5-AMINOLEVULINIC ACID PHOTODYNAMIC THERAPY FOR THE TREATMENT OF PREMALIGNANT DISORDERS OF THE VULVA

Vulvar Lichen sclerosus (VLS), a premalignant vulvar disorder, is a chronic
disorder which needs to be treated and cannot be cured. For High grade Squamous
Intraepithelial lesions (HSIL) it has been established that Imiquimod, which in
the Netherlands now is accepted as initial treatment of choice, is successful
in around 50% of cases (Key papers: van Seters et al., 2008; Terlou et al.,
2011). For VLS as well as HSIL there is room for new treatments.

Photodynamic therapy, using the porphyrin precursors such as aminolevulinic
acid (ALA-PDT), has been used to treat a variety of skin conditions (actinic
keratosis, squamous cancer in situ (Bowens disease) and basal cell carcinomas
(key paper: De Haas et al., 2008). Attempts have been made to treat uVIN and LS
using ALA-PDT but have encountered disappointing response rates and significant
clinical side effects such as pain during the illumination. We have shown that
delivering ALA-PDT in two-light fractions separated by an interval of 2 hours
results in a significant enhancement in therapeutic efficacy. Furthermore, we
have successfully translated this knowledge into the clinic where we have shown
a clinically significant increase in efficacy for the treatment of non-melanoma
skin cancer (Key papers: De Haas et al., 2006; De Vijlder et al., 2011). In
superficial basal cell carcinoma (sBCC) the 5 year response rate following
light fractionated ALA-PDT is 89% and compares very well with the efficacy of
surgical interventions of this disease. Based on the above findings, we
hypothesise that ALA-PDT, applied in a fractionated regime in order to increase
effectiveness, will be a very effective new treatment for premalignant vulvar
lesions such as VLS and HSIL.

An important consideration is the pain associated with an ALA-PDT illumination.
We and others have shown that reducing the rate at which light is delivered to
tissue (dose rate, fluence) results in significantly less pain. We have also
shown that the treatment parameters for light fractionated PDT can be adapted
to maintain the increase in efficacy at low dose rate while the overall
treatment time is acceptable.

Based on these finding we hypothesise that low dose rate light fractionated
ALA-PDT will be an effective and well tolerated therapy for VLS and HSIL.

Primary objective: To assess the efficacy of low dose rate light fractionated
aminolevulinic acid-Photodynamic Therapy (ALA-PDT) for treatment of VLS and
HSIL. Clinical and histological response.

Secondary objectives: Tolerence of ALA-PDT by monitoring pain during and after
the treatment. To monitor quality of life before and after treatment. To
determine clearance of HPV after treatment of uVIN; to assess normalization
immunocompetent cell counts and of expression of a number of markers (Ki67,
p16, p53, CD31, CD34, mir-155) after treatment.

Primair: Bepalen van de doeltreffendheid van ALA-PDT (2 lichtfracties, lage
licht intensiteit) voor behandeling van VLS en HSIL (klinische en histologische
respons). Meten van de kwaliteit van leven voor en na behandeling d.m.v.
gestandaardiseerde kwaliteit van leven vragenlijsten

Secundair: Verdraagzaamheid van ALA-PDT: meten van de pijn die de patiënt
ondervindt tijdens en vlak na belichting van de aangedane vulvahuid. Bepalen
van klaring HPV na behandeling van HSIL; meten of er normalisatie optreedt van
het immuunsysteem na behandeling; meten of er normalisatie optreedt van de
expressie van een aantal markers (Ki67, p16, p53, CD31, CD34, mir-155).

This study is designed as a randomized controlled trial where ALA-PDT
illumination is compared to standard treatments for VLS and HSIL.

VLS patients will be randomized to receive 20% ALA gel or Clobetasol Propionaat
0,05% ointment. HSIL patients will be randomized to receive 20% ALA gel or 5%
imiquimod cream. Patients receiving ALA-PDT will subsequently be illuminated
with two light fractions of, depending on the optical properties of individual
lesions, approximately 10 and 40 J cm-2 at 4 and 6 hours after a single
application of 20% ALA gel at a dose rate of 10 mW cm-2. The dose rate we
intend to adopt is one fifth (1/5) of the dose rate we currently use for the
treatment of wide field actinic keratosis (this is associated with the most
significant effect while remaining tolerable). If lower dose rates are
necessary to reduce pain in, for example, the treatment of wide fields, we will
use a lower dose rate and keep the overall treatment time constant.

Some risk and burden is linked to standardized protocol procedures, such as
biopsy sampling and vaginal assessment. Although these are routine procedures,
carried out by medical qualified personnel, they may cause side effects or
discomfort to the subject. However, it is expected that these procedures will
generally be well tolerated. ALA-gel will be applied on the morning of the
treatment and is tolerated well. Illumination will be done in a two-fold
illumination scheme (to increase effectiveness and decrease pain) in which a
cumulative fluence of 50 J.cm-2 will be delivered in two fractions of 10 and 40
J cm-2 at 4 and 6 hours after a single application of 20% ALA gel. From earlier
experience we know this will be painful and therefore pain relief will be
provided by Paracetamol 1000mg 4 times a day starting the day before treatment
and at the day of treatment. If pain relief is not sufficient during
illumination, 5mg Oxycodon will be provided. Upon discharge, the patients will
be advised to use paracetamol.

Regular treatment with imiquimod will be applied twice weekly for 16 weeks.
Known local side effects are erythema, ulceration, vesiculation, excoriation
and discharge, and are readily reversible with discontinuation of dosing. For
pain relief, patients will be advised to use paracetamol. Regular treatment
with 0.05% Clobetasol Propionaat ointment will be applied for in the following
regime: week 1 to 4: once a day; week 5 to 8: 4 days per week, from week 9:
start lifetime chronic intermittent treatment 2 to 4 days per week. The most
common side effect associated with dermovate is irritation at the application
site. The patient may experience burning, dryness, itching and redness. The
effects are usually temporary.