Comparison of Topical Methyl Aminolevulinate Photodynamic Therapy with Cryotherapy Or Fluorouracil for Treatment of Squamous

Home , Methyl aminolevulinate

STUDY Comparison of Topical Methyl Aminolevulinate Photodynamic Therapy With Cryotherapy or Fluorouracil for Treatment of Squamous Cell Carcinoma In Situ Results of a Multicenter Randomized Trial

Colin Morton, MD; Michael Horn, MD; Joyce Leman, MD; Brigitte Tack, MD; Christophe Bedane, MD; Milan Tjioe, MD; Sally Ibbotson, MD; Abdallah Khemis, MD; Peter Wolf, MD

Objective: To compare the efficacy, tolerability, and cos- weeks. Lesions with a partial response at 3 months were metic outcome of photodynamic therapy (PDT) using topi- re-treated. cal methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ. Main Outcome Measures: Clinically verified complete response of lesions; blinded and on-site Design: Randomized, placebo-controlled study, with assessment of cosmetic outcome (4-point rating scale). follow-up at 3 and 12 months after last treatment. Results: At 12 months, the estimated sustained lesion Setting: Forty outpatient dermatology centers in 11 complete response rate with methyl aminolevulinate PDT European countries. was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P=.047), Patients: Random sample of 225 patients with histo- and better than that with fluorouracil (80% vs 69%; odds logically confirmed squamous cell carcinoma in situ ratio, 1.64; 95% confidence interval, 0.78-3.45; P=.19). (lesion size, 6-40 mm) and no evidence of progression. Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT Interventions: Treatment with PDT with methyl ami- vs 66% with cryotherapy and 76% with fluorouracil, and nolevulinate (160 mg/g; n=96) or matching placebo cream was maintained at 12 months. (n=17), cryotherapy (n=82), or topical fluorouracil (5% cream; n=30). Methyl aminolevulinate or placebo cream Conclusion: Methyl aminolevulinate PDT is an effec- was applied for 3 hours before illumination with broad- tive treatment option for squamous cell carcinoma in situ, band red light (75 J/cm2, 570-670 nm). Treatment was with excellent cosmesis. repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 Arch Dermatol. 2006;142:729-735

ONMELANOMA SKIN CAN- Current treatment guidelines7 suggest cer, including intraepi- that the available treatment options thelial squamous cell car- (including cryotherapy, curettage, exci- Author Affiliations: Forth cinoma (SCC in situ), is sion, and topical fluorouracil) are broadly Valley Dermatology Centre, the most common can- similar in efficacy, with recurrence rates of Stirling Royal Infirmary, Stirling, Scotland (Drs Morton cer in white persons, particularly in north- about 5% to 10% at 12 months. However, N 1 2 and Leman); Medical University western Europe, the United States, and cryotherapy can be painful (up to 10-fold Graz, Graz, Austria (Drs Horn and Wolf); Center Hospitalier See also page 755 Universitaire, Caen, France CME course available at (Dr Tack); Hoˆpital Dupuytren, www.archdermatol.com higher risk of pain than with curettage8), Limoges, France (Dr Bedane); which may limit treatment of multiple St Radboud University Hospital, Australia,3 and the incidence continues to lesions, and healing, particularly of large le- Nijmegen, the Netherlands 4 sions, can be slow (up to 3 months8). Topi- (Dr Tjioe); Ninewells Hospital, rise. Squamous cell carcinoma in situ is especially common in elderly patients, cal fluorouracil can require prolonged treat- Dundee, Scotland 7 (Dr Ibbotson); and Hoˆpital typically occurring on the lower part of the ment and typically causes local irritation. de l’Archet, Nice, France legs.5 The condition is associated with a Photodynamic therapy (PDT) is a non- (Dr Khemis). small risk of progression (about 3%).6 invasiveandpreciselydirectedtreatmentthat

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MAL PDT Placebo PDT Cryotherapy Fluorouracil 96 Treated 17 Treated 82 Treated 30 Treated 3 Not Treated 0 Not Treated 0 Not Treated 1 Not Treated 2 Consent Withdrawn 1 Lost to Follow-up 1 Spontaneous Remission

MAL PDT Placebo PDT Cryotherapy Fluorouracil 4 Discontinued 2 Discontinued 4 Discontinued 1 Discontinued 1 Consent Withdrawn 1 Lost to Follow-up 2 Lost to Follow-up 1 Adverse Event 3 Adverse Events 1 Adverse Event 1 Adverse Event 1 Other Reason

MAL PDT Placebo PDT Cryotherapy Fluorouracil 91 PP Analysis 15 PP Analysis 77 PP Analysis 26 PP Analysis 1 Missing 3-mo Assessment 1 Diagnosis Not Confirmed 3 With Fluorouracil Applied for <50% Planned

Figure 1. Disposition of patients in the study. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy; and PP, per protocol.

offers promise in this indication. The procedure involves ac- Cryotherapy was performed with a handheld liquid nitro- tivation of a photosensitizing agent by visible light, with sub- gen spray, using a single freeze/thaw cycle. After an initial ice sequent release of reactive oxygen species, especially singlet field formation with a 2-mm rim of clinically healthy tissue, oxygen, which in turn produces local tissue destruction.9 the ice field was maintained for a minimum of 20 seconds. Topi- The aim of this study was to investigate PDT using topical cal 5% fluorouracil cream (Efudix; Valeant Pharmaceuticals In- ternational, Basingstoke, England;) was applied for 4 weeks, methyl aminolevulinate, already shown to be effective in the 10-13 14,15 once daily during the first week and twice daily thereafter. Pa- treatmentofbasalcellcarcinoma andactinickeratoses, tients attended the clinic at weeks 0, 1, and 4, and completed as a treatment for SCC in situ. a diary noting the date and time of each application of cream. In each group, lesions with a partial response (described in the METHODS next section) at 12 weeks were retreated.

PATIENTS RESPONSE EVALUATION

Patients 18 years or older with histologically confirmed diag- Clinical lesion response was assessed as complete (complete nosis of SCC in situ from a biopsy specimen taken within 5 disappearance of a lesion), partial (reduction in lesion size Ն25% months, and with no evidence of any change in appearance sug- and Ͻ100%), or none (Ͻ25% reduction or an increase in size). gestive of lesion progression, were enrolled in 40 hospital out- Response was followed up at 3 and 12 months after the last treat- patient dermatology clinics in 11 European countries. Lesions ment. Cosmetic outcome was assessed by the treating investi- that had been treated within the previous 3 months or that were gator for all patients in whom all lesions had responded com- strongly pigmented, less than 6 mm or more than 40 mm in pletely by means of a 4-point scale (excellent, good, fair, or poor) diameter, or located on the genitalia were excluded. The study based on the presence of signs and symptoms including scar- was approved by the ethics committee responsible for each cen- ring, atrophy, change in pigmentation, redness, and fibrosis. ter, and all patients gave written informed consent. In addition, cosmetic outcome was assessed from photo- graphs taken before and after treatment by an independent ob- PROCEDURES server who was blinded to the nature of the study treatment. Adverse events were noted at each visit, together with their se- Eligible patients were randomized to PDT with topical methyl verity, duration, and need for additional therapy. aminolevulinate cream, 160 mg/g (Metvix; PhotoCure ASA, Oslo, Norway/Galderma SA, Paris, France), or matching placebo cream STATISTICAL ANALYSIS in a double-blinded fashion, or standard therapy chosen by the treating investigator (cryotherapy or fluorouracil). Assuming that the patient complete response rate with methyl aminolevulinate PDT and standard therapy (cryotherapy or fluo- TREATMENTS rouracil) was 85%, at least 90 patients were required in each active treatment group (methyl aminolevulinate PDT and stan- Before application of methyl aminolevulinate or placebo cream, dard therapy) to be able to show with an ␣ of 5% and a power the lesions were prepared by gentle surface debridement with a cu- of 90% that methyl aminolevulinate PDT was no more than 15% rette. Methyl aminolevulinate PDT was performed as previously inferior to standard therapy. In addition, assuming that the pa- described.10,11,13-15 Briefly, the cream was applied to the lesions for tient complete response rate with placebo PDT was 35%, at least 3 hours, then washed off with 0.9% saline solution before illumi- 15 patients were required in this group (␣, 5%; power, 90%). nation with noncoherent red light (CureLight lamp, PhotoCure Efficacy analyses were based on the per-protocol popula- ASA; wavelength, 570-670 nm; light dose, 75 J/cm2). Patients wore tion, excluding patients in whom the diagnosis of SCC in situ protectiveeyewearwhenlesionsclosetotheeyesweretreated.Treat- was not confirmed or who received less than 50% of fluoro- ment was repeated once after 1 week for a complete treatment cycle. uracil medication and only 1 treatment in the first PDT cycle,

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MAL PDT Placebo PDT Cryotherapy Topical Fluorouracil (n = 96) (n = 17) (n = 82) (n = 30) Sex, M:F, No. (%) 36:60 (38:62) 6:11 (35:65) 34:48 (41:59) 11:19 (37:63) Age, mean (range), y 71.9 (43-89) 73.4 (53-88) 74.0 (45-99) 72.5 (39-86) Race, No. (%) white 68 (71) 14 (82) 56 (68) 20 (67) Skin type (Fitzpatrick score), No. (%)* I 10 (10) 4 (24) 3 (4) 6 (20) II 45 (47) 9 (53) 40 (49) 11 (37) III 36 (38) 3 (18) 32 (39) 12 (40) IV/V 5 (5) 1 (6) 7 (9) 1 (3) Total No. of lesions 124 24 91 36 No. of lesions per patient, No. (%)* 1 81 (84) 13 (76) 77 (94) 26 (87) 2 8 (8) 2 (12) 2 (2) 2 (7) Ն3 7 (7) 2 (12) 3 (4) 2 (7) Largest lesion diameter, mean (range), mm 18.9 (5-40) 19.3 (8-40) 19.4 (6-45) 20.9 (9-37) Lesion size, No. (%), mm* 5-14 48 (39) 8 (33) 27 (30) 8 (22) 15-29 54 (44) 12 (50) 52 (57) 20 (56) Ն30 22 (18) 4 (17) 11 (12) 8 (22) Missing 0 0 1 (1) 0 Lesion location, No. (%)* Face, scalp 29 (23) 6 (25) 26 (29) 7 (19) Neck, trunk 15 (12) 2 (8) 13 (14) 4 (11) Extremities 80 (65) 16 (67) 52 (57) 25 (69)

Abbreviations: MAL, methyl aminolevulinate; PDT, photodynamic therapy. *Because of rounding, percentages may not all total 100.

and patients or lesions with missing response assessment at 3 7 with fluorouracil. Patient and lesion characteristics of months. The complete lesion response rate was analyzed by a the 4 treatment groups were similar (Table 1). time-to-failure approach.16 For lesions that did not respond com- Treatment was administered as per protocol, with a mean pletely at 3 months, failure time was recorded as 3 months, and illumination time of 10 minutes 37 seconds and mean light for lesions recurrent at the 12-month assessment, the failure dose of 75 J/cm2 (methyl aminolevulinate PDT), mean total time was 12 months. Factors of influence were analyzed by means of a complementary log-log model and logistic regres- freezing time of 25 seconds (cryotherapy), and mean num- sion model with maximum lesion diameter as the covariate.17 ber of fluorouracil applications of 42 and 45 in the first and The odds ratio for complete response (methyl aminolevuli- second treatment periods, respectively. Most lesions were nate PDT vs standard therapy) and the corresponding 95% con- treated with 1 methyl aminolevulinate PDT treatment cycle fidence interval (CI) were calculated by the method proposed (84%), 1 cryotherapy session (71%), and 1 fluorouracil treat- by Guo and Lin.16 Cosmetic outcome was summarized with 95% ment period (72%) (Table 2). CI, with the use of Clopper-Pearson CI for the rates. LESION COMPLETE RESPONSE RATES RESULTS The clinically verified complete response rate of lesions 3 Of 229 patients enrolled in the study, 225 had at least 1 months after last treatment was 93% (103/111) in the methyl lesion treated; 96 (43%) with 124 lesions were treated aminolevulinate PDT group, 21% (4/19) in the placebo PDT with methyl aminolevulinate PDT, 17 (8%) with 24 le- group, 86% (73/85) in the cryotherapy group, and 83% (24/ sions were treated with placebo PDT, 82 (36%) with 91 29) in the fluorouracil group (Table 3). The estimated lesions were treated with cryotherapy, and 30 (13%) with sustained complete response rate of lesions at 12 months 36 lesions were treated with topical fluorouracil. Four was 80% in the methyl aminolevulinate PDT group, 67% randomized patients were not treated: 3 patients allocated in the cryotherapy group, and 69% in the fluorouracil group to methyl aminolevulinate PDT (2 withdrew consent and (Figure 2), with a statistically significant difference be- 1 had a spontaneous remission) and 1 patient allocated to tween methyl aminolevulinate PDT and the combined stan- fluorouracil who was unavailable for follow-up. dard therapy group (odds ratio, 1.73; 95% CI, 1.03-2.93, Patient disposition is summarized in Figure 1. Six- P=.04). The odds for a lesion to be in complete response teen patients were excluded from the per-protocol popu- after 12 months were 73% higher in the methyl aminolevu- lation: 5 treated with methyl aminolevulinate PDT, 2 with linate PDT group than in the standard therapy group. On placebo PDT, 5 with cryotherapy, and 4 with fluoroura- further analysis, methyl aminolevulinate PDT was sig- cil. In total, 31 lesions were excluded from the per- nificantly different from cryotherapy (odds ratio, 1.77; protocol population: 13 treated with methyl aminolevu- 95% CI, 1.01-3.12; P=.047), although methyl ami- linate PDT, 5 with placebo PDT, 6 with cryotherapy, and nolevulinate PDT and fluorouracil did not differ signifi-

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No. (%) of Lesions No. (%) of Patients

1 Cycle* or 2 Cycles* or 1 Cycle* or 2 Cycles* or Treatment No. Treatment Period Treatment Periods No. Treatment Period Treatment Periods MAL PDT† 124 104 (84) 20 (16) 96 78 (81) 18 (19) Placebo PDT‡ 24 12 (50) 12 (50) 17 9 (53) 8 (47) Cryotherapy 91 65 (71) 26 (29) 82 62 (76) 20 (24) Topical fluorouracil 36 26 (72) 10 (28) 30 21 (70) 9 (30)

Abbreviations: MAL, methyl aminolevulinate; PDT, photodynamic therapy. *One PDT cycle was 2 treatment sessions separated by 1 week; 1 treatment period was 1 cryotherapy session or 1 period of fluorouracil chemotherapy. †Five lesions in 2 patients were treated with 1 PDT treatment, and 1 lesion in 1 patient was treated with 3 PDT treatments. ‡Six lesions in 2 patients were treated with 3 PDT treatments.

Table 3. Lesion CR Rates at 3 Months and Lesion Recurrence Rate at 12 Months, Per-Protocol Population

No. (%) of Lesions

MAL PDT Placebo PDT Cryotherapy Topical Fluorouracil Variable (n = 124) (n = 24)* (n = 91) (n = 36) Lesion CR rate at 3 mo After first treatment 81/111 (73) 4/19 (21) 58/85 (68) 20/29 (69) After last treatment 103/111 (93) 4/19 (21) 73/85 (86) 24/29 (83) Lesion recurrence rate at 12 mo 15/103 (15) 2/4 (50) 15/73 (21) 4/24 (17) Lesion CR rate after last treatment and recurrence rate by location Face/scalp Response 27/28 (96) 2/5 (40) 17/21 (81) 5/6 (83) Recurrence 2/27 (7) 1/2 (50) 6/17 (35) 0/5 (0) Neck/trunk Response 13/14 (93) 1/2 (50) 13/13 (100) 2/2 (100) Recurrence 2/13 (15) 1/1 (100) 1/13 (8) 1/2 (50) Extremities Response 63/69 (91) 1/12 (8) 43/51 (84) 17/21 (81) Recurrence 11/63 (17) 0/1 (0) 8/43 (19) 3/17 (18) Lesion CR rate after first and last treatments and lesion recurrence rate by lesion size, mm‡ 5-14 Response, first treatment 37/42 (88) 1/7 (14) 20/24 (83) 6/6 (100) Response, last treatment 40/42 (95) 1/7 (14) 21/24 (88) 6/6 (100) Recurrence 4/40 (10) 1/1 (100) 0/21 (0) 0/6 (0) 15-29 Response, first treatment 37/48 (77) 3/10 (30) 32/49 (65) 12/16 (75) Response, last treatment 43/48 (90) 3/10 (30) 43/49 (88) 12/16 (75) Recurrence 5/43 (12) 1/3 (33) 12/43 (28) 3/12 (25) Ն30 Response, first treatment 14/21 (67) 0/2 (0) 6/11 (55) 2/7 (29) Response, last treatment 20/21 (95) 0/2 (0) 8/11 (73) 6/7 (86) Recurrence 6/20 (30) 0/0 (0) 2/8 (25) 1/6 (17) Missing 0 0 1/1 (100) 0

Abbreviations: CR, complete response; MAL, methyl aminolevulinate; PDT, photodynamic therapy. *For patients treated with placebo PDT, only the evaluation after the first PDT cycle was considered, since those patients were treated with MAL PDT in the second cycle.

cantly (odds ratio, 1.64; 95% CI, 0.78-3.45; P=.19). Lesion recurrence rates 12 months after the last treat- Maximum lesion diameter at baseline had a statistically ment were 15% (15/103) in the methyl aminolevulinate significant influence on the lesion complete response PDT group, 50% (2/4) in the placebo PDT group, 21% rate in all treatment groups (PϽ.001). Overall, the esti- (15/73) in the cryotherapy group, and 17% (4/24) in the mated sustained lesion complete response rates 12 fluorouracil group (Table 3). months after last active treatment by diameter were 82% in lesions up to 14 mm, 77% in lesions 15 to 19 mm, COSMETIC OUTCOME 71% in lesions 20 to 29 mm, and 55% in lesions 30 mm or larger. Lesion response seemed to be independent of Cosmetic outcome (on-site evaluation) at 3 months was lesion location. clearly superior with methyl aminolevulinate PDT com-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 pared with either cryotherapy or fluorouracil, with a good or excellent outcome in 94% (77/82) (95% CI, 86%- 100 98%) of patients treated with methyl aminolevulinate PDT vs 66% (43/65) (95% CI, 53%-77%) treated with cryo- 75 therapy and 76% (16/21) (95% CI, 53%-92%) treated with fluorouracil; and this was maintained for 12 months 50 (Figure 3). Blinded reading of cosmetic outcome showed a high degree of concordance between the evaluation made Lesion CR Rate, % 25 MAL PDT by the investigator and the independent reviewer Fluorouracil (Figure 4). Crytherapy 0 0 1 2 3 4 5 6 7 8 9 10 11 12 SAFETY Time, mo

Local adverse events were commonly reported in each Figure 2. Estimated sustained lesion complete response (CR) rate over time, treatment group (Table 4). Most treatment-related lo- per-protocol population. MAL indicates methyl aminolevulinate; cal events reported with methyl aminolevulinate PDT were PDT, photodynamic therapy. mild (60%) or moderate (34%), and only 6% were re- garded as severe. By comparison, 12% of related local

events with cryotherapy were severe. Fair/Poor Good Excellent Serious adverse events (including 4 deaths) were reported for 9 patients: 4 treated with methyl aminolevu- MAL PDT Cryotherapy Fluorouracil linate PDT, 2 with placebo, and 3 with cryotherapy. With 100 6 3 6 the exception of lymphangitis and skin necrosis re- 90 16 24 34 ported for 1 patient in the cryotherapy group, these events 80 38 were considered by the investigator as related to preex- 34 31 70 isting conditions and not related to treatment. Three pa- 28 tients, 2 in the methyl aminolevulinate PDT group (bleed- 60 50 37 ing skin with aggravated cough; skin pain and malaise) 35 40 81 and 1 in the fluorouracil group (skin ulceration), dis- Outcome, % continued treatment because of suspected treatment- 30 60 63 48 related adverse events. 20 29 27 10 COMMENT 0 3 mo 12 mo 3 mo 12 mo 3 mo 12 mo

Until now, there have been few well-designed, con- Figure 3. Comparison of overall cosmetic outcome at 3 and 12 months, as trolled randomized studies of SCC in situ, with current assessed by the on-site investigator, per-protocol population. MAL indicates treatment guidelines7 predominantly based on limited data methyl aminolevulinate; PDT, photodynamic therapy. from open uncontrolled studies. The results of this pan- European study, the largest randomized controlled study reported to date, clearly demonstrate that topical methyl aminolevulinate PDT is an effective treatment option for Fair/Poor Good Excellent SCC in situ, with sustained lesion response rates at 12 months significantly higher than those for cryotherapy MAL PDT Cryotherapy Fluorouracil and higher (although not statistically so) than those for 100 6 11 fluorouracil (80% vs 67% and 69%). Methyl aminolevu- 90 24 24 34 linate PDT was at least as effective as standard therapy 80 34 53 for larger lesions. Topical methyl aminolevulinate PDT 70 40 also gave a superior cosmetic outcome compared with both 60 28 cryotherapy and topical fluorouracil, an important clini- 41 cal advantage given that, as most patients with SCC in situ 50 37 40 are elderly, with lesions typically on the lower extremi- Outcome, % 29 ties5,18,19 (57%-69% of lesions were on the extremities in 30 60 49 48 this study), healing and hence optimal cosmesis can be 20 35 29 compromised. The profile of local adverse events with 10 18 methyl aminolevulinate PDT observed in the current study 0 10-15 On-Site Blinded On-Site Blinded On-Site Blinded was consistent with that previously reported. Investigator Reviewer Investigator Reviewer Investigator Reviewer Methyl aminolevulinate PDT is a relatively simple noninvasive procedure that permits treatment of mul- Figure 4. Overall cosmetic outcome at 3 months, as assessed by the on-site tiple lesions during 1 session (with the option to safely investigator and by the blinded independent reviewer, per-protocol repeat treatment if required), which has practical population. MAL indicates methyl aminolevulinate; PDT, photodynamic advantages, particularly in elderly patients unwilling to therapy.

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No. (%) of Patients

MAL Placebo Placebo Topical PDT PDT ؉ MAL PDT* Cryotherapy Fluorouracil Adverse Events (n = 96) (n = 17) (n=8) (n = 82) (n = 30) Ն1 AE 60 (63) 10 (59) 4 (50) 40 (49) 23 (77) Ն1 Local AE 48 (50) 8 (47) 2 (25) 35 (43) 23 (77) Frequently reported treatment-related local AEs† Pain 19 (20) 4 (24) 2 (25) 20 (24) 10 (33) Erythema 8 (8) 2 (12) 1 (13) 8 (10) 10 (33) Burning sensation 16 (17) 3 (18) 0 6 (7) 2 (7) Crusting 8 (8) 1 (6) 2 (25) 3 (4) 4 (13) Stinging 9 (9) 1 (6) 1 (13) 1 (1) 2 (7) Application site reaction 0 0 0 6 (7) 1 (3) Irritation 3 (3) 0 0 1 (1) 4 (13) Itching 1 (1) 2 (12) 0 0 5 (17) Edema 2 (2) 0 0 5 (6) 0 Blistering 0 0 0 4 (5) 0 Hyperpigmentation 3 (3) 0 0 0 1 (3) Warmth 3 (3) 0 0 1 (1) 0

Abbreviations: AE, adverse event; MAL, methyl aminolevulinate; PDT, photodynamic therapy. *Patients in this group all received placebo PDT in the first PDT cycle. †Adverse skin reactions reported by more than 2 patients, and considered by the investigators as of uncertain or related causality.

undergo invasive procedures. Although follow-up to 24 and Smerud Medical Research ASA participated in study months is still continuing, the high clearance rate with supervision. methyl aminolevulinate PDT at 3 months, which was Previous Presentation: Interim results of this study (not sustained at 12 months, together with favorable cos- final data as reported herein) were presented at the an- metic outcome and safety profile, indicates that methyl nual general meeting of the British Association of Derma- aminolevulinate PDT is a promising treatment alterna- tology Meeting; July 7, 2004; Belfast, Northern Ireland. tive that warrants consideration in the clinical manage- Acknowledgment: Other investigators who enrolled sub- ment of SCC in situ. jects in the study were as follows: Finland: A. Laukkanen, MD, Kuopio University Hospital, Kuopio; A. Oikarinen, Accepted for Publication: January 17, 2006. MD, Oulu University Hospital, Oulu; T. Reunala, MD, Correspondence: Colin Morton, MD, Forth Valley Der- Tampere University Hospital, Tampere; and O. Saksela, matology Centre, Stirling Royal Infirmary, Livilands Gate, MD, University Central Hospital, Helsinki. France: Stirling, Scotland FK8 2AU. N. Basset-Se´guin, MD, St Louis Hospital, Paris; J. C. Beani, Author Contributions: Study concept and design: Morton. MD, CHU Michallon, Grenoble; A. Claudy, MD, CHU Ed- Acquisition of data: Morton, Horn, Leman, Tack, Bedane, ouard He´rriot, Lyon; M. Delaunay, MD, Hoˆpital Saint- Tjioe, Ibbotson, Khemis, and Wolf. Analysis and inter- Andrè, Bordeaux; B. Dreno, MD, CHU Hotel-Dieu, Nantes; pretation of data: Morton, Horn, Leman, Tack, Bedane, L. Thomas, MD, Hoˆpital Hotel-Dieu, Lyon; and Tjioe, Ibbotson, Khemis, and Wolf. Drafting of the manu- P. Thomas, MD, CHU Claude Huriez, Lille. Germany: script: Morton. Critical revision of the manuscript for im- C. Beier, MD, Go¨ethe Universita¨t, Frankfurt; H. Fesq, MD, portant intellectual content: Morton, Horn, Leman, Tack, Dermatologische Klinik der TU Mu¨ nchen, Mu¨ nchen; Bedane, Tjioe, Ibbotson, Khemis, and Wolf. Statistical K. Gardlo, MD, Heinrich-Heine Universita¨t, Du¨ ssel- analysis: Morton and Wolf. Obtained funding: Morton. Ad- dorf; and P. Lehmann, MD, Klinik fu¨ r Dermatologie, ministrative, technical, and material support: Morton, Horn, Allergologie und Umweltsmedizin, Wuppertal. Norway: Leman, Tack, Bedane, Tjioe, Ibbotson, Khemis, and Wolf. J. Ø. Holm, MD, Ulleva˚l Sykehus, Oslo; T. Morken, MD, Study supervision: Morton, Horn, Tack, Bedane, Ibbotson, Haukeland Sykehus, Bergen; and J. Rønnevig, MD, Riks- Khemis, and Wolf. hospitalet, Oslo. Switzerland: L. Braathen, MD, Inselspi- Financial Disclosure: Dr Morton has received financial tal, Bern, and R. Dummer, MD, Universita¨tsspital, Zu¨ rich. support from Galderma, PhotoCure ASA, Photothera- Sweden: M. Maroti, MD, La¨nsjukhuset Ryhov, Jo¨nko¨p- peutics UK, and Schering AG for performing clinical ing. United Kingdom: R. Azurdia, MD, Royal Liverpool trials. and Broadgreen University Hospitals, Liverpool, En- Funding/Support: This study was supported by PhotoCure gland; N. Cox, MD, Cumberland Infirmary, Carlisle, En- ASA, which paid the recruiting centers to cover study costs gland; A. Y. Finlay, MD, University of Wales College of and helped obtain funding. Medicine, Cardiff, Wales; and R. Groves, MD, Chelsea Role of the Sponsors: PhotoCure ASA and Parexel Med- and Westminster Hospital, London, England. We thank stat Research AS, participated in study concept and de- Eckart Haneke, MD, for performing blinded assessment sign; Parexel GmbH participated in statistical analysis; of cosmetic outcome.

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