Topical sinecatechins ointment in treatment of primary superficial Basal Cell Carcinoma: a double blind, randomized, placebo-controlled trial.

Basal cell carcinoma (BCC) is the most frequently occurring nonmelanoma skin
cancer in Caucasians, representing approximately 80% of cases. Incidence rates
for men and women in the Netherlands are 165 and 157 per 100,000 person-years
respectively and are still rising 3-10% annually. In 2009, the lifetime risk
for developing a first histologically confirmed BCC for men was approximately 1
in 5 (21%) and for women it was 1 in 6 (18%).
A simplified classification of BCC includes the following three histological
subtypes: nodular (40,6), superficial (30,7%) and infiltrative BCC (28,7%).
Superficial BCCs (sBCCs) differ from the other subtypes as they tend to appear
at a younger age, usually occur on the trunk and are often multiple. This
subtype has the fastest growing incidence.
A characteristic feature of BCCs is their low risk to metastasize, though if
untreated they may induce considerable functional and cosmetic morbidity as
they are locally invasive. Surgery is the first treatment of choice for BCC.
However due to the rising incidence and the extensive workload this entails, a
non-invasive topical treatment is often chosen for sBCC as they grow down from
the epidermis into the superficial dermis and therefore are easily accessible
for topical treatment. Photodynamic therapy (PDT), imiquimod cream or
5-fluorouracil cream are available topical treatments for sBCC however their
tumour free survival rates are not equal to the higher tumour free survival
rates of surgical treatment. Next to the efficacy, the now available topical
treatments are associated with local skin reactions at the treatment site,
mainly erythema and erosion (imiquimod cream and 5-fluorouracil cream) or pain
and burning sensation (PDT). This creates the need for additional or
alternative non-invasive topical treatments.

The main exogenous predisposing risk factor of BCC is ultraviolet light
exposure. However BCC tumourigenesis is multifactorial. The vast majority of
BCCs occur sporadically. Approximately 90% of sporadic BCCs have identifiable
mutations in at least one allele of the patched 1 (PTCH1) gene, an inhibitor of
the Hedgehog (Hh) signalling pathway. This relieves the inhibition of
smoothened (SMO) by PTCH1 and SMO sends signals through a series of interacting
proteins, including suppressor of fused (SUFU), resulting in activation of the
downstream Gli family of transcription factors, leading to proliferation.
A recent study presents convincing evidence that canonical Wingless-type MMTV
integration site (Wnt) signalling pathway is essential for a tumorigenic
response to deregulated Hh signalling in skin. Several earlier studies also
report a link between the Hh and Wnt pathways in BCC. The canonical Wnt pathway
regulates the ability of the *-catenin protein to accumulate and enter the
nucleus, where it interacts with proteins and converts them into
transcriptional activators, leading to proliferation.
The tumour suppressor gene p53, which controls the intrinsic pro-apoptotic
pathway, is mutated in 40% of sporadic BCCs.

The active constituents of green tea are promising because of their supposed
anti-BCC-carcinogenesis effects as described by several epidemiological, cell
culture and animal studies. The so-called polyphenols known as catechins are
the active constituents of green tea and the catechin
epigallocatechin-3-gallate (EGCG) is the major and most active catechin. EGCG
is thought to have a cytotoxic effect on skin cancer cells and has the
availability of inhibition of cell growth and induction of apoptosis. It is
also suggested that EGCG plays a role in inactivation of *-catenin signalling,
an important component of the WNT pathway.
Sinecatechins 10% ointment (Veregen®) is a standardized extract of green tea
leaves of the species Camellia sinensis, containing mainly green tea
polyphenols, particularly catechins (more than 85%). The lead catechin in
sinecatechins ointment is EGCG. It is approved by the US Food and Drug
Administration (FDA) for genital warts in adults.
There are no clinical trials on human subjects with topical EGCG on sBCC yet.
With this trial we are the first to try to validate the anti-carcinogenic
potentials of topical EGCG in humans with sBCC. We assess the effectiveness of
sinecatechins 10% (Veregen®) versus placebo for the topical treatment of sBCCs.

Primary Objective: To determine whether topical sinecatechins 10% (Veregen®)
ointment application can lead to a histological clearance (efficacy) of a
superficial basal cell carcinoma.

Secondary Objective(s): To assess compliance and adverse reactions (safety). To
assess histological effects with additional immunohistochemic stains; Bcl-2
(anti-apoptosis), Ki67 (proliferation).

Clinical double blind, randomized, placebo-controlled intervention trial

21 patients with sinecatechins 10% ointment twice daily for six weeks
21 patients with placebo twice daily for six weeks

First visit, punch biopsy, telephonic consultation and surgical excision are
part of regular care of superficial basal cell carcinoma. Treatment with
sinecatechins ointment or placebo, inclusion visit and two control visits are
part of the study.

A potential risk when participating in this study is an allergy for one of the
components of the sinecatechins 10% ointment or placebo.
Local skin reactions at application site represent a special safety issue for
topically applied treatments. Therefore we will evaluate and describe local
skin reactions separately from other adverse events. Local skin reactions can
be easily controlled and therefore are acceptable for the subjects. We do not
expect any other risks.