Fractional laser assisted photodynamic therapy in actinic keratosis: A pilot study

Actinic keratoses (AK) are cutanous neoplasms prevalent in up to 40% to 60% of
Caucasians older than 40 years and 80% of whites older than 60 years.
Presumable 0.25-1% of AK develops into a squamous cell carcinoma (SCC) yearly.
The risk of developing a SCC within untreated AK can increase to 10% to 20% per
decade depending on the study. The development of SCC on sun-damaged skin is a
gradual process; however, most AK lesions do not progress to invasive SCC and
it currently is not possible to clinically or histopathologically determine
which AK lesions will progress to SCC.
Many therapies exist, such as ablative therapies, including curettage and
cryotherapy or topical chemotherapy, including topical fluorourail and
imiquimod. Disadvantages of these approaches are hypopigmentation, scarring,
limitation of the body surface area (BSA) and the need for a high patient
compliance with topical applicants. Another category of treatment is
photodynamic therapy (PDT). This is based on the concept of combining a
photo-sensitizer and light, also called photochemotherapy. Photo-sensitizers
that are used are 5-amniolevulinic acid (5- ALA) or methyl-aminovelunate, which
are applied 3.5-4 hours before treatment under occlusion.
ALA-PDT is known to be painful for patients. A study done by Arits et al shows
that pain scores in PDT are higher in subgroups with Fitzpatrick skintype I and
II, lesion type AK and chronic use of oral analgesics. There was also a trend
towards higher mean pain scores for subgroups aged over 70, tumour localization
in the head/neck region and use of oral analgesics before PDT.
Other light sources that could be effective when combined with a photo
sensitizer, in the treatment of actinic keratosis, were investigated. The
absorption spectrum of protoporphyrin IX, the conversion product of 5-ALA
responsible for the photodynamic reactions has a peak in the 585 nm range. In
several studies study the pulsed pulsed dye laser (LP-PDL) for the treatment of
AK*s and the safety and efficacy of this treatment was assessed. They concluded
that this treatment is safe and effective and report minimal discomfort and
excellent post treatment cosmetic results. ,
Several studies indicate that ablative fractional laserresurfacing (AFR)
facilitates topically applied photosensitizers such as ALA or Metvix. AFR
creates vertical channels that may facilitate topical PDT drug penetration and
thereby improve PDT response in the deeper skin layers. It could then be more
effective in thicker AK lesions.
Prior studies done in the field of photodynamic therapy suggest that an average
incubation time of 3 hours is needed for the PDT topical drugs to reach the
maximum fluorescence level. Haederhal et al. performed a study in which
maximal fluorescence was reached at 1,5 hour after fractional laser treatment
of pig skin. A deeper photodynamic reaction was seen, and therefore maximal
fluorescence time was reduced to 50%. So far this has not been investigated in
human skin.
The purpose of this pilot study is to assess whether ablative fractional laser
assisted photodynamic therapy is an effective treatment for AK and can reduce
incubation time of topical PDT drugs with 50% using an AFR density of 50%.

Objective is to perform a pilot study in order to assess wether a randomized
controlled study can follow. This randomized study is necessary to proof
effectiveness compared to regular photodynamic therapy.
Objective is to present an effective and patient friendly treatment for
(chronic) actinic keratosis.

This is a pilot study that will take place at the department of Dermatology in
the Catharina Hospital Eindhoven, the Netherlands.

Patients: Patients aged older than 30 years with clinically proven actinic
keratosis on the vertex and/or forehead.

Inclusion: Patients will be included by dermatologists, dermatologic residents
and a trained physician assistant after informed consent is given.

Study design:
In this pilot study we would like to investigate whether there is good response
to AFR pre-treatment in laser-mediated PDT. The eventual goal will be to set up
a clinical randomized trial in which the true effect of AFR in PDT has to be
examined.
In this study the response will be measured using Total Lesion Number Score
(TLNS), Total Thickness Score (TTS) and in follow-up visits an independent
investigator will determine Investigator Global Improvement Indices Score
(IGII-score).

TLNS: Total amount of actinic keratosis lesions
TTS: R = complete remission / no AK
1 = lesion is visible, not palpable
2 = lesion visible and palpable
3 = lesion elevated with visible keratosis
4 = lesion hyperkeratotic and > 1 mm thick

Investigator Global Improvement Indices (IGII):
-2 = significantly worse
-1 = little worse
0 = no improvement
1 = poor improvement
2 = little improvement
3 = significant improvement
4 = complete remission

Follow up:
All patients will be visiting the outpatient department in the following
frequency:
- 10 days
- 1 months
- 3 months
During each follow-up visit colour photographs will be taken and whenever there
is a new area that needs to be treated or in case of recurrence, this will be
registered clearly.

Interventions
UltraPulse, fractional CO2, Lumenis, 10.600 nm, 10 mJ/pulse, 0.12 mm spot size,
5% ablation rate 1-3 minutes of treatment duration
This laser therapy is followed by the application of a photosensitizer
(MAL/METVIX). Patients will wait 1,5 hour for the photosensitizer to work.
After that the illumination will be performed using the Pulsed Dye Laser
(Candela, WA); 595 nm, spot diameter 7 mm; 7J/cm2, pulse duration 10 ms, 1-3
minutes of treatment duration.

UltraPulse, fractional CO2, Lumenis, 10.600 nm, 10 mJ/pulse, 0.12 mm spot size,
5% ablation rate

Patients will undergo a short (1-3 minutes) treatment with the fractional
ablative laser (UltraPulse, fractional CO2, Lumenis, 10.600 nm)This treatment
will not be without any pain sensation, however the ablative fractional laser
is used as treatment for other purposes aswell.
Next - comparable to regular photodynamic therapy - a photosensitizer cream
will be applicated on the treatment zone.
The cream will be removed after 1,5 hour, after which illumination with the
Pulsed dye laser will be performed. Merely this is assessed as painless by
patients.
After treatment patients will be seen in follow-up, 10 days, 1, 2 and 3 months
after treatment. Regular follow-up visits will be done afterwards (outside
study).