Treatment of superficial basal cell carcinoma by topical photodynamic therapy with fractionated 5-aminolevulinic acid 20% versus two stage topical photodynamic therapy with methylaminolevulinate

Basal cell carcinoma throughout the world
Skin cancer is the most common cancer, with basal cell carcinoma (BCC) being
the most common form of all skin cancers. There are 44.000 new BCCs each year,
and it's incidence is still rising. Of all types of BCC, superficial basal cell
carcinoma (sBCC), is the histopathologic subtype with the fastest growing
incidence, especially on the trunk in younger patients.It is a common health
problem and although there is no chance of metastasis it can lead to more
aggressive forms of BCC with the ability to cause serious local destruction.

Treatment options
The DBC (diagnose behandel combinatie) cost price, the amount received for
diagnostic and treatment of one BCC, for surgical excision is partly free
negotiable between each hospital and health insurances. Only the DBC cost price
of patients whose health insurance has no contract with the hospital is public
for everyone. This leads to around 18 million euro (based on a cost price of
400.00 euro for 44.000 new BCCs per year) that is yearly spent on the surgical
treatment of BCC in the Netherlands and cost will only increase in future with
the growing incidence.
For most BCC subtypes the only effective treatment is surgery but for sBCC
other non-invasive treatments like photodynamic therapy (PDT) are suitable. It
is well accepted in today*s dermatologic practice that surgical excision can be
considered as over-treatment for sBCC. PDT is superior to surgical excision in
primary sBCC of any size in low-risk sites. As a consequence unnecessary
anaesthesia and incisions are avoided thereby preventing side-effects, such as
scars, haematomas or functional disruption, and healthy tissue is preserved.
Both 5-aminolevulinic acid (5-ALA) and the more lipophilic
methylaminolevulinate (MAL) can be used as a precursor of the photosensitiser.
These agents generate an excess of protoporphyrin IX in metabolic active cells,
which are illuminated by a specific light source leading to release of reactive
oxygen radicals in tissue. The result is apoptosis and necrosis of tumour
cells. MAL is a worldwide registered agent for the use of topical PDT in sBCC
while 5-ALA is not registered in the European Union. In the Netherlands both
fractionated 5-ALA 20% and MAL PDT in 2 sessions are used as treatment for
sBCC. Although there are studies showing the effectiveness of both treatment
regimens, the effectiveness, costs and patient preferences have never been
studied in a prospective randomised trial.

Developments in treatment: photodynamic therapy
PDT has become increasingly implemented in standard care for sBCC in the last
years. Nowadays, in the Maastricht University Medical Centre, about 60% of
patients are treated with PDT. Similar situations are found in the Erasmus MC
Rotterdam and the Vie Curi Medical Centre Venlo. On national level, around two
thirds of patients are treated with MAL PDT in 2 sessions and one third with
fractionated 5-ALA 20% PDT. Because MAL was first marketed and registered as a
treatment option for premalignant and superficial malignancies most hospitals
in the Netherlands use this topical agent. However, there is no evidence which
of the 2 agents is more (cost-)effective and/ or preferred by patients. 5-ALA
20% PDT versus MAL PDT

There are only a few randomised controlled studies on treatment of the most
common skin cancer. Choice of PDT treatment with fractionated 5-ALA 20% or MAL
in 2 sessions often depends on the experience and choice of the physician or
the availability of the precursor in a hospital. World-wide, most studies are
performed with MAL and it has been accepted as the standard of care in PDT.
However, according to the literature, the effectiveness in terms of clearance
rates is in different studies lower for MAL in two sessions compared to
fractionated 5-ALA 20% PDT: 79% versus 97% intention to treat (ITT) after one
year in sBCC. Contra dictionary, MAL has the theoretical benefit of being more
and faster absorbed in the cell than 5-ALA 20% and, thereby, should generate a
higher production of protoporphyrin IX. In addition MAL has higher selectivity
for tumour cells, inducing fewer side-effects in normal tissue. This
discrepancy between theoretical working mechanism and clearance rates needs
further clinical research of the effectiveness of both treatments.
PDT is a hospital administered treatment modality during which patients have to
come to the hospital one day (fractionated 5-ALA 20%) or two days one week
apart (MAL in 2 sessions). Patient compliance could be higher with fractionated
5-ALA 20% than with MAL in 2 sessions because patients have to visit the
hospital a second time. At some parts of the body patients experience a
variable burning pain sensation during PDT which might influence completing the
treatment. Kuijpers et al. found no significant differences in pain scores
between ALA-PDT in 2 sessions and MAL-PDT in 2 sessions. We expect 5-ALA 20%
PDT to have more side-effects in our study as patients are treated twice on the
same day.
Furthermore it is important to take into consideration the differences in
patient acceptability costs (see *economic evaluation*). A well-designed
superiority study comparing the two topical PDT treatment modalities:
fractionated 5-ALA 20% (superior) and MAL in 2 sessions will provide the
answers needed to establish the position of the two modalities in the treatment
of patients with sBCC. Our hypothesis is that 5-ALA 20% is as more effective
than MAL PDT with the same potential side-effects. Patients* compliance might
be higher in the 5-ALA 20% group treated on one day and health care costs can
be reduced by using 5-ALA 20% instead of the more expensive MAL cream. The
conclusions from the proposed study can serve as a basis for updating
guidelines for the treatment of sBCC to catch up with recent developments in
clinical practice.

To compare effectiveness, costs and patient preferences in the treatment of
sBCC with fractionated 5-ALA 20% PDT versus MAL PDT in 2 sessions.

Clinical, prospective, randomized, single-blinded multicenter study

- 81 patients with fractionated 5-ALA 20% PDT on the same day (2 hour free
interval)
- 81 patients with MAL PDT in 2 sessions (1 week interval)

There is no burden for patients with sBCC. The will be treated according to
regular care like physical examination, photography, punch biopsy and PDT
treatment.