Topical Vitamin D3, Diclofenac or a combination of both to treat Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most frequent malignant tumor in Caucasians
and the incidence is still increasing with 3-8% each year.
Since BCCs generally occur on sun-exposed areas of the skin, the rice in
incidence is mainly explained by the increasing exposure to (intermittent)
ultraviolet radiation. Surgical excision is still the standard treatment for
(micro) nodular BCCs. The costs as well as the increased workload are stressing
the health care system even further and posing BCC an important health care
problem. Since half of the BCCs arise primarily on the face & (bald) head and
treatment by surgical excision may result in a disfiguring scar, patients often
experience a dramatic decrease of their quality of life. Hence, there is an
urgent medical and societal need for a simple and cheap (targeted) treatment,
preferably to be performed by the patients themselves. This treatment must be
safe and effective. Such treatment is not available yet.
BCC tumorigenesis is complex and must be multifactorial. Genetic alterations of
multiple components of the Sonic Hedgehog (SHH) pathway are involved in
sporadic BCC pathogenesis; inactivating mutations in Patched-1 (PTCH1) and
activating mutations of Smoothened (SMO) and Suppressor of Fused (SU(FU)). With
this knowledge, inhibition of the SHH pathway by a SMO antagonist was
successfully administered, however treatment resulted only in partial clinical
response of BCC. Recently, involvement of the Wingless (Wnt) pathway has been
proven to be essential in BCC tumorigenic response. Moreover, a recent study of
our own department provides the first evidence that epigenetic alterations,
particularly promoter hypermethylation, influence both the SHH and Wnt pathway
(own data, not published), which can serve as therapeutic targets. Both
non-steroidal anti-inflammatory drugs (NSAIDS) and vitamin derivatives are able
to directly or indirectly target the Wnt pathway. Furthermore, vitamin D3 is
able to inhibit Smoothened (SMO) in vitro, which results in inhibition of the
SHH pathway. Although in vivo studies are lacking, we assume that topical
application of these drugs may inhibit BCC growth and/or may cure BCC and thus
might provide very promising future perspectives. Calcitriol and NSAIDs
ointments are both already available for other indications and save in use.
Eventually, our approach may result in a systematic approach to BCC, targeting
both genetic and epigenetic changes to treat and/or prevent further tumour
growth.

Primary Objective:
To determine whether topical application of Calcitriol (Silkis) 3 µg/g,
Diclofenac 10% or a combination of both can lead to a 40% histological
reduction (*)/increase (*) of expression of the following antibodies: Ki67 (*),
BCL2 (*), Caspase 3 (*) and Cox2 (*) (proliferation and apoptosis), LC3B (*)
(autophagy), HIF1α (*) (hypoxia), β-catenin (*), sFRP4 (*) and sFRP5 (*) (Wnt
pathway activity).

Secondary Objectives:
To asses macroscopic tumour changes, toleration of the therapy and patient
satisfaction.

open-label, singel-blinded, randomized-controlled intervention trial.

Application of 3u/g Calicitriol, Diclofenac 3% or a combination of both.
Patients should apply the crème(s) twice daily on the tumor untill 1 cm around
it and subsequently cover it with a plaster (Tegaderm).

Patients participating should apply the study crème twice daily during 8 weeks
at the tumour and subsequently cover it. This will take the patients 5 minutes
a day. As part of the study, patients should visit the hospital once extra for
a controlvisit. This takes about 15 minutes. Apart from this, all patients will
recieve regular care as exists for BCC care.
Side effects of the crèmes are hardly to be expected. Side effects that may
occur are redness and skin irritation, but can easily be controlled. In case
of an allergic reaction for one of the ingredients, treatment for this patient
will be stopped. Previous studies showed that local application of vitamin D as
well as Diclofenac is safe and does not lead to therapeutic plasma levels. The
benefit for the patients is that the tumor may possibly shrink, resulting in a
smaller scar due to the surgery.
Largest benefit will be made for future patients if it turned out that these
new therapies are effective.