ARTICLE
Basal cell carcinoma (BCC) is a locally aggressive tumour that originates
from epidermal or hair follicle basal cells. Its management depends on
the tumour size, the area involved, the age and medical status of the
patient [1]. Surgical excision is the treatment of choice, but electrodesiccation,
CO2 laser photocoagulation, cryosurgery or radiation are also
recommended [1, 2]. Alternatively, non-surgical modalities such as intralesional
5-fluorouracil, alpha-interferon, photodynamic therapy or imiquimod have
been used with varying outcomes [2-6]. Cidofovir is a nucleotide analogue,
active both intravenously and topically against a variety of DNA viruses
[7]. Intralesional doses of cidofovir were found to be effective for the
treatment of DNA virus related tumours both in animals and patients [8-14].
Cidofovir has been supposed to exert direct anti-neoplastic activity,
through the induction of apoptosis and the inhibition of angiogenesis
[15-19]. On the base of these observations, four patients affected by
BCC, who refused conventional surgery, accepted to be experimentally treated
with a cream containing 1% cidofovir.
Patients and methods
Patients signed a written informed consent before starting topical cidofovir.
The cream was compounded as follows: 375 mg of cidofovir (Vistide, Pharmacia-Upjhon)
were mixed with 32.5 g of a base cream (Dermobase grassa Restiva; Istituto
Ganassini, Milano, Italy). They were told to apply the cream on and 5
mm all around their lesions once a day for 10 days, then every other day
for another 50 days. During the study period, patients were seen weekly,
and then entered a follow-up period for evaluating BCC recurrence. The
follow-up is still in progress. Histopathologic confirmation of the diagnosis
was requested at the beginning in order to confirm clinical diagnosis,
and at the end of treatment to verify histological healing.
Patient 1
A 75-year-old man presented with a non-ulcerated 10 x 14 mm BCC on the
right side of his head (Fig.
1a). After histological diagnosis confirmation, the patient initiated
topical 1% cidofovir. Starting from day 5 he complained of the onset of
erythema, a burning sensation and erosion on the site of treatment, which
regressed within 10 days after therapy was over. Thirty days after the
end of treatment, the BCC appeared clinically healed (Fig.
1b), but the entire neoplastic area was surgically excised. Histopathologic
examination showed a normal aspect epidermis, and round nests of basaloid
cells with a palisade arrangement located in the superficial and mid dermis.
Numerous apoptotic bodies were detectable among the cells of neoplastic
nests. A dense lymphocytic infiltrate, with a predominance of CD4+
cells, surrounded the neoplastic tissue.
Patient 2
A 52-year-old male presented with a BCC on the left aspect of his nose
(Fig. 2a). Before undergoing
surgery, the patient asked to be treated with a conservative technique,
so topical cidofovir was proposed. After histological diagnosis confirmation,
the patient carefully applied the cream following the same schedule, and
clinically healed within 1 week from the end of application (Fig.
2b). A 3-mm punch biopsy on the previous pathologic area, was performed
3 months after the end of treatment and showed no evidence of residual
malignancy. A 26-month follow-up did not reveal any relapses.
Patient 3
A 46-year-old woman presented with a history of BCC on the right side
of her upper lip, which had been incompletely excised 1 year earlier.
The lesion had relapsed about 3 months from surgery. On clinical examination,
a BCC 14 x 13 mm in size was present at one border of the surgical scar.
As a surgical approach was considered disfiguring, 1% cidofovir cream
was proposed. From day 7 inflammation followed by erosion developed at
the site of the cream application. The patient completed the therapy and
the neoplastic area healed within 20 days from the end of treatment, leaving
a very slight scar. A 4-mm punch biopsy, performed on the previous
lesional area, 3 months after therapy was over, did not detect any residual
neoplastic tissue. No recurrence has occurred after a 24-month follow-up
period.
Patient 4
A 25-year-old nurse presented with a BCC on her sternum. In the attempt
to avoid disfiguring scars to her neckline, she asked to be treated with
a non-surgical technique. She refused histopathological diagnosis confirmation,
but agreed to the experimental use of topical cidofovir. This patient
also recorded local reactions at the site of application: erythema, itching
and erosion, which were otherwise well tolerated. Clinical healing was
obtained after 15 days from the end of treatment. A punch biopsy on previous
pathological tissue, performed 3 months later the end of the therapy,
confirmed healing. At a 20-month follow-up the patient is still free from
disease.
Comment
The efficacy of topical cidofovir in the treatment of recurrent herpes
simplex, molluscum contagiosum, and HPV infections has been reported by
several authors [7, 12]. Intralesional administrations of cidofovir were
found effective in the treatment of HPV-related neoplasms such as cervical
intraepithelial neoplasia [8], oesophageal or respiratory papillomatous
tumours [9-11], and erythroplasia of Queyrat of the glans penis [19].
In addition, regression of HSV-8 related Kaposi's sarcoma [12], and Epstein
Barr Virus associated nasopharyngeal carcinoma [13] were reported too.
If confirmed, these observations might bring about new interesting therapeutic
options for the treatment of such types of cancer in which DNA viruses
act as inducers of malignant transformation. Recently, cidofovir has been
found to be effective in the treatment of virus independent neoplasms
such as squamous cell carcinomas of the lower eyelid in a man [14], melanoma
and haemangioma in guinea pigs [15-17]. The mechanism of action of cidofovir
as an antineoplastic agent is still under evaluation. There is evidence
that cidofovir might act by inhibiting rapidly proliferating cells through
a reduction in DNA thymidine incorporation, the activation of tumour suppressor
genes and the induction of apoptosis [15-17]. In this report 4 patients
who, for various reasons, refused conventional therapy for their BCC,
were experimentally treated with 1% cidofovir cream.
All the patients achieved complete clinical regression of their BCC
after treatment. In patient 1 the lesional area, although clinically cleared,
was completely excised 30 days after therapy finished. Histopathologic
inflammatory infiltrate, which was over expressed if compared with the
former diagnostic biopsy, could be consistent with a cellular immune response
against neoplastic tissue. In case 2, 3 and 4 histopathologic clearing
verification was performed 3 months after the end of therapy because we
hypothesized that histological regression could be slowness rather than
clinical healing. Obviously, the use of a punch biopsy as evidence of
histologic healing potentially limits the accuracy of these results, we
are aware that the entire lesional area should have been removed and examined
to ascertain healing. On the other hand, the complete clinical regression
of BCC, and the absence of recurrences after an average 24-month follow-up
period may be indicative of healing. The patients are, however, still
kept under observation. No systemic side effects related to the treatment
were noted. The final cosmetic results were excellent. Medication with
1% cidofovir requires good compliance because of the long duration of
the treatment and the onset of discomforting local side effects, such
as erythema, erosion, burning sensation, bleeding and crusting. Although
the cases herein presented could hardly make up a series, this experience
shows the potential effectiveness of 1% cidofovir in the non-surgical
treatment of BCCs. We emphasise that surgical excision is the simplest,
safest and usually curative technique for BCCs. Further experiences using
controlled, blind studies are needed to confirm these very preliminary
results.
Article accepted on 3/9/02
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