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

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

Figure 2.
Estimated sustained lesion complete response (CR) rate over time, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Estimated sustained lesion complete response (CR) rate over time, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Figure 3.
Comparison of overall cosmetic outcome at 3 and 12 months, as assessed by the on-site investigator, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Comparison of overall cosmetic outcome at 3 and 12 months, as assessed by the on-site investigator, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Figure 4.
Overall cosmetic outcome at 3 months, as assessed by the on-site investigator and by the blinded independent reviewer, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Overall cosmetic outcome at 3 months, as assessed by the on-site investigator and by the blinded independent reviewer, per-protocol population. MAL indicates methyl aminolevulinate; PDT, photodynamic therapy.

Table 1. 
Patient and Lesion Characteristics at Baseline, All Patients Treated
Patient and Lesion Characteristics at Baseline, All Patients Treated
Table 2. 
Number of Treatments Received
Number of Treatments Received
Table 3. 
Lesion CR Rates at 3 Months and Lesion Recurrence Rate at 12 Months, Per-Protocol Population
Lesion CR Rates at 3 Months and Lesion Recurrence Rate at 12 Months, Per-Protocol Population
Table 4. 
Adverse Events, All Treated Patients
Adverse Events, All Treated Patients
1.
Slaper  HVelders  GJMDaniel  JSde Gruijl  FRvan der Leun  JC Estimates of ozone depletion and skin cancer incidence to examine the Vienna Convention achievements. Nature 1996;384256- 258
PubMedArticle
2.
Scott  JFears  TR Incidence of Non-melanoma Skin Cancer in the United States.  Washington, DC National Institutes of Health1981;NIH publication 82-2433
3.
Green  ABattistutta  DHart  VLeslie  DWeedon  DNambour Study Group, Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. Am J Epidemiol 1996;1441034- 1040
PubMedArticle
4.
Marks  R The epidemiology of non-melanoma skin cancer: who, why and what can we do about it. J Dermatol 1995;22853- 857
PubMed
5.
Cox  NH Body site distribution of Bowen's disease. Br J Dermatol 1994;130714- 716
PubMedArticle
6.
Kao  GF Carcinoma arising in Bowen's disease. Arch Dermatol 1986;1221124- 1126
PubMedArticle
7.
Cox  NHEedy  DJMorton  CA Guidelines for the management of Bowen's disease. Br J Dermatol 1999;141633- 641
PubMedArticle
8.
Ahmed  IBerth-Jones  JCharles-Holmes  SO’Callaghan  CJIlchyshyn  A Comparison of cryotherapy with curettage in the treatment of Bowen's disease: a prospective study. Br J Dermatol 2000;143759- 766
PubMedArticle
9.
Hsi  RARosenthal  DIGlatstein  E Photodynamic therapy in the treatment of cancer. Drugs 1999;57725- 734
PubMedArticle
10.
Rhodes  LEde Rie  MEnström  Y  et al.  Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol 2004;14017- 23
PubMed
11.
Horn  MWolf  OWulf  HC  et al.  Topical methyl aminolevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 2003;1491242- 1249
PubMedArticle
12.
Basset-Seguin  NIbbotson  SEmtestam  L  et al.  MAL-PDT vs cryotherapy in primary sBCC: results of 48-month follow up. J Eur Acad Dermatol Venereol 2005;19 ((suppl 2)) 237
13.
Vinciullo  CElliott  TFrancis  K  et al.  Photodynamic therapy with topical methyl aminolaevulinate for difficult-to-treat basal cell carcinoma. Br J Dermatol 2005;152765- 772
PubMedArticle
14.
Freeman  MVinciullo  CFrancis  D  et al.  A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix®) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003;1499- 106
PubMedArticle
15.
Pariser  DMLowe  NJStewart  DM  et al.  Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003;48227- 232
PubMedArticle
16.
Guo  SWLin  DY Regression analysis of multivariate grouped survival data. Biometrics 1994;50632- 639
PubMedArticle
17.
Prentice  RLGloeckler  LA Regression analysis of grouped survival data with applications to breast cancer data. Biometrics 1978;3457- 67
PubMedArticle
18.
Kossard  SRosen  R Cutaneous Bowen's disease: an analysis of 1001 cases according to age, sex, and site. J Am Acad Dermatol 1992;27406- 410
PubMedArticle
19.
Thestrup-Pedersen  KRavnborg  LReymann  F Morbus Bowen: a description of the disease in 617 patients. Acta Derm Venereol 1988;68236- 239
PubMed
Study
June 2006

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

Author Affiliations

Author Affiliations: Forth Valley Dermatology Centre, Stirling Royal Infirmary, Stirling, Scotland (Drs Morton and Leman); Medical University Graz, Graz, Austria (Drs Horn and Wolf); Center Hospitalier Universitaire, Caen, France (Dr Tack); Hôpital Dupuytren, Limoges, France (Dr Bedane); St Radboud University Hospital, Nijmegen, the Netherlands (Dr Tjioe); Ninewells Hospital, Dundee, Scotland (Dr Ibbotson); and Hôpital de l’Archet, Nice, France (Dr Khemis).

Arch Dermatol. 2006;142(6):729-735. doi:10.1001/archderm.142.6.729
Abstract

Objective  To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ.

Design  Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment.

Setting  Forty outpatient dermatology centers in 11 European countries.

Patients  Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression.

Interventions  Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated.

Main Outcome Measures  Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale).

Results  At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months.

Conclusion  Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.

Nonmelanoma skin cancer, including intraepithelial squamous cell carcinoma (SCC in situ), is the most common cancer in white persons, particularly in northwestern Europe,1 the United States,2 and Australia,3 and the incidence continues torise.4 Squamous cell carcinoma in situ is especially common in elderly patients, typically occurring on the lower part of the legs.5 The condition is associated with a small risk of progression (about 3%).6

Current treatment guidelines7 suggest that the available treatment options (including cryotherapy, curettage, excision, and topical fluorouracil) are broadly similar in efficacy, with recurrence rates of about 5% to 10% at 12 months. However, cryotherapy can be painful (up to 10-fold higher risk of pain than with curettage8), which may limit treatment of multiple lesions, and healing, particularly of large lesions, can be slow (up to 3 months8). Topical fluorouracil can require prolonged treatment and typically causes local irritation.7

Photodynamic therapy (PDT) is a noninvasive and precisely directed treatment that offers promise in this indication. The procedure involves activation of a photosensitizing agent by visible light, with subsequent release of reactive oxygen species, especially singlet oxygen, which in turn produces local tissue destruction.9 The aim of this study was to investigate PDT using topical methyl aminolevulinate, already shown to be effective in the treatment of basal cell carcinoma1013 and actinic keratoses,14,15 as a treatment for SCC in situ.

METHODS
PATIENTS

Patients 18 years or older with histologically confirmed diagnosis of SCC in situ from a biopsy specimen taken within 5 months, and with no evidence of any change in appearance suggestive of lesion progression, were enrolled in 40 hospital outpatient dermatology clinics in 11 European countries. Lesions that had been treated within the previous 3 months or that were strongly pigmented, less than 6 mm or more than 40 mm in diameter, or located on the genitalia were excluded. The study was approved by the ethics committee responsible for each center, and all patients gave written informed consent.

PROCEDURES

Eligible patients were randomized to PDT with topical methyl aminolevulinate cream, 160 mg/g (Metvix; PhotoCure ASA, Oslo, Norway/Galderma SA, Paris, France), or matching placebo cream in a double-blinded fashion, or standard therapy chosen by the treating investigator (cryotherapy or fluorouracil).

TREATMENTS

Before application of methyl aminolevulinate or placebo cream, the lesions were prepared by gentle surface debridement with a curette. Methyl aminolevulinate PDT was performed as previously described.10,11,1315 Briefly, the cream was applied to the lesions for 3 hours, then washed off with 0.9% saline solution before illumination with noncoherent red light (CureLight lamp, PhotoCure ASA; wavelength, 570-670 nm; light dose, 75 J/cm2). Patients wore protective eyewear when lesions close to the eyes were treated. Treatment was repeated once after 1 week for a complete treatment cycle.

Cryotherapy was performed with a handheld liquid nitrogen spray, using a single freeze/thaw cycle. After an initial ice field formation with a 2-mm rim of clinically healthy tissue, the ice field was maintained for a minimum of 20 seconds. Topical 5% fluorouracil cream (Efudix; Valeant Pharmaceuticals International, Basingstoke, England;) was applied for 4 weeks, once daily during the first week and twice daily thereafter. Patients attended the clinic at weeks 0, 1, and 4, and completed a diary noting the date and time of each application of cream. In each group, lesions with a partial response (described in the next section) at 12 weeks were retreated.

RESPONSE EVALUATION

Clinical lesion response was assessed as complete (complete disappearance of a lesion), partial (reduction in lesion size ≥25% and <100%), or none (<25% reduction or an increase in size). Response was followed up at 3 and 12 months after the last treatment. Cosmetic outcome was assessed by the treating investigator for all patients in whom all lesions had responded completely by means of a 4-point scale (excellent, good, fair, or poor) based on the presence of signs and symptoms including scarring, atrophy, change in pigmentation, redness, and fibrosis. In addition, cosmetic outcome was assessed from photographs taken before and after treatment by an independent observer who was blinded to the nature of the study treatment. Adverse events were noted at each visit, together with their severity, duration, and need for additional therapy.

STATISTICAL ANALYSIS

Assuming that the patient complete response rate with methyl aminolevulinate PDT and standard therapy (cryotherapy or fluorouracil) was 85%, at least 90 patients were required in each active treatment group (methyl aminolevulinate PDT and standard therapy) to be able to show with an α of 5% and a power of 90% that methyl aminolevulinate PDT was no more than 15% inferior to standard therapy. In addition, assuming that the patient complete response rate with placebo PDT was 35%, at least 15 patients were required in this group (α, 5%; power, 90%).

Efficacy analyses were based on the per-protocol population, excluding patients in whom the diagnosis of SCC in situ was not confirmed or who received less than 50% of fluorouracil medication and only 1 treatment in the first PDT cycle, and patients or lesions with missing response assessment at 3 months. The complete lesion response rate was analyzed by a time-to-failure approach.16 For lesions that did not respond completely at 3 months, failure time was recorded as 3 months, and for lesions recurrent at the 12-month assessment, the failure time was 12 months. Factors of influence were analyzed by means of a complementary log-log model and logistic regression model with maximum lesion diameter as the covariate.17 The odds ratio for complete response (methyl aminolevulinate PDT vs standard therapy) and the corresponding 95% confidence interval (CI) were calculated by the method proposed by Guo and Lin.16 Cosmetic outcome was summarized with 95% CI, with the use of Clopper-Pearson CI for the rates.

RESULTS

Of 229 patients enrolled in the study, 225 had at least 1 lesion treated; 96 (43%) with 124 lesions were treated with methyl aminolevulinate PDT, 17 (8%) with 24 lesions were treated with placebo PDT, 82 (36%) with 91 lesions were treated with cryotherapy, and 30 (13%) with 36 lesions were treated with topical fluorouracil. Four randomized patients were not treated: 3 patients allocated to methyl aminolevulinate PDT (2 withdrew consent and 1 had a spontaneous remission) and 1 patient allocated to fluorouracil who was unavailable for follow-up.

Patient disposition is summarized in Figure 1. Sixteen patients were excluded from the per-protocol population: 5 treated with methyl aminolevulinate PDT, 2 with placebo PDT, 5 with cryotherapy, and 4 with fluorouracil. In total, 31 lesions were excluded from the per-protocol population: 13 treated with methyl aminolevulinate PDT, 5 with placebo PDT, 6 with cryotherapy, and 7 with fluorouracil. Patient and lesion characteristics of the 4 treatment groups were similar (Table 1).

Treatment was administered as per protocol, with a mean illumination time of 10 minutes 37 seconds and mean light dose of 75 J/cm2 (methyl aminolevulinate PDT), mean total freezing time of 25 seconds (cryotherapy), and mean number of fluorouracil applications of 42 and 45 in the first and second treatment periods, respectively. Most lesions were treated with 1 methyl aminolevulinate PDT treatment cycle (84%), 1 cryotherapy session (71%), and 1 fluorouracil treatment period (72%) (Table 2).

LESION COMPLETE RESPONSE RATES

The clinically verified complete response rate of lesions 3 months after last treatment was 93% (103/111) in the methyl aminolevulinate PDT group, 21% (4/19) in the placebo PDT group, 86% (73/85) in the cryotherapy group, and 83% (24/29) in the fluorouracil group (Table 3). The estimated sustained complete response rate of lesions at 12 months was 80% in the methyl aminolevulinate PDT group, 67% in the cryotherapy group, and 69% in the fluorouracil group (Figure 2), with a statistically significant difference between methyl aminolevulinate PDT and the combined standard therapy group (odds ratio, 1.73; 95% CI, 1.03-2.93, P = .04). The odds for a lesion to be in complete response after 12 months were 73% higher in the methyl aminolevulinate PDT group than in the standard therapy group. On further analysis, methyl aminolevulinate PDT was significantly different from cryotherapy (odds ratio, 1.77; 95% CI, 1.01-3.12; P = .047), although methyl aminolevulinate PDT and fluorouracil did not differ significantly (odds ratio, 1.64; 95% CI, 0.78-3.45; P = .19).Maximum lesion diameter at baseline had a statistically significant influence on the lesion complete response rate in all treatment groups (P<.001). Overall, the estimated sustained lesion complete response rates 12 months after last active treatment by diameter were 82% in lesions up to 14 mm, 77% in lesions 15 to 19 mm, 71% in lesions 20 to 29 mm, and 55% in lesions 30 mm or larger. Lesion response seemed to be independent of lesion location.

Lesion recurrence rates 12 months after the last treatment were 15% (15/103) in the methyl aminolevulinate PDT group, 50% (2/4) in the placebo PDT group, 21% (15/73) in the cryotherapy group, and 17% (4/24) in the fluorouracil group (Table 3).

COSMETIC OUTCOME

Cosmetic outcome (on-site evaluation) at 3 months was clearly superior with methyl aminolevulinate PDT compared with either cryotherapy or fluorouracil, with a good or excellent outcome in 94% (77/82) (95% CI, 86%-98%) of patients treated with methyl aminolevulinate PDT vs 66% (43/65) (95% CI, 53%-77%) treated with cryotherapy and 76% (16/21) (95% CI, 53%-92%) treated with fluorouracil; and this was maintained for 12 months (Figure 3). Blinded reading of cosmetic outcome showed a high degree of concordance between the evaluation made by the investigator and the independent reviewer (Figure 4).

SAFETY

Local adverse events were commonly reported in each treatment group (Table 4). Most treatment-related local events reported with methyl aminolevulinate PDT were mild (60%) or moderate (34%), and only 6% were regarded as severe. By comparison, 12% of related local events with cryotherapy were severe.

Serious adverse events (including 4 deaths) were reported for 9 patients: 4 treated with methyl aminolevulinate PDT, 2 with placebo, and 3 with cryotherapy. With the exception of lymphangitis and skin necrosis reported for 1 patient in the cryotherapy group, these events were considered by the investigator as related to preexisting conditions and not related to treatment. Three patients, 2 in the methyl aminolevulinate PDT group (bleeding skin with aggravated cough; skin pain and malaise) and 1 in the fluorouracil group (skin ulceration), discontinued treatment because of suspected treatment-related adverse events.

COMMENT

Until now, there have been few well-designed, controlled randomized studies of SCC in situ, with current treatment guidelines7 predominantly based on limited data 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 SCC in situ, with sustained lesion response rates at 12 months significantly higher than those for cryotherapy and higher (although not statistically so) than those for fluorouracil (80% vs 67% and 69%). Methyl aminolevulinate PDT was at least as effective as standard therapy for larger lesions. Topical methyl aminolevulinate PDT also gave a superior cosmetic outcome compared with both cryotherapy and topical fluorouracil, an important clinical advantage given that, as most patients with SCC in situ are elderly, with lesions typically on the lower extremities5,18,19 (57%-69% of lesions were on the extremities in this study), healing and hence optimal cosmesis can be compromised. The profile of local adverse events with methyl aminolevulinate PDT observed in the current study was consistent with that previously reported.1015

Methyl aminolevulinate PDT is a relatively simple noninvasive procedure that permits treatment of multiple lesions during 1 session (with the option to safely repeat treatment if required), which has practical advantages, particularly in elderly patients unwilling to undergo invasive procedures. Although follow-up to 24 months is still continuing, the high clearance rate with methyl aminolevulinate PDT at 3 months, which was sustained at 12 months, together with favorable cosmetic outcome and safety profile, indicates that methyl aminolevulinate PDT is a promising treatment alternative that warrants consideration in the clinical management of SCC in situ.

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Article Information

Correspondence: Colin Morton, MD, Forth Valley Dermatology Centre, Stirling Royal Infirmary, Livilands Gate, Stirling, Scotland FK8 2AU.

Financial Disclosure: Dr Morton has received financial support from Galderma, PhotoCure ASA, Phototherapeutics UK, and Schering AG for performing clinical trials.

Previous Presentation: Interim results of this study (not final data as reported herein) were presented at the annual general meeting of the British Association of Dermatology Meeting; July 7, 2004; Belfast, Northern Ireland.

Accepted for Publication: January 17, 2006.

Author Contributions:Study concept and design: Morton. Acquisition of data: Morton, Horn, Leman, Tack, Bedane, Tjioe, Ibbotson, Khemis, and Wolf. Analysis and interpretation of data: Morton, Horn, Leman, Tack, Bedane, Tjioe, Ibbotson, Khemis, and Wolf. Drafting of the manuscript: Morton. Critical revision of the manuscript for important intellectual content: Morton, Horn, Leman, Tack, Bedane, Tjioe, Ibbotson, Khemis, and Wolf. Statistical analysis: Morton and Wolf. Obtained funding: Morton. Administrative, technical, and material support: Morton, Horn, Leman, Tack, Bedane, Tjioe, Ibbotson, Khemis, and Wolf. Study supervision: Morton, Horn, Tack, Bedane, Ibbotson, Khemis, and Wolf.

Funding/Support: This study was supported by PhotoCure ASA, which paid the recruiting centers to cover study costs and helped obtain funding.

Role of the Sponsors: PhotoCure ASA and Parexel Medstat Research AS, participated in study concept and design; Parexel GmbH participated in statistical analysis; and Smerud Medical Research ASA participated in study supervision.

Acknowledgment: Other investigators who enrolled subjects in the study were as follows: Finland: A. Laukkanen, MD, Kuopio University Hospital, Kuopio; A. Oikarinen, MD, Oulu University Hospital, Oulu; T. Reunala, MD, Tampere University Hospital, Tampere; and O. Saksela, MD, University Central Hospital, Helsinki. France: N. Basset-Séguin, MD, St Louis Hospital, Paris;J. C. Beani, MD, CHU Michallon, Grenoble; A. Claudy, MD, CHU Edouard Hérriot, Lyon; M. Delaunay, MD, Hôpital Saint-Andrè, Bordeaux; B. Dreno, MD, CHU Hotel-Dieu, Nantes; L. Thomas, MD, Hôpital Hotel-Dieu, Lyon; and P. Thomas, MD, CHU Claude Huriez, Lille. Germany: C. Beier, MD, Göethe Universität, Frankfurt; H. Fesq, MD, Dermatologische Klinik der TU München, München; K. Gardlo, MD, Heinrich-Heine Universität, Düsseldorf; and P. Lehmann, MD, Klinik für Dermatologie, Allergologie und Umweltsmedizin, Wuppertal. Norway: J. Ø. Holm, MD, Ullevål Sykehus, Oslo; T. Morken, MD, Haukeland Sykehus, Bergen; and J. Rønnevig, MD, Rikshospitalet, Oslo. Switzerland: L. Braathen, MD, Inselspital, Bern, and R. Dummer, MD, Universitätsspital, Zürich. Sweden: M. Maroti, MD, Länsjukhuset Ryhov, Jönköping. United Kingdom: R. Azurdia, MD, Royal Liverpool and Broadgreen University Hospitals, Liverpool, England; N. Cox, MD, Cumberland Infirmary, Carlisle, England; A. Y. Finlay, MD, University of Wales College of Medicine, Cardiff, Wales; and R. Groves, MD, Chelsea and Westminster Hospital, London, England. We thank Eckart Haneke, MD, for performing blinded assessment of cosmetic outcome.

References
1.
Slaper  HVelders  GJMDaniel  JSde Gruijl  FRvan der Leun  JC Estimates of ozone depletion and skin cancer incidence to examine the Vienna Convention achievements. Nature 1996;384256- 258
PubMedArticle
2.
Scott  JFears  TR Incidence of Non-melanoma Skin Cancer in the United States.  Washington, DC National Institutes of Health1981;NIH publication 82-2433
3.
Green  ABattistutta  DHart  VLeslie  DWeedon  DNambour Study Group, Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. Am J Epidemiol 1996;1441034- 1040
PubMedArticle
4.
Marks  R The epidemiology of non-melanoma skin cancer: who, why and what can we do about it. J Dermatol 1995;22853- 857
PubMed
5.
Cox  NH Body site distribution of Bowen's disease. Br J Dermatol 1994;130714- 716
PubMedArticle
6.
Kao  GF Carcinoma arising in Bowen's disease. Arch Dermatol 1986;1221124- 1126
PubMedArticle
7.
Cox  NHEedy  DJMorton  CA Guidelines for the management of Bowen's disease. Br J Dermatol 1999;141633- 641
PubMedArticle
8.
Ahmed  IBerth-Jones  JCharles-Holmes  SO’Callaghan  CJIlchyshyn  A Comparison of cryotherapy with curettage in the treatment of Bowen's disease: a prospective study. Br J Dermatol 2000;143759- 766
PubMedArticle
9.
Hsi  RARosenthal  DIGlatstein  E Photodynamic therapy in the treatment of cancer. Drugs 1999;57725- 734
PubMedArticle
10.
Rhodes  LEde Rie  MEnström  Y  et al.  Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol 2004;14017- 23
PubMed
11.
Horn  MWolf  OWulf  HC  et al.  Topical methyl aminolevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 2003;1491242- 1249
PubMedArticle
12.
Basset-Seguin  NIbbotson  SEmtestam  L  et al.  MAL-PDT vs cryotherapy in primary sBCC: results of 48-month follow up. J Eur Acad Dermatol Venereol 2005;19 ((suppl 2)) 237
13.
Vinciullo  CElliott  TFrancis  K  et al.  Photodynamic therapy with topical methyl aminolaevulinate for difficult-to-treat basal cell carcinoma. Br J Dermatol 2005;152765- 772
PubMedArticle
14.
Freeman  MVinciullo  CFrancis  D  et al.  A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix®) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003;1499- 106
PubMedArticle
15.
Pariser  DMLowe  NJStewart  DM  et al.  Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003;48227- 232
PubMedArticle
16.
Guo  SWLin  DY Regression analysis of multivariate grouped survival data. Biometrics 1994;50632- 639
PubMedArticle
17.
Prentice  RLGloeckler  LA Regression analysis of grouped survival data with applications to breast cancer data. Biometrics 1978;3457- 67
PubMedArticle
18.
Kossard  SRosen  R Cutaneous Bowen's disease: an analysis of 1001 cases according to age, sex, and site. J Am Acad Dermatol 1992;27406- 410
PubMedArticle
19.
Thestrup-Pedersen  KRavnborg  LReymann  F Morbus Bowen: a description of the disease in 617 patients. Acta Derm Venereol 1988;68236- 239
PubMed
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