ARTICLE
Auteur(s) : Tiziana Surrenti, Linda De Angelis, Antonella
Di Cesare, Maria Concetta Fargnoli, Ketty Peris
Department of Dermatology, University of L’Aquila, Via Vetoio,
Coppito 2, 67100 L’Aquila, Italy
accepté le 14 Mai 2007
Basal cell carcinoma (BCC) is the most common cancer in the
Caucasian population, with an incidence that continues to rise
worldwide [1]. The standard treatments of BCC include surgical
excision and Mohs’s micrographic surgery with a 5-year recurrence
rate of 3-14% and of 1% for primary BCC, respectively [2-4].
Cryosurgery or curettage and electrodesiccation may be indicated
for low-risk, small lesions (< 1.5 cm in diameter)
[2]. The cumulative 5-year recurrence rate for cryosurgery varies
from 4% to 17% in the different studies while data on recurrence
rates after curettage and electrodesiccation are limited [2, 4].
Radiation therapy is recommended for large BCCs in older patients
with an overall 5-year recurrence rate of 7.4% for primary BCCs
[4]. A non-surgical treatment, including 5-fluorouracil,
intralesional interferon-α or bleomycin, topical imiquimod or
photodynamic therapy, may be chosen for patients with large
non-aggressive BCC such as superficial BCC, for patients with
lesions located in the mid-face area or ear, and for patients whose
general health status makes them unsuitable surgical candidates [2,
4].Photodynamic therapy (PDT) is a non-invasive treatment for
actinic keratosis, BCC and Bowen’s disease, in which tumour tissue
is selectively destroyed [5-8]. In PDT, a photosensitizing agent
such as methyl aminolevulinate (MAL) is applied to the lesion, and
the lesion is irradiated by visible light in the red spectrum
(570-670 nm). Reactive oxygen species form and lead to the
selective destruction of tumour tissue [8]. Several studies have
reported the clinical benefits and good safety profile of MAL-PDT
in the treatment of superficial and nodular BCCs, with response
rates of 85%-92% in superficial BCC and 73%-91% in nodular BCC
[9-14]. We performed an open-label clinical trial to further
evaluate the efficacy, safety, tolerability and cosmetic outcome of
MAL-PDT in selected patients with superficial and/or nodular BCC.
Materials and methods
Patients were selected for treatment with MAL-PDT among those with
superficial or nodular BCCs who attended the out-patient clinic of
the Department of Dermatology, University of L’Aquila, Italy, from
February 2004 to March 2005. Patients aged ≥ 18 years were included
in the study if they satisfied at least one of the following
criteria: i) contraindication to surgical excision due to bleeding
abnormalities or cardiac risk; ii) multiple or recurrent BCCs; iii)
patient’s request for alternative treatment due to needle/surgery
phobia.
Patients with morpheaform BCC lesions, xeroderma pigmentosum or
porphyria were excluded. Women who were pregnant or breast-feeding
were also excluded. All patients provided written informed consent,
and the study was conducted in accordance with the ethical
guidelines of the Declaration of Helsinki.
Superficial BCC lesions were prepared by surface debridement
using a dermal curette to remove scales and crusts [15], in order
to facilitate penetration of the MAL cream and red light. For all
nodular BCCs, an intratumoral debulking curettage without local
anaesthesia was performed to reduce the tumour thickness, by
removing only visible parts of the tumour and sparing the
underlying dermis and adjacent normal skin. A 1 mm thick layer
of 160 mg/g MAL cream was then applied on the lesion and on
5-10 mm of the surrounding skin and covered with an occlusive
dressing for 3 hours. After the dressing was removed, the cream was
washed off with saline solution and the lesion was immediately
illuminated with non-coherent red light (634 nm ± 3 nm, light dose
37 J /cm2) from a LED device (Aktilite®128,
Galderma, France).
Initial treatment consisted of 2 sessions of MAL-PDT, with an
interval of 1 week between sessions. Before the second session, any
crusts on the previously treated area were gently removed using a
dermal curette. BCC lesions with partial clinical remission 1 month
after 2 MAL-PDT sessions were treated once monthly with additional
MAL-PDT sessions up to a maximum of 8 treatment sessions. Clinical
response was evaluated at months 1, 3, 6 and 12 after the last
treatment and then every 3 months by measurement and photographic
documentation of treated lesions. Figure 1 illustrates the
MAL-PDT treatment and follow-up schedule. During the treatment and
follow-up periods, use of concomitant topical medication (e.g.
fluorouracil, imiquimod) at the treatment site was not
permitted.
Efficacy was rated as i) complete response, corresponding to
clinical disappearance of BCC; ii) partial response, clinically
corresponding to ≥ 40% and < 100% reduction in tumour size; iii)
no response, defined as < 40% reduction in tumour size as
compared to initial clinical examination and iv) worsening, defined
as an increase in tumour size from baseline.
In patients who easily accepted the surgical procedure and
presented BCC lesions not too small in size
(diameter < 1 cm), a punch biopsy (3-5 mm) was
performed before treatment at the most palpable and infiltrative
area of the lesion, and the histopathologic examination confirmed
the diagnosis of BCC. A punch biopsy (4 mm) with serial step
sections was performed in all successfully treated BCCs four weeks
after the last treatment.
The presence and severity of symptoms (itching, pain, burning)
and local adverse reactions (erythema, edema, erosions,
ulcerations, scaling, crusting) were evaluated by the physicians at
each visit and rated on a 4-point scale (0 = none, 1 = mild,
2 = moderate, 3 = severe). The cosmetic outcome was assessed
independently by the physicians and the patients, who rated the
outcome on a 4-point scale (excellent = 4; good = 3, fair = 2 and
poor = 1) at 3, 6 and 12 months after the last MAL-PDT
treatment.
Results
We treated 118 BCCs in 69 patients, including 47 males and 22
females (age range: 36-85 years; mean: 66.7 years). All patients
were of Caucasian origin and had skin type I-III according to the
Fitzpatrick’s classification [16]. In all cases, the diagnosis of
BCC was clear-cut, based on clinical and dermoscopic features [17].
A pre-treatment punch biopsy was performed in 42/118 (32
superficial and 10 nodular BCCs) lesions and confirmed the
diagnosis of BCC.
Lesions consisted of 94 superficial BCCs (including 6 pigmented
lesions), and 24 nodular BCCs (including 2 pigmented lesions).
Lesions were located on the trunk (58), face (47), head and neck
region (11) and lower extremities (2). The lesions varied in size
between 0.5 and 9.3 cm (median size: 1.6 cm). Twenty-five
BCCs (21 superficial and 4 nodular) in 15 patients were recurrent
and had been previously treated with surgical excision (8),
curettage (9), imiquimod 5% cream (4) and cryosurgery (4).
Seventeen patients had multiple BCCs, including 13 patients with
sporadic BCCs, 2 patients with Gorlin syndrome and 2 patients who
were kidney transplant recipients. Thirty-five patients with
sporadic BCCs were poor surgical candidates due to compromised
general health status (e.g., cardiac risk, bleeding abnormalities).
Two patients with sporadic BCCs required an alternative treatment
due to the needle/surgery phobia.
One patient, with 1 nodular BCC, discontinued the study after
the first MAL-PDT session for reasons not related to study
procedures. One month after 2 MAL-PDT sessions, we observed
complete clinical regression in 84/94 (89.4%) superficial BCCs,
including 3 pigmented BCC lesions and in 12/23 (52.2%) nodular BCCs
(figures 2A-B; 3A-B,
4).
A partial response was observed in 10/94 (10.6%) superficial
BCCs and in 11/23 (47.8%) nodular BCCs, one month after 2 MAL-PDT
sessions (figure
4). No further clinical improvement was observed in 6
superficial and 2 nodular BCCs with treatment repetition to a
maximum of 4 MAL-PDT sessions or in 4 superficial and 9 nodular
BCCs with treatment repetition to a maximum of 8 MAL-PDT sessions.
No non-response or worsening was observed.
None of the patients experienced systemic adverse events or
phototoxic reactions. Local side effects such as pain, stinging and
burning sensations were reported by all patients during the
illumination procedure. Based on the 4-point scale, these reactions
were 1 to 2 in intensity and never required treatment
discontinuation. After each MAL-PDT session, all patients
experienced erythema and crusting, which resolved without treatment
within a few days. One month after MAL-PDT treatment, 6 lesions
(6.25%) had hyperpigmentation, which resolved spontaneously 2-3
months after treatment discontinuation. The cosmetic outcome was
evaluated 3, 6 and 12 months after the last treatment and judged
independently by the physicians and the patients as excellent in
80/96 (83%) and good in 16/96 (17%) cases.
One month after 2 MAL-PDT sessions, post-treatment
histopathological examination of 96 cleared BCCs (84 superficial
and 12 nodular BCCs) showed the absence of residual neoplastic
cells (figures 2C-D; 3C-D).
Of these, 82 superficial BCCs and 12 nodular BCCs showed no
recurrence after a follow-up period of 6-18 months (mean: 12
months). Recurrence has been observed in 2 of 84 (2.4%) superficial
BCCs, at 6 months and at 12 months after treatment
discontinuation.
Discussion
Since the recent introduction of MAL, several trials in Europe,
USA, and Australia have been performed to investigate the efficacy
and safety of MAL-PDT for the treatment of both superficial and
nodular BCC [9-14].
In our study MAL-PDT treatment was successful in 84 of 94
superficial BCCs, giving a 85% complete response rate, which is
comparable to the rates reported in previous studies (85-92%) [6,
7, 9, 12].
In previous reports of MAL-PDT, a complete clinico-pathologic
response has been detected in 73%-91% of nodular BCC lesions and
the higher response rate was achieved when debulking curettage was
performed [9, 10, 12, 13]. For this reason, we prepared all nodular
lesions by debulking curettage. In our study, a complete regression
was observed in 52.2% (12/23) of nodular BCC lesions. Therefore,
MAL-PDT may be indicated only in selected patients with nodular BCC
in consideration of its non-invasiveness and good-to-excellent
cosmetic outcome.
Interestingly, we noticed no additional clinical benefit with
treatment continuation beyond 2 sessions to a maximum of 8 MAL-PDT
sessions for either superficial or nodular BCCs. This finding
supports the licensed use in Europe of only 2 MAL-PDT sessions for
treatment of BCC.
Moreover, the efficacy of MAL-PDT has been confirmed for the
treatment of “difficult to treat” BCCs, defined as large or
recurrent lesions, BCCs located in the mid-face area or BCC lesions
in patients in whom surgery was contraindicated or in patients
prone to poor cosmetic outcome with conventional treatment [12,
13].
Consistent with previous studies [9-14], MAL-PDT appeared safe
and well-tolerated, with only mild local side effects observed in
our patients. The cosmetic outcome was graded as excellent in 83%
and good in 17% of cases, results consistent with those of previous
studies [9-14].
In our study, recurrence was observed in 2 of 84 (2.4%)
successfully treated superficial BCCs, one at 6 months after
treatment discontinuation and the other at 12 months. No recurrence
was observed in nodular BCCs after a mean follow-up of 12 months,
although the sample size was limited. In addition, a longer
follow-up period is necessary to draw more definite conclusions on
recurrence rate.
In conclusion, our results support earlier findings that MAL-PDT
for superficial BCC is a safe, efficacious and well-tolerated
treatment that results in a favourable cosmetic outcome. MAL-PDT
might be considered a treatment option especially for superficial
BCC in patients not eligible for surgical treatment.
Acknowledgements
The Authors thank Barbara Rutledge for editing assistance.
Financial support: none. Conflict of interest: none.
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