Surgical excision versus photodynamic therapy and topical 5-fluorouracil in treatment of Bowen*s disease: a multicenter randomized controlled trial

The incidence of non-melanoma skin cancer increases with basal cell carcinoma
(BCC) and squamous cell carcinoma (SCC) being the most common types.1 Bowen*s
disease (BD), an intra-epidermal SCC in situ, has an incidence of
14.9-27.8/100,000 in North America. 2-4 Although BD is not invasive, treatment
is aimed at decreasing any progression risk into invasive SCC.
There are multiple treatment options for BD, such as surgical excision (SE),
(photodynamic therapy (PDT) and 5-fluorouracil cream (5FU). SE is most commonly
used and very effective. Observational studies showed sustained clearance at 1
year of 95% or higher. The major advantage of SE is histological evaluation to
rule out an invasive component and assess the completeness of excision.
Disadvantages are risk of a complication (bleeding, infection, pain), stress of
the procedure and the development of a scar. Non-invasive treatments as
photodynamic therapy (PDT) and 5-fluorouracil cream (5FU) are both recognized
as acceptable alternative treatment options for surgery in international
guidelines. The opportunity of treating multiple lesions at once and a good
cosmetic result are important benefits of both treatments.
There is no consensus on the most optimal therapy in BD. SE seems to be the
most effective treatment, but randomized trials comparing SE with non-invasive
treatments such as PDT and 5FU, are lacking. A Cochrane systematic review on
treatments of BD found methyl aminolevulinate (MAL)-PDT as effective as 5FU,
and they found 5-aminolevulinic acid (ALA)-PDT to be more effective than 5FU,
based on the results of one study. However definitive conclusions could not be
drawn and the need for head-to-head comparison was highlighted.
This is the first study with a prospective comparison between SE, 5FU and PDT.
Our study will lead to a better understanding of (cost) effectiveness, patient
satisfaction and cosmetic outcome of the most commonly used therapies and will
supply the necessary evidence for (inter)national guidelines.

Primary Objective: To determine the (cost)effectiveness of 5-fluorouracil cream
(5FU) and photodynamic therapy (PDT), compared to surgical excision (SE) in
Bowen*s Disease (BD).
Secondary Objectives: To determine the (cost)effectiveness of 5-fluorouracil
cream (5FU) compared to photodynamic therapy (PDT) in Bowen*s Disease (BD). To
examine if 5-fluorouracil cream (5FU) and photodynamic therapy (PDT) result in
greater patient satisfaction and/or cosmetic result compared to surgical
excision (SE) in Bowen*s Disease (BD).

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 AK and 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, long-term probability of
sustained clearance, cost-effectiveness, patient satisfaction, compliance, side
effects and cosmetic outcome. Long-term is defined as at least 3 years
post-treatment. All patients will be invited for the long-term follow-up visit
at least 3 years after finishing treatment, with the last patient finishing
treatment at April 16th 2021.

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.

Surgical excision (SE)
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 and will last 30-45 minutes.

Methylaminolevulinc acid - photodynamic therapy (Metvix®, Galderma), (MAL-PDT)
PDT involves the application of methyl aminolevulinate (MAL) to the affected
skin (by means of a cream), which is converted within the cells into the
photosensitizer protoporphyrin IX. Surface illumination with 585-720 nm is then
used to trigger the photodynamic reaction causing destruction of tumor cells by
both apoptosis and necrosis.
MAL-PDT (Metvix®, Galderma) has been registered for treatment of BD in Europe,
two sessions should be administered with an interval of one week between
sessions.
In order to prepare lesions for MAL-PDT scales and crusts should be removed
before applying the MAL cream. A layer of Metvix (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 (Tegaderm®, a gauze and tinfoil), in
order to prevent contact with (UV) light. After 3 hours the occlusive dressing
will be removed and the area is illuminated with Omnilux® (Galderma) or
Aktilite® (Photo Therapeutics Ltd) (632 nm, 37 J/cm2). During the MAL-PDT
treatment cooling of the surrounding skin is allowed (with a coldpack located
centimeters from the treatment area). After PDT, silver sulfadiazine cream will
be applied on the treatment area and the treatment site is covered again with
the above mentioned occlusive dressings, to prevent exposure to daylight during
48 hours. Treatment is performed by an authorized nurse in the hospital.
Patients are instructed to prevent exposure to sun during 2 days
post-treatment. After treatment local skin reactions can appear, such as
erythema, crusts and a burning sensation. Rarely local skin inflammation that
needs antibiotic treatment, occurs. The side effects mentioned usually
disappear within 1-2 weeks.

5% 5-Fluorouracil (Efudix) (5FU)
5FU cream is a topically applied chemical ablative agent that inhibits DNA
synthesis, prevents cell proliferation, and causes tumour necrosis. This
results in erythema, oedema, scaling and erosions.
5FU is applied on the treatment area by the patient in a thin layer twice daily
during 4 weeks. During treatment local skin reactions, such as erythema and
crusts, will appear in most patients. Rarely local skin inflammation that needs
antibiotic treatment occurs.
Post-treatment erythema, crusts and tenderness will persist for approximately
1-2 weeks.

Participation requires patients to receive a treatment they cannot choose
themselves, however all treatments are considered to be standard care and have
no additional risks. All patients, with new and recurrent BD, will benefit from
this study as it leads to better treatment of BD in the future. As the chance
of developing a new BD in the future is increased in patients with previous BD,
the patient might benefit from the results of this trial in the future.
Participation in the study will cost the patient a bit more time than regular
care. It requires one extra consultation to sign informed consent. Furthermore,
filling out the questionnaire (patient diary) requires approximately 10-20
minutes in total. This will lead to better understanding of the impact of the
different treatments of BD on patients and treatment compliance.