Prospective randomised controlled study on imiquimod 5% cream as pre-treatment of Mohs micrographic surgery for primary large nodular basal cell carcinoma in the face.

Basal cell carcinoma (BCC) is the most common malignancy of the skin (1). While
the mortality rate due to this tumour is insignificant, an increasing group of
especially younger patients are concerned about the cosmetic outcome of the
treatment of a facial tumour. Various therapeutic modalities exist (1). In most
cases surgical excision will take place. Mohs micrographic surgery (MMS) is an
advanced technique, which is used mainly for BCC in the face and with high risk
for recurrence, in the H-zone or > 2 cm (2). The size of the defect after
excision of the tumour can significantly be reduced by using MMS, compared to
the standard surgical excision. The cosmetic outcome is therefore overall
better. In addition treatment of primary tumours does have a better cosmetic
outcome compared to recurrent tumours (3). MMS has the lowest recurrence rate
in the treatment of BCC (2). It is however, a time consuming and therefore
costs are higher (3).
New non-surgical treatments for BCC are investigated, such as imiquimod 5%
cream (imiquimod). Imiquimod is an immune respons modifier, it induces
cytokines which stimulate a cell-mediated immunerespons (4). Imiquimod 5% cream
has been demonstrated to be safe and effective in the treatment of anogenital
warts (5).
Studies show that imiquimod has a beneficial effect on small superficial and
small nodular BCCs, total or partial clearance is obtained (5-9).
Imiquimod could be used for BCC as an additional treatment before surgery, and
not only serve as a monotherapy. It could be an excellent pre-treatment for MMS
for larger nodular BCC. Pre-treatment with imiquimod 5% cream could reduce
tumour size and result in a smaller defect after MMS, and therefore result in a
better cosmetic outcome. Furthermore, it could reduce the number of Mohs rounds
needed to clear the tumour completely and therefore reduce the costs of this
treatment.

In other words; when imiquimod cream and MMS are combined, the chance on a
better outcome is increased. Imiquimod reduces tumour size and defect size. MMS
provides radicality, so that risk of recurrence is low. These factors all
provide a better cosmetic outcome. While BCC grows very slowly, a delay of 3
months between diagnosis and treatment is accepted.

Objectives
1. Reduction of defect size after MMS with a pre-treatment with imiquimod 5%
cream
2. Reduction of tumour size of large nodular facial BCC, after pre-treatment
with imiquimod 5% cream.
3. Improvement of cosmetic results.
4. Histological evaluation of apoptosis by using caspase 3 and evaluation of
the upregulation of FasR to determine the sensitivity of the BCC for apoptosis.
5. Calculation of cost-effectiveness.
6. Comparing quality of life between groups.
7. Recurrence rates.

Study design:
Prospective randomised controlled study.
Treatment with imiquimod cream for 4 weeks. 6 Weeks after treatment MMS will be
performed.
The control group will only undergo MMS.
Follow-up 12 months.
The study will take place in The Catharina Hospital Eindhoven

Product:
Imiquimod 5% cream (Aldara®) applied locally on the skin, on the target tumour
and 1 cm around the tumour. The cream has to be applied at night and left for
approximately 8 hours.
It has to be applied once daily, 5 days a week, for 4 weeks.
No other local treatment modality is allowed on the target area during the
study, in both groups.

Adverse events that have been reported are mainly mild local skin reactions;
these include erythema, itching, pain, erosions, and excoriations (5-7).
Multiple studies report less adverse events when using the lower frequency
dosing regimens (5-8,14,16). When reviewing literature, it appears that 87% of
the patients reports at least one local skin reaction, some patients need a
rest period if the local reactions are severe. 2% Of the patients stopped
treatment prematurely because of local skin reactions (17). In the trial
described by Schulze et al, 2 of 166 patients stopped therapy due to adverse
events. In one patient bleeding occurred in the treatment area and the other
patient develop a bacterial skin infection. It is not clear if the bleeding
occurred due to the treatment, BCC do bleed easily, spontaneously (16).
Systemic adverse events have been studied. No clinical or laboratory (blood and
urine) changes were observed (6,7,9). Subjective systemic adverse events were
mentioned in the study of Beutner et al, mainly fatigue, headache and fever.
Temperatures were measured and no fevers were noted (5).
In previous large controlled trials about imiquimod cream for anogenital warts,
no differences in frequency or severity of systemic adverse events were seen
between the imiquimod group and the placebo group (5).

Possible benefits: Reduction of tumour size, decrease of defect, improvement
cosmetic result.