Euro PDT 2014 highlights

Euro PDT 2014 highlights

Nice, April 4th and 5th 2014

Pre-treatment• Influence of pre-treatment on face and scalp AK on efficacy and tolerability. Patrick Gholam, Heidelberg, Germany• Pretreatment with calcipotriol enhances MAL-induced PpIX formation. A murine study. Christiane Bay, Copenhagen, Denmark• Fx Laser + Daylight-PDT vs Daylight-PDT vs c-PDT vs laser alone in OTR. Katrine Togsverd-Bo, Copenhagen, Denmark• Conventional MAL-PDT with microneedling on actinically damaged skin. Luis Torezan, Sao Paulo, Brazil

New approaches for PDT• Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe. Jean-Philippe Lacour, Nice, France• A new approach to a gentle PDT treatment. Stine Regin Wiegell, Copenhagen, Denmark• Pulse PDT: A promising new way to reduce inflammation in PDT without reducing efficacy. Hans Christian Wulf, Copenhagen, Denmark

From oncology to antimicrobial PDT• DEBATE: PDT in sBCC Studies results => when choosing PDT for sBCC. Rianne M.J.P. Gerritsen, Njimegen, The Netherlands & Nicole Kelleners-

Smeets, Maastricht, The Netherlands• Patch-PDT: convenient and effective for actinic cheilitis? Sonja Radakovic, Vienna, Austria• PDT field treatment vs. lesion treatment in AK. Rianne M.J.P. Gerritsen, Nijmegen, The Netherlands• MAL-PDT vs Imiquimod 5% cream for skin cancer prevention. Elena Sotirou, Thessaloniki, Greece• MAL-PDT for mycosis fungoides: a prospective open study and review of literature . Gaelle Quéreux, Nantes, France• Antimicrobial PDT in chronic leg and foot ulcers. Stan Brown, Leeds, UK• Clinical and microbiological healing of onychomycosis after 3 sessions of conventional MAL-PDT vs placebo. Yolanda Gilaberte, Huesca, Spain

Abbreviations



Enhancing PDT tolerance• Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe. Jean-Philippe Lacour, Nice, France• A new approach to a gentle PDT treatment. Stine Regin Wiegell, Copenhagen, Denmark• Pulse PDT: A promising new way to reduce inflammation in PDT without reducing efficacy. Hans Christian Wulf, Copenhagen, Denmark



Abbreviations


Influence of pre-treatment with urea cream 40% on face and scalp AK on efficacy and tolerability.

Patrick Gholam, Heidelberg, Germany

METHODS: Retrospective monocentric study44 subjects aged 73.2 ± 7.7 years (mean±SD) with multiple grade I-II AK (mean 11.1 per patient) on the forehead (mean field size 117 cm²):15 patients with curettage (CUR) prior to MAL application15 patients with 10% salicylic acid (SA) one day prior to MAL-PDT (field application)14 patients with 40% urea (UR) one day prior to MAL-PDT (field application)Pain was assessed during illumination, efficacy was assessed at 1 month (1MAL-PDT session)

Curettage N=15

10% Salicylic acid N=15

40% UreaN=14

p value

Lesion CR (%) 68.5 61.4 60.8 NSMean pain score

+/-SD4.4 +/- 2.1 6.32 +/- 2.7 6.1 +/- 1.8 <.005

Influence of pre-treatment with urea cream 40% on face and scalp AK on efficacy and tolerability.

Patrick Gholam, Heidelberg, Germany

RESULTS: Significantly more pain with keratolytic pretreatment No difference in lesion response ratesSide effects:Curettage: slight bleeding and pain Pretreatment with SA or UR: mild erythema in most patients In the UR group 2 patients showed distinct irritation of the skin and one patient an erosionCosmetic result 4 weeks after PDT was excellent in all three groups (no scars, no hyper/hypopigmentation)

CONCLUSION: Keratolytic pretreatment with urea and salicylic acid compared to curettage:- comparable lesion response rates and cosmetic outcome- increase in pain during PDT and pronounced local reactions.

Pretreatment with calcipotriol enhances MAL-induced PpIX formation. A murine study.

Christiane Bay, Copenhagen, Denmark

BACKGROUND: PpIX is highly correlated with terminal cell differentiation. Since vitamin D is a pro-differentiating hormone, we examined the potential of calcipotriol (CAL) to intensify PpIX fluorescence from MAL.

METHODS:Calcipotriol cream (50 μg/g) was applied for 3 days prior to topical incubation for 3 hours with MAL cream (160 mg/g) in UV-exposed (n=19) and non-UV-exposed (n=21) hairless mice.

RESULTS:Without pretreatment, PpIX fluorescence is higher in UV-exposed skin (P<0.01)PpIX fluorescence increased (~ 61%) with calcipotriol pretreatment in both UV-exposed mice and non-UV-exposed mice (p<0.01). With calcipotriol pretreatment, PpIX fluorescence is similar in UV- and non-UV-exposed mice.

CONCLUSION:Calcipotriol enhances MAL-induced PpIX fluorescence in both UV-exposed and non-UV-exposed skin in this normal skin murine model.

Fx Laser + Daylight-PDT vs Daylight-PDT vs c-PDT vs laser alone in OTR.

Katrine Togsverd-Bo, Copenhagen, Denmark

METHODS:16 OTR with 542 grade I-III AK in field-cancerized skin (scalp, chest, extremities). For each patient, after application of sunscreen and curettage, 4 symmetrical skin areas were randomized to:- Conventional PDT (cPDT): 3 hours incubation followed by by red light irradiation at 37 J/cm²

- Daylight PDT (DL-PDT): MAL incubated 2½ hours without occlusion

- Ablative fractional laser resurfacing (AFL) alone: 2,940 nm Er:YAG laser at 2.3 mJ/pulse, 1.15W, two stacks, 50 microsecond pulse-duration, 2.4% density

- AFL-DL-PDT

cPDT DL-PDT AFL AFL-DL-PDT p value

Lesion CR at 3 months (%) 50 46 5 74 <.001

Mean maximum pain score

4.5 0.1 0.6 0.22 <.001

Fx Laser + Daylight-PDT vs Daylight-PDT vs c-PDT vs laser alone in OTR.

Katrine Togsverd-Bo, Copenhagen, Denmark

RESULTS: At 3 months, AFL-DL-PDT induced higher efficacy: 74% lesion CR compared to DL-PDT (46%), cPDT (50%) and AFL (5%) for all grades of AK (p<0.001). Mean maximal pain scores during AFL-dPDT (0.22), DL-PDT (0.1) and AFL (0.6) were significantly lower compared to cPDT (4.5) (p<0.001). Erythema and crusting were more intense in AFL-DL-PDT than DL-PDT and cPDT (p<0.01)No pigmentary changes or scar formation at 3 months follow-up

CONCLUSIONS: AFL-DL-PDT enhances efficacy with excellent tolerability in difficult-to-treat AK in OTR.

Conventional MAL-PDT with microneedling on actinically damaged skin.

Luis Torezan, Sao Paulo, Brazil

METHODS:Split-face study: 10 patients with symmetrically distributed AKs and photodamage were randomized:- conventional MAL-PDT (Metvix®, Galderma, Brazil) with previous gentle curettage - MAL-PDT combined with 1.5 mm high microneedling (Dermaroller®) after MAL application (MN-PDT). After 90 min of incubation, patients were illuminated with red LED light (635 nm, 37 J/cm²).

RESULTS:Average AK clearance was 88.3%, with no difference between the sides.At day 30, global scores for photodamage, mottled pigmentation, roughness, and sallowness improved on both sides (p < .05), but fine lines improved only on the MN-PDT side (p = .004). At day 90, facial erythema (p = .04) and coarse wrinkles (p = .002) also improved on the MN-PDT side, in addition to fine lines for conventional MAL-PDT (p = .01). Erythema (p = .009), edema (p = .01), crusting (p = .01) and pain(p = .004) were more common and intense on the MN-PDT side. One patient developed a secondary bacterial infection at day 7 on the MN-PDT side.

CONCLUSION:Microneedling-assisted PDT is a safe and effective method and can produce superior cosmetic results to conventional MAL-PDT for improving photodamaged skin.


New approaches for PDT• Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe. Jean-Philippe Lacour, Nice, France• A new approach to a gentle PDT treatment. Stine Regin Wiegell, Copenhagen, Denmark• Pulse PDT: A promising new way to reduce inflammation in PDT without reducing efficacy. Hans Christian Wulf, Copenhagen, Denmark



Abbreviations


Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe

Jean-Philippe Lacour, Nice, France

OBJECTIVES: Evaluate efficacy and safety of daylight MAL PDT (DL-PDT) with 2-hour exposure outside during continuous formation of PpIX, compared to conventional MAL-PDT (c-PDT) with LED lamps in treating facial/scalp AK.METHODS: Randomized, controlled, investigator-blinded, intra-individual non-inferiority multicentric studies subjects with ≥ 5 symmetrically distributed facial/scalp AK, treated with DL-PDT on one side vs c-PDT on the other side. Australian study

N=100European study

N=108Gender Male 75% 91.7%

Age Mean 66.9 72.8

Skin phototypeI 56% 9.3%II 33% 63.9%III 11% 22.2%

AK characteristicsMean AK per side 14 8.9

Face (vs scalp) 75% 51.3%Grade I % 97% 58%

Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe

Jean-Philippe Lacour, Nice, France

RESULTS (preliminary for European study): DL-PDT was non-inferior to cPDT in terms of complete lesions response rate at week 12 in both study.In the Australian study, no relationship between efficacy & weather or light doseIn the Australian study, with DL-PDT, most lesions in complete response at Week 12 remained cleared at 6 months : 97% for mild AK, 93% for moderate AK:DL-PDT was significantly less painful than c-PDT on a VAS scale (0-10):Daylight-PDT was well tolerated

CONCLUSION: DL-PDT can be considered an effective, safe and convenient alternative for treatment of facial/scalp AK.

Australian studyN=90 per protocole

Mild AK

European studyN=96 per protocole

Mild and moderate AK

DL-PDT cPDT P value DL-PDT cPDT P valueLesion CR at week 12 (%) 89 93 NS 70.1 73.6 NS

Mean pain score 0.8 5.7 <.001 0.7 4.4 <0.001Related adverse events (%) 39 59 49.6 61.1

A new approach to a gentle PDT treatment Stine Regin Wiegell, Copenhagen, Denmark

OBJECTIVE: Evaluate if topical corticosteroid would reduce post-PDT erythema after treatment of multiple AK.

METHODS:Randomized split-face study21 patients with multiple symmetrically distributed face and scalp AK (mean=13.7 AK/treated area) MAL-PDT with potent corticosteroid (0.05% clobetasol propionate) before and after PDT on one side

RESULTS:Potent topical corticosteroid significantly reduced PDT-induced erythema at 24h (p=0.012)No difference in complete lesion response at 3 months (mean 84%) No difference in PpIX fluorescence prior to illuminationNo correlation between lesion response rate and increased erythema or PpIX fluorescence Positive correlation between PpIX fluorescence and increased erythema 24h in MAL-PDT areas (same tendency on the corticosteroid side)

CONCLUSION:Topical corticosteroid may be an easy way to make PDT treatment of large visible areas more acceptable

Pulse PDT: A promising new way to reduce inflammation in PDT without reducing efficacy

Hans Christian Wulf, Copenhagen, Denmark

PULSE PDT FOR AK:- New PDT procedure with the aim to keep most PpIX within the affected cells to destroy these by apoptosis, and to

avoid extracellular leakage...- Pulse PDT for AK procedure: MAL application time of only 30 minutes is used, giving a pulse of MAL, while illumination

is still performed after 3 hours.

SPLIT FACE STUDY: 22 patients with symmetrically distributed face and scalp AK:- Conventional PDT on one side- Pulse PDT on the other side

RESULTS on the pulse PDT side (compared to conventional PDT side):- PpIX fluorescence before illumination significantly lower (p= 0.0001)- Erythema at 24h significantly reduced (p=0.022)- Same maximum pain score during illumination (7.0 vs 7.5)- Same complete lesion response at 3 months (81.7% vs 83.3%)

CONCLUSION: Can be combined with corticosteroid. Studies on daylight-Pulse-PDT are needed to make PDT painless and with minimal inflammation


Enhancing PDT tolerance• Results of 2 randomised, controlled, phase III studies with Daylight-PDT in Australia and Europe. Jean-Philippe Lacour, Nice, France• A new approach to a gentle PDT treatment. Stine Regin Wiegell, Copenhagen, Denmark• Pulse PDT: A promising new way to reduce inflammation in PDT without reducing efficacy. Hans Christian Wulf, Copenhagen, Denmark



Abbreviations


DEBATE: PDT in sBCC Studies results When choosing PDT for sBCC

Rianne M.J.P. Gerritsen, Njimegen, The NetherlandsNicole Kelleners-Smeets, Maastricht, The Netherlands

PDT for sBCC is most appropriate in patients: - Who want an excellent cosmetic outcome - Who have bad experiences with other treatments - Who don’t want serious adverse events- With multiple tumours- Who choose PDT themselves- With contra-indications for surgery

Optimization of PDT procedure for BCC requires a careful selection of the lesions… For BCC, Lower response with PDT might be expected:- If tumour depth is superior to 1 mm - In case of location on the limbs - With the following pathological characteristics: nodular and infiltrative types, as well as

ulceration Fantini et al. EADV 2011

Patch-PDT: convenient and effective for actinic cheilitis ?

Sonja Radakovic. Vienna, Austria

METHOD:Pilot study: 10 patients (9 women, 1 man) including 5 with histologically confirmed actinic cheilitis2 patients: 1 Alacare®-PDT session, 8 patients: 2 Alacare®-PDT sessions (2 weeks apart)Pain reduction: diclofenac (n=1), local anesthesia (n=3)

RESULTS:Overall complete lesion response : 9/12 (75)%:- At 1 month (n=3): CR 1, PR 2- At 2 months (n=3): CR 2, PR 1- At 3 months (n=6): CR 6Excellent cosmetic outcomeAdverse events:- Phototoxic reaction: minimal (2 patients), moderate (5 patients), strong (4 patients)- Pain was mostly moderate: no treatment interruption- Herpes simplex infection: 4/10 patients

CONCLUSION:Alacare®-PDT: promising approach for actinic cheilitis.

Lesion treatment Field treatment P value

Mean number of AK at baseline 8.6 8.95 .221

Percentage of grade I AK at baseline 89.5 86.6 .809

Lesion CR at 3 months

At M3 (n=20) 81.1 80.8 .669

At M6 (n=15) 75.3 76.1 .814

At M9 (n=16) 84.3 76.6 .009

Number of new lesions (n=16)

At M3 16 7 .257

At M6 11 13 .493

At M9 20 10 .014

Mean number of remaining AK

At M3 (n=20) 1.7 1.7 .717

At M6 (n=15) 2.1 2.1

At M9 (n=16) 1.4 2.1 .013

PDT field treatment vs lesion treatment in AK Rianne M.J.P. Gerritsen, Nijmegen, The Netherlands

HYPOTHESIS: If PDT treatment targets an area of field change, it may reduce the risk of development of further new tumors and recurrence.

STUDY DESIGN: Single centre, prospective, randomized, split face, investigator blind study, in 20 patients with at least 5 up to 10, grade I or II, AK lesions, symmetrically distributed on two 50 cm² contra-lateral areas, on the face or scalp. One side was treated with ‘lesion to lesion’ MAL-PDT; the other with ‘field’ MAL-PDT

PDT field treatment vs lesion treatment in AK Rianne M.J.P. Gerritsen, Nijmegen, The Netherlands

RESULTS: Baseline characteristics comparable in both treatment areas: mean AK was 8.6 (lesion) vs 8.95 (field), mostly grade I AK (89.5 vs 86.6%). Significant lesion reduction (p=.000) in both lesion and field treatment areas at M3, M6 and M9 At M3 and M6, no significant differences between both treatment protocols were found with respect to lesion reduction or number of new lesions. At M9, the number of remaining AK was significantly lower in ‘the lesion to lesion’ treated area (1.4 vs 2.1, p = .013), whereas the number of new lesions was significantly lower in the ‘field’ side (10 vs 20, p=.014).

DISCUSSION: Treating a mean of 8-9 AK in a field of 50 cm² approaches a field treatment. When performing a field treatment, extra attention should be paid to the visible lesions.

MAL-PDT vs Imiquimod 5% cream for skin cancer prevention

Elena Sotirou, Thessaloniki, Greece

OBJECTIVES: To compare efficacy and safety of MAL- PDT versus Imiquimod (IMIQ) 5% in the prevention of new NMSC in immunocompetent patients with field changes.

METHODS: Prospective study with intra individual comparison. 44 patients with face or scalp 50cm² field cancerization areas were randomized to receive MAL-PDT (2 sessions one week apart) on one side, and IMIQ 5% (3 days a week: 4 weeks on-2 weeks off-4 weeks on) on the mirror field.

RESULTS:At any time point, number of new lesions didn’t statistically differ. For instance at 12 months: 16 for PDT vs 22 for IMIQ. A time-related gradual decline of the prophylactic effect of both treatments was observed.Both treatments were well tolerated but adverse events were more intense at the fields treated with IMIQ (topical treatment demanded in 27% in the IMIQ group vs 0% in PDT group).Patients’ preference favored MAL-PDT (59% vs 41%) Cosmetic outcome was good/excellent without statistically significant difference

CONCLUSIONS: MAL-PDT and IMIQ 5% equally prevent development of new AKs in patients with field changes. MAL-PDT appears to be superior in terms of patients’ preference.

MAL-PDT for mycosis fungoides: a prospective open study and review of literature Gaelle Quéreux, Nantes, France

OBJECTIVE:To assess PDT effectiveness and tolerability in early-stage MF (stage IA or IB).

METHOD:Prospective study with 12 patients with 29 histologically proven stage IA or IB MF (maximum 5 lesions per patient).MAL-PDT sessions were repeated monthly for 6 months.

RESULTS:Assessment 1month after the 6th session: Objective response in target lesions in 75% of patients (6 CR, 3PR). Response rates similar between plaques and patches but higher in sun protected (83%) compared to sun-exposed areas (33%) (trend without reaching significance; p=0.058). New lesions appeared in 5/12 patients in untreated areas. Adverse events were localized at the MAL-PDT application sites (grade 1 or 2). Pain score during illumination ranged from 0.5 to 7 (mean 4.5). Most patients were highly satisfied and preferred PDT to the topical chemotherapy previously used.

CONCLUSION:Large prospective study, PDT appears as a reproducible procedure, effective and appreciated for early-stage MF

Quéreux G et al. J Am Acad Dermatol 2013

Antimicrobial PDT in chronic leg and foot ulcersStan Brown, Leeds, UK

OBJECTIVE:Aim to develop special, novel photosensitisers PPA904 (Phenothiazinium family) and protocols to achieve broad-spectrum, antimicrobial action

PHASE II: RCT single dose study in leg ulcer/diabetic foot ulcer: PPA904 vs placebo.32 patients with chronic wounds: 16 leg ulcers and 16 diabetic foot ulcers

RESULTS:In PPA904 treated groups, bacterial counts (including MRSA) were significantly lower immediately post PDT compared with before PDT. Approximative reduction = 1 log (p < 0.001). No significant bacterial reduction in the corresponding placebo groupsTreatment deemed safe and pain-freeChronic leg ulcers: After 3 months, 4/8 healed on PPA904, 1/8 on placebo.

Morley et al. Br J Dermatol. 2012

Antimicrobial PDT in chronic leg and foot ulcersStan Brown, Leeds, UK

PHASE II:RCT repeat dose study in leg ulcers 57 patients with chronic (> 3 months) leg ulcers bacterially colonised with >104 cfu/mL:- 9 subjects in Part 1 – to assess safety of new formulation / parameters- 48 subjects in Part 2 – PPA904 vs placeboAll subjects received up to 12 weekly treatments: PPA904 or placebo gel applied for 15 mins followed by illumination with red light (680nm, 100J/cm²)

RESULTS: Greater bacterial load reduction with PPA904, compared to placebo (p<0.0001)Bacterial load returns towards starting point after 1 weekNon-significant trend towards healing compared to placebo (wounds healed: 7 (29.2%)With PPA904 vs 5 (20.8%) with placebo)

CONCLUSION:PPA904-PDT can reduce bacterial load, and potentially lead to improved wound healing.

Clinical and microbiological healing of onychomycosis after 3 sessions of conventional MAL-PDT vs placebo

Yolanda Gilaberte, Huesca, Spain

OBJECTIVE: To assess efficacy and safety of MAL-PDT for the treatment of onychomycosis

METHOD:Multicentre, randomized, placebo-controlled clinical trial comparing 3 sessions (1 week apart) of conventional MAL-PDT with placebo-PDT in both clinically and microbiologically diagnosed onychomycosis (If conventional antifungals not effective, contraindicated or denied by the patient). Nail plates were softened 12 hours with 40% ointment urea before treatment.

FIRST IMPRESSIONS ON RESULTS (end of study July 2014):60 patients have been included. MAL-PDT seems to work better than red lightMAL-PDT seems to work better than classical antifungal for non-dermatophyte moldsCulture became negative, after the second treatment in most of the cases Treatment failures with dermatophytes could be associated with multiple nails infection and presence of tinea pedis during the follow-up

CONCLUSION:In onychomycosis caused by dermatophytes combination of MAL-PDT for the nail and topical antifungal for the foot may prevent failures and recurrences.

Abbreviations AK Actinic KeratosisBCC Basal Cell Carcinoma (s=superficial; n=nodular)C-PDT Conventional PDTCR Complete ResponseDL-PDT Daylight mediated PDTLED Light-Emitting DiodeMAL Methyl aminolevulinateMF Mycosis fungoidesMRSA Methicillin-resistant Staphylococcus aureusNMSC Non-Melanoma Skin CancerNS Not significantOTR Organ Transplant RecipientPDT Photodynamic TherapyPpIX Protoporphyrin IXPR Partial responseSD Standard deviation

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Euro PDT 2014 highlights