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 fluo- rouracil 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 (REPRINTED) ARCH DERMATOL/ VOL 142, JUNE 2006 WWW.ARCHDERMATOL.COM 729 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 229 Randomized 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, (REPRINTED) ARCH DERMATOL/ VOL 142, JUNE 2006 WWW.ARCHDERMATOL.COM 730 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Patient and Lesion Characteristics at Baseline, All Patients Treated 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.