88].Red LED light is used most often for PDT treatment of SCC in-situ,however,a square wave intense pulsed light,cleared all nine lesions in one series at4months[89].Although one patient with clinically diagnosed SCC in-situ treated with PDT was diagnosed with melanoma at the same site a few months following treatment,it is uncertain if the treatment contributed,given the lack of initial histology [90].Therapy guidelines recommend PDT as the treatment of choice for both large and small plaques of SCC in-situ on poor healing sites and a good choice for large lesions in good healing sites[91].In a patient-reported outcome study, satisfaction was high,with90%of respondents indicatinga very favourable impression of ALA-PDT for SCC in situ[92].There is reduced efficacy of PDT for micro-invasive and nodular invasive SCC where24month clearance rates of 57%and26%have been reported.In view of its metastatic potential and reduced efficacy rates,PDT is not recom-mended for invasive SCC[72].Basal cell carcinomaSuperficial Basal cell carcinoma(Strength of Recommendation A,Quality of Evidence1),Nodular Basal cell carcinoma(Strength of Recommendation A, Quality of Evidence1)MAL is currently the only photosensitizing agent approved for superficial and/or nodular BCC.Initial clearance rates of92-97%for sBCC were achieved with protocols of either 1single initial treatment or2treatments7days apart, followed by a repeat two-treatment cycle at3months,if required[93,94].Recurrence rates of9%at1year were noted in both studies,with22%of initially responding lesions recurring over5years of follow-up.91%of nodular BCC were clinically clear3months following MAL-PDT, with a sustained lesion clearance response rate of76%after 5years of follow-up[15,95].Histologically confirmed response rates were observed in a further two randomized studies of MAL-PDT for nBCC. Treatment site excisions revealed clearance in73%,most effective for facial lesions where89%achieved complete histological response[96].A poorer response was reported in a large series of194BCC,with an82%clearance rate for sBCC,but only33%of nodular lesions clearing following MAL-PDT by standard protocol.The authors describe no debulking of the tumour prior to PDT[97].PDT for BCC is conventionally delivered using LED light sources but in a pilot study of daylight MAL-PDT,90%of 30lesions were clear3months after a single cycle of two treatments one week apart,although6BCC recurred over 12months[35].MAL-PDT was equivalent to surgery(92%vs.99%ini-tial clearance,9%and0%recurrences at1year)for sBCC but inferior to excision for nBCC when recurrence rates are compared(91%vs.98%initial clearance,14%and 4%recurrences at5years)[94,95].Cosmetic outcome is superior following PDT compared with surgery. Clearance rates were equivalent when MAL-PDT was com-pared with cryotherapy for sBCC,97%and95%at3months respectively,with overall clearance after5years identical at76%of lesions initially treated but with superior cosme-sis following PDT[94].A comparison of MAL-PDT with imiquimod or topical5-FU for sBCC achieved tumour-free rates at12months of73%,83%,and80%,indicating that using these protocols,5-FU is non-inferior and imiquimod superior to one cycle of MAL-PDT[98].ALA has also been widely used in treating BCC,with a weighted initial clearance rate of87%noted for sBCC treated by ALA-PDT in a review of12studies,compared with53%for nodular lesions[99].When ALA-PDT was compared with cryotherapy for both superficial and nodu-lar BCC,there was no significant difference in efficacy although healing times were shorter and cosmesis superior with PDT[100].In a randomized comparison trial of single versus frac-tionated ALA-PDT for sBCC,5years after treatment, fractionated PDT produced a superior response(88%vs. 75%respectively)[26].Fractionated ALA-PDT was equiv-alent to surgery in initially clearing lesions but with a 31%failure rate over5years,compared with only2% following surgery when a different75J/75J protocol was used,although80%of lesions remained clear at2years using the20J/80J dosing described above[28,101].Suc-cess of treatment depended on tumour thickness,with a probability of recurrence-free survival over5years of94% if BCC≤0.7mm.In a comparison of PDT with min-imal curettage,pre-ALA application versus conventional surgery,there was also no evidence of superiority of PDT [102].Responsiveness of BCC is influenced by lesion thickness, with reduced efficacy with increasing tumour thickness in a study using ALA-PDT[103].Lesions in the H-zone also have reduced sustained clearance rates[104].A six-year clinical and histological follow-up of53BCCs treated by ALA-PDT reported81%of treated sites disease free at72 months[105].A large cohort of33patients with naevoid basal cell car-cinoma syndrome(NBCCS)were treated by topical or systemic PDT depending on whether the lesions were less than/greater than2mm thick on ultrasound,with an overall local control rate at12months of56.3%[106].A recent report observed that MAL-PDT for NBCCS improves patient satisfaction and reduces the need for surgical pro-cedures[107].Topical PDT is recommended as a good treatment for sBCC, and a fair treatment for low-risk nBCC[108].Given recur-rence rates that are higher than for surgery,PDT is best considered for thin nodular lesions where surgical excision is relatively contraindicated or where patient preference, reflecting past therapy history,co-morbidities and/or cos-metic considerations,results in a willingness to accept a higher risk of recurrence.Emerging indicationsTreatment of non-melanoma skin cancer in organ transplant recipients(Strength of Recommendation B,Quality of Evidence I)Organ transplant recipients(OTR)have a greatly increased incidence of SCC,with PDT suggested for treating AK or SCC in-situ[109,110].A prospective study compared theefficacy of ALA-PDT for AK and SCC in-situ in immuno-competent patients(IC)with OTR[111].At four weeks, complete remission rates were similar(IC94%vs.OTR 88%),but differed at12weeks(IC89%vs.OTR68%) and48weeks(IC72%vs.OTR48%)[111].Three month remission rates following MAL-PDT vary between71% and90%[112,113].Reduced efficacy of PDT in OTR may result from the large number of intraepithelial lesions, more prominent hyperkeratosis and an altered local immune response.Location of lesions also appears important for the outcome:the response for AK to PDT on the hands ranged between22and40%[112,113].In a comparison of MAL-PDT to topical5-FU,one-month clearance rates were89% and11%,with more pain but better cosmesis following PDT [114].Prevention of non-melanoma skin cancer in organ transplant recipients(Strength of Recommendation B,Quality of Evidence I)The increase in incidence of OTR to SCC has been attributed to impairment of the cutaneous immune-surveillance due to systemic immunosuppressive medica-tion with cyclosporine and azathioprine,known also to induce specific effects enhancing the potential for de-novo formation of NMSC[115–118].Regularly applied photo-protection can reduce AK lesion counts and PDT has also been investigated as a preventive therapy[119].MAL-PDT delayed the development of new lesions in an intra-patient randomised study of27OTR with AK(9.6vs.6.8months for control site)[120].In a multicentre study of MAL-PDT compared with no treatment in81OTR,there was an initial significant reduction in new lesions,mainly AK,but this effect was lost by27months,12months after the last of the5PDT treatments[121].No significant dif-ference in the occurrence of SCC was observed in a study of blue light ALA-PDT versus no treatment after2years follow-up in40OTR[122].However,another study of blue-light ALA-PDT,repeated at4-8week intervals for2years, observed a reduction in SCC in12OTRs,compared with the number developing in the year prior to treatment,with a mean reduction at12and24months of79%and95% [123].Field cancerization(Strength of Recommendation B,Quality of Evidence I)The concept offield cancerization was introduced by Slaughter in1953[124].In the skin,it suggests that the clin-ically normal appearing skin around AKs and SCCs have subclinical features of genetically damaged cells,which can potentially develop into a neoplastic lesion.In gen-eral oncology it is defined as the pathological and genetic changes found in the tissue peripheral to a tumour,result-ing from‘preconditioning’of the affected organ by various carcinogenic agents[125].The major carcinogen for skin cancer is UV radiation with UV induced Tp53mutations common in NMSC[126].In sun-exposed skin of patients over50years old,p53mutated clones can be found in> 70%[127].In animal models,these Tp53mutated clones represent an early stage of skin carcinogenesis[128].The presence of Tp53mutations defines at the molecular level UV-inducedfield cancerization in the skin[129].The subclinical changes offield cancerization can be eval-uated by reflectance confocal microscopy[130].Organ transplant patients have multiple clones of mutated cells on sun exposed skin with disappearance of Tp53cells and cellular atypia observed following PDT[131,132].A recent consensus noted that PDT might prevent new AKs and the transformation of AK to SCC in OTR and propose cyclic PDT[133].The preventive potential offield PDT in immunocompetent photo-damaged individuals was stud-ied,where ALA-PDT delayed new AK development by about6months[134].Cutaneous T-cell Lymphoma(CTCL)(Strength of Recommendation C,Quality of Evidence IIiii) Skin-infiltrating malignant lymphocytes are susceptible to PDT and ALA-PDT(non-standardised protocols) and MAL-PDT(BCC protocol)can achieve therapeutic response[135–144].Complete remission was observed in 4/5with unilesional patch,plaque and nodular disease after a median of6MAL-PDT treatments[142].MAL-PDT cleared plaque lesions in6/12after a mean of5.7treatments [143].Ten patients with unilesional patch and plaque dis-ease received2-6MAL-PDT treatments with clinical and histological clearance in5and a partial remission in two, with response maintained in6/7after8-31months[144]. In a retrospective observational study,only5/19patients with unilesional plaque stage or isolated lesions cleared, with two relapsing during follow-up[65].In a further retrospective study of12patients with paucilesional dis-ease,there were6complete responders,3partial,following monthly MAL-PDT repeated for6months[145].The above reports and series indicate a potential for PDT in localized patch/plaque CTCL,with a possible indica-tion for lesions in the body folds that cannot be exposed to phototherapy.Acne(Strength of Recommendation B,Qualityof Evidence I)P.acnes produces small amounts of porphyrins permitting a direct photodynamic effect without external sensitizer but the addition of topical ALA enhances porphyrin synthesis by the pilosebaceous unit[146,147].PDT can promote antimicrobial and anti-inflammatory effects,inhibition and destruction of sebaceous glands,and enhanced epidermal turnover promoting reduced follicular obstruction[148]. PDT can significantly reduce inflammatory lesions and decrease sebum excretion,supported by a study of13 patients with facial acne who all improved when treated with ALA-PDT[149,150].However,in another study, ALA-PDT reduced inflammatory lesions but without a reduction of P.acnes count nor sebum excretion[151].In a study of21patients,following2treatments,there was a68%reduction in inflammatory acne lesions after MAL-PDT,but no reduction in non-inflammatory lesions[152]. In a split-face study,the same group compared ALA-with MAL-PDT,observing a similar reduction in inflammatory lesions but ALA-PDT showed more prolonged and severe side-effects[11].In a split-face study in30patients com-paring MAL-PDT versus light only,a54%versus20% reduction in inflammatory parameters was noted between active and control groups,with non-significant difference in。