Surgical Excision Versus Photodynamic Therapy and Topical 5-fluorouracil in Treatment of Bowen's Disease

Study Overview
=================
Brief Summary
-----------------
There is limited quality research on the effectiveness of treatments in Bowen's disease (BD). Patient and lesion characteristics, patient preferences and costs should be considered when choosing therapy. Surgical excision (SE), photodynamic therapy (PDT) and 5-fluorouracil (5FU) are mentioned as treatment options in guidelines. However no clear and evidence based recommendations are made in terms of effectiveness. Objective: The aim of this study is 1) to evaluate the (cost)effectiveness of 5FU and PDT compared to SE in BD and 2) to compare the effectiveness of 5FU with that of PDT. With a better understanding of the (cost)effectiveness of alternative treatment options, the investigators will supply the necessary evidence for national and international guidelines, to achieve more uniformity in treatment of BD. Study design: Randomized controlled non-inferiority multicenter trial. Study population: Patients ≥18 years, with a histological proven primary lesion of Bowen's disease, visiting Maastricht University Medical Centre, Catharina hospital Eindhoven, VieCuri MC Venlo or Zuyderland Medical Centre Heerlen. Intervention: One group undergoes SE with a 5mm safety margin followed by routine histological examination. The other group receives PDT with application of methyl aminolevulinate (MAL) cream followed by two illuminations with a one-week interval. The third group receives 5FU cream, which has to be applied by the patient twice daily for 4 weeks. Main study parameters/endpoints: The primary outcome is the proportion of patients with sustained clearance at 12 months post-treatment. Secondary outcomes are proportion of patients with clearance at 3 months, 3-year and 5-year probability of sustained clearance, cost-effectiveness, patient satisfaction, patient preferences, compliance, side effects and cosmetic outcome. Post-treatment, patients will be asked to answer a short questionnaire regarding side effects, experience with the treatment and satisfaction.

Detailed Description
-----------------
This is a multicenter randomized controlled non-inferiority trial, conducted in one academic and three non-academic hospitals. A multicenter approach (academic and non-academic centers) increases the generalizability of the study results. The study takes place at the dermatology department of Maastricht University Medical Centre (MUMC+), Catharina hospital Eindhoven, VieCuri Medical Centre Venlo and Zuyderland Medical Centre Heerlen. A non-inferiority design was chosen because although the noninvasive treatments are expected to be somewhat less effective in terms of remaining free of recurrence, there are other benefits such as higher patient satisfaction, patient preferences and better cosmetic outcome. It should be noted that BD is a noninvasive disease and recurrences can be treated with surgical excision without compromising the patient's health. After giving permission and signing the informed consent form, eligible patients will be randomly assigned to one of three treatment groups: 1) PDT, 2) 5% 5FU cream, 3) surgical excision. All interventions are part of regular care. For the treatment of BD 5% 5FU cream (Efudix®) has been approved by the European Medicines Agency (EMA). The coordinating investigator who is not blinded to the randomized treatment will prescribe the 5FU cream or give orders to plan PDT or excision and provide patients with further information. The supervising dermatologist will be blinded to treatment allocation, and will be asked to assess outcome measures such as clearance and cosmetic evaluation. Relevant baseline characteristics will be registered (e.g. prior history of skin cancer, age, gender, use of immunosuppressant medication in history, prior treatments for non-melanoma skin cancer), dermatological description of the lesion, size and localization of the lesion and the histological tumour thickness. The presence of other lesions, besides the target lesion, and their treatment will be recorded The primary outcome will be the proportion of patients with sustained clearance at 12 months follow-up after the end of treatment. Secondary outcomes will be the proportion of patients with clearance at 3 months, 3-year and 5-year probability of sustained clearance, cost-effectiveness, patient satisfaction, compliance, side effects and cosmetic outcome. Residual tumour at 3 months follow-up and recurrent tumour at 12 months follow-up is considered as treatment failure and will be treated with surgery.

Official Title
-----------------
Surgical Excision Versus Photodynamic Therapy and Topical 5-fluorouracil in Treatment of Bowen's Disease: a Multicenter Randomized Controlled Trial

Conditions
-----------------
Bowen's Disease

Intervention / Treatment
-----------------
* Drug: Methyl Aminolevulinate (Mal) for Topical Administration, 16.8%, 1 Gram
* Drug: 5Fluorouracil
* Other: Surgical excision


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥ 18 years Histologically proven primary Bowen's disease Lesions ≥ 4mm and ≤ 40mm in diameter Fitzpatrick skin type I-IV Female in child bearing potential should be using contraceptive measures, during and till 3 months post-treatment Exclusion Criteria: Bowen's Disease located at ears, periocular, nail unit or periungual tissue, nose, genital and mucous membranes High clinical suspicion of invasive SCC Interfering treatment of other (N)MSC in target area Not able to self-apply cream on lesions located on the back or other difficult to reach locations Pregnancy Breastfeeding Allergy to study drugs Genetic skin cancer disorders Not understanding Dutch language Porphyria Not able to give informed consent Immuno-compromised status Use of systemic retinoid in the past 3 months Use of immunosuppressant drugs in the past 3 months and / or at time of treatment (such as oral glucocorticoids, cytostatic, antibodies, drug acting on immunophilins, in-terferon, opioids, TNF binding proteins, MMF, biologic agents). Inhalation corticoster-oids / nasal corticosteroids are permitted.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgical excision<br>Standard surgical excision with 5 mm safety margin | Other: Surgical excision<br>* Local anesthesia with lidocain 1% (1-2ml) will be used before performing standard surgical excision with 5 mm safety margin followed by routine histological examination. The skin will be closed using cutaneous sutures, which will be removed after 1-2 weeks. The surgical excision will take place in the hospital by the treating physician<br>|
| Active Comparator: Photodynamic therapy<br>PDT with application of methyl aminolevulinate (MAL) cream followed by two illuminations with a one-week interval | Drug: Methyl Aminolevulinate (Mal) for Topical Administration, 16.8%, 1 Gram<br>* A layer of methylaminolevulinc acid 160 mg/g cream (about 1 mm thick) is applied to the lesion, with a clinical margin of 5-10 mm surrounding of normal skin and then covered by an occlusive dressing. After 3 hours the occlusive dressing will be removed and the area is illuminated with Omnilux or Actilite (Galderma). After PDT the treatment site is covered again with the above mentioned occlusive dressings during 48 hours. Treatment is performed by an authorized nurse in the hospital. Two sessions should be administered with an interval of one week between sessions.<br>* Other names: Metvix;|
| Active Comparator: 5% 5-Fluorouracil<br>5FU cream, which has to be applied by the patient twice daily for 4 weeks. | Drug: 5Fluorouracil<br>* 5-FU is applied on the treatment area by the patient in a thin layer twice daily during 4 weeks.<br>* Other names: Efudix;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained clearance (no residue, recurrence nor progression) | The main study endpoint is the proportion of patients with sustained clearance (no residue, recurrence nor progression) 12 months post-treatment. | 12 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the proportion of patients with clearance at 3 months post-treatment, 3-year and 5-year probability of sustained clearance, cost-effectiveness, patient satisfaction, patient preferences, compliance, side effects and cosmetic outcome. | the proportion of patients with clearance at 3 months post-treatment, 3-year and 5-year probability of sustained clearance, cost-effectiveness, patient satisfaction, patient preferences, compliance, side effects and cosmetic outcome. | 3 months, 3-years and 5- years post-treatment |