ARTICLE
Auteur(s) : Lieven
Annemans1,2, Karin Caekelbergh2, Rik
Roelandts3, Hugo Boonen4, Christoph
Leys5, Arjen F Nikkels6, V van Den
Haute7, L van Quickenborne8, Evelien
Verhaeghe9, Bernard Leroy10
1Faculty of Medicine, University of Ghent, De
Pintelaan 185, 9000 Ghent, Belgium
2IMS Health, Brussels, Belgium
3Universitaire Ziekenhuizen, Leuven, Belgium
4H. Hart, Mol, Belgium
5ULg University, Liège, Belgium
6Klinik St Jozef, Saint Vith, Belgium
7Clinique 2 Alice, Uccle, Belgium
8A.Z. Sint Lucas, Brugge, Belgium
9Universitair Ziekenhuis, Ghent, Belgium
10Cliniques Universitaires St Luc, Brussels, Belgium
accepté le 22 Avril 2008
Actinic keratosis (AK) is a skin lesion which is induced by
prolonged exposure to ultraviolet light. AK lesions can evolve into
squamous cell carcinoma and are the most common type of skin lesion
with malignant potential. In the Northern hemisphere, AK prevalence
is about 11% for adult patients above 21 years old and 25% above 30
[1]. In the UK, AK prevalence was found to be 5.9% in women and
15.4% in men [2]. BCC is the most frequent cutaneous carcinoma
(75-80%) [3]. In France, 2 studies found similar results in 2
regions at the end of the 1990s (Champagne-Ardenne and Haut Rhin)
with about 120 new cases for 100,000 inhabitants [4]. Statistics
from the Belgian Cancer Registry Foundation1 show an absolute number of 2836 BCC cases
recorded for 100,000 inhabitants in the Flemish part of Belgium in
2001. BCC typically occurs in areas of chronic sun exposure. It is
usually slow growing and rarely metastasizes, but it can cause
clinically significant local destruction and disfigurement if
neglected or treated inadequately. Prognosis is excellent with
proper therapy.
There are a range of effective treatment options for AK and BCC
including cryotherapy, curettage, excision, topical treatments,
radiotherapy and photodynamic therapy. There is no one therapy
which is found to be perfect for treating AK and BCC, as all have
associated drawbacks e.g. poor cosmetic outcome and scarring with
cryotherapy, excision and surgery and skin irritation with topical
treatments [5-10].
Methyl aminolevulinate (MAL; Metvix®; Galderma,
Lausanne, Switzerland) is a 160 mg.g–1 topical
photosensitiser molecule, application of which results in the
selective accumulation of photoactive molecules in the neoplastic
tissue. Exposure to red light in the presence of oxygen generates
reactive oxygen species which kill neoplastic cells. Healthy
surrounding tissue that has not accumulated the photoactive
porphyrins is spared.
For the treatment of AK, clinical trials have demonstrated that
MAL-photodynamic therapy (MAL-PDT) presented a comparable lesion
response rate to that with cryotherapy as well as a superior
cosmetic outcome [11-13]. For BCC treatment, clinical trials have
shown that MAL-PDT is safe and efficacious and that it is the
preferred treatment for patients due to the better cosmetic outcome
[14, 15]. In addition, for superficial BCC (sBCC), MAL-PDT offered
a lesion response very similar to cryotherapy [16, 17].
Increasingly, pharmacoeconomics is playing an important role in
healthcare decision making, alongside the traditional determining
factors of safety and efficacy. The prevalence of AK and BCC means
that they are very significant in terms of pharmacoeconomics and as
a result a number of economic evaluations of treatment of these
conditions have been carried out [18-22].
An economic model evaluation of MAL-PDT treatment and a
comparator of the management of AK and BCC have been previously
published [18]. This model was based on a medical decision tree
simulating all possible outcomes associated with the medical
decision to apply MAL-PDT or a comparator. The time horizon was 1
year for AK and 5 years for BCC. The comparators were cryotherapy
in AK and excision surgery in BCC. Clinical data were obtained from
the phase III programme. For AK, data used were from a large
multicentre randomised phase III clinical study which compared
MAL-PDT with cryotherapy and placebo [12]. In this trial, 89% of
the lesions were treated with a complete cycle of MAL-PDT (two
sessions, seven days apart) whilst the remaining 11% received only
one session. For BCC the data used in the model were taken from two
large, prospective, open, randomised comparative multicentre phase
III trials, one which included primary superficial BCC (sBCC)
lesions [16] and one primary nodular BCC (nBCC) lesions [17]. In
the study on sBCC, each patient received one treatment session
followed three months later by a cycle of 2 sessions if the
response was incomplete. In the study on nBCC, each patient
received a cycle of 2 sessions followed 3 months later by a second
cycle in the case of incomplete response. For the model, unit costs
for all interventions, investigations, medication and medical
visits were derived from the official listings of the Belgian
Health Insurance (2002).
The model economic evaluation concluded that for treatment of
AK, the cost per full responder is comparable to cryotherapy over a
one-year period. For BCC, MAL-PDT is better value for money than
excision surgery with a cost per full responder lower for nBCC and
sBCC over a 5-year period.
The purpose of the present study was twofold. Firstly, the
design of this real-life practice study allowed verification of the
results obtained in previous randomised clinical trials (RCT).
Secondly, from this real-life data the actual cost of treatment of
AK and BCC with MAL-PDT could be calculated and used to verify the
predictions made with the model-based economic evaluation of the
treatment.
Materials and methods
This prospective, observational, one arm, open study was performed
in accordance with Good Clinical Practices and with the Helsinki
declaration, and in compliance with local regulatory requirements.
It was conducted in hospital institutions as, in Belgium, treatment
of AK and BCC with MAL-PDT is reimbursed only when carried out by
dermatologists within a hospital setting. Patients were recruited
from 8 dermatological centres in Belgium (4 university and 4 non
university centres) following approval of the protocol by the
central ethics committee. The inclusion period for this study was
from September 2004 until October 2005. All patients gave written
informed consent.
Patients
Eligible patients had to present with AK and/or BCC lesions and be
suitable for MAL-PDT treatment according to the Belgian
reimbursement criteria as follows:
- – Thin or non hyperkeratotic and non pigmented AK lesions
of the face or scalp, and at the same time: a treatment by
cryotherapy or 5-FU (fluorouracil) was shown to be insufficient, or
the patient presented at least 10 lesions, or recurrent
lesions.
- – Superficial and/or nodular BCC for which other available
therapies were not adapted because of safety concerns and/or poor
cosmetic results such as: lesions on the middle part of the face or
on the ears, lesions on skin severely damaged by the sun, widely
spread lesions (more than 10 mm in diameter), recurrent
lesions
Potential patients were excluded from the study if they were
under 18-years-old, pregnant or lactating, already participating in
a clinical trial or had contra-indications to the study
treatment.
Study procedures
From study start (receipt of informed consent and decision to treat
with MAL-PDT) the following data were collected:
- – Pre-treatment patient information: Patient demography,
baseline lesion characteristics, previous therapy, number of
pre-treatment consultations and investigations (e.g.
biopsies).
- – Information about the MAL-PDT: Lesion preparation,
quantity of MAL-PDT used (mg and pricing units, where 1 pricing
unit = 200 mg of cream), application time, illumination time,
number of consultations during treatment, concomitant therapies,
anaesthesia used, tolerability (adverse events).
- – Post treatment patient information (data collected until
end of follow up period, 6 months from first MAL-PDT application):
Patient clinical response, cosmetic outcome (assessed by
physicians), subsequent treatment, number of post treatment
consultation and investigations, tolerability.
Outcomes
Clinical outcomes
The follow up period was 6 months from the date of first
application of Metvix. During this period the clinical response and
cosmetic outcome of the lesions were recorded per field and
tolerability data were collected. Outcomes were classified as
follows:
- – Clinical response was to be characterised as either
complete (complete disappearance of the lesion, assessed visually
and by palpation) or incomplete (incomplete disappearance of the
lesion, assessed visually and by palpation).
- – Cosmetic outcome was classified as excellent (no
scarring, atrophy or induration and no or slight occurrence of
redness or change in pigmentation compared to adjacent skin); good
(no scarring, atrophy or induration, but moderate redness or change
in pigmentation compared to adjacent skin); fair (slight to
moderate occurrence of scarring, atrophy or induration) or poor
(extensive occurrence of scarring, atrophy or induration).
Adverse events including skin discomfort were recorded in order
to assess patient tolerability of MAL-PDT treatment.
Health economic outcomes
From the data collected in this real-life practice study, the total
cost of care and the cost per lesion associated with MAL-PDT
treatment were calculated for AK and BCC. In addition, the data
collected for BCC were further analysed to give costs associated
with nBCC and sBCC.
The average cost of MAL-PDT treatment was calculated based on
the number of visits and diagnostic techniques performed during the
study period, the quantity of MAL-PDT used during treatment and the
cost of reimbursable concomitant therapies. The costs were
calculated by multiplying each item of resource use with its unit
cost from the health care payer’s perspective, i.e. the Belgian
public health insurance Rijksinstituut voor Ziekte- en
Invaliditeitsverzekering/Institut National d’Assurance Maladie
(RIZIV/INAMI). For the unit costs, a weighted average cost
(VIPO/Non-VIPO, VIPO being a French abbreviation for widowed,
invalid, pensioner or orphan) was taken, considering that the study
population consisted of 68.4% of patients > 65 years of
age.
In the original model [18] the resource “medical act” was
included in the evaluation. The term medical act in this situation
describes ablation or destruction of a superficial benign or
malignant tumour of the skin by any procedure (surgical without
stitching, electrocoagulation or any other procedure). This
resource was not reported by the investigators during this
real-life practice study. Discussion with participating
investigators revealed that in actual fact this cost should be
applied at least once per patient during MAL-PDT treatment, but had
not been recorded because in Belgium there is no cost coding for
such an act so the investigators had not acknowledged it. It was
therefore agreed that the cost for “medical act” was to be included
in the cost per lesion calculations.
Comparison of cost calculated from present study with costs
from previous model
In order to ensure that the costs of care derived from the present
study could be accurately compared to those from the original model
[18], the model costs were updated. The updated figures took into
account different study durations as the present study duration was
6 months whilst model costs were calculated based on a time horizon
of 1 year for AK and 5 years for BCC. The updated model costs were
also based on updated unit costs and only resources which were used
in the real-life practice study were included in the updated model
costs. Cost per lesion was also calculated using the model data.
Statistical methods
Data were analysed using SPSS 11.0 (Statistical Package for the
Social Sciences). Only descriptive statistics were performed.
Results
In total, 241 patients were included. Six patients had both AK and
BCC lesions; for the purposes of statistical analysis the data of
these 6 patients were considered as two different patients.
Therefore, statistical analysis was carried out on 247 cases.
Study population
The mean age was 69 years and there were 116 females (47%) and 131
males (53%). All patients were Caucasian.
Fifteen patients (13%) with AK and 14 patients (11%) with BCC
were lost to follow-up. Two patients withdrew from the study
prematurely due to non serious adverse events, one because of
oedema, erythema, severe crust forming and pain and one because of
severe crust forming.
Baseline disease characteristics
The median time between initial diagnosis and study start (i.e.
decision to treat with MAL-PDT) was 1.4 months (min: 0, max: 155.7
months) for AK and 0.0 months (min: 0, max: 277.2 months) for BCC.
The initial diagnosis was made histologically for 15.5% of AK and
44% of BCC lesions, and the rest were only clinically diagnosed.
Actinic keratoses
AK patients had an average of 7.1 lesions at baseline. In total,
18.8% of patients had 1 lesion, 24.8% had 2 to 5 lesions, 1.7%
had 6 to 10 lesions and 54.7% had more than 10 lesions (table 1). For the purpose of analysis of the
results, where an investigator indicated that a patient had >10
lesions but did not give the exact number of lesions, this figure
was taken to be 11. The average lesion size (length × width) was
20.3 × 12.9 mm.
Approximately one third of AK lesions were described as “primary
lesions”, i.e. had not yet been treated or cured. The remaining two
thirds were “recurrent lesions” i.e. lesions cured by previous
therapy (e.g. excision, elecrosurgery, cryotherapy, 5-FU,
imiquimod) but subsequently recurred.
Table 1 Baseline lesion characteristics
|
AK (N = 117)
|
BCC (N = 130)
|
|
Average number of lesions per patient Mean ± SD
|
7.1 ± 4.7
|
1.7 ± 2.1
|
|
Number of lesions/patient:
|
|
|
|
1 lesion
|
22 (18.8%)
|
-
|
|
2-5 lesions
|
29 (24.8%)
|
-
|
|
6-10
|
2 (1.7%)
|
-
|
|
> 10
|
64 (54.7%)
|
-
|
|
Total number of lesions (whole study population) N
|
829
|
221
|
- Lesion size (mm)
- Mean ± SD
|
|
sBCC
|
nBCC
|
|
Length
|
20.3 ± 35.4
|
17.8 ± 15.2
|
18.9 ± 21.0
|
|
Width
|
12.9 ± 23.6
|
13.1 ± 12.3
|
13.5 ± 17.3
|
|
Primary lesions N (%)
|
106 (32.3%)
|
163 (88.6%)
|
|
Recurrent lesions N (%)
|
222 (67.7%)
|
21 (11.4%)
|
Basal cell carcinoma
BCC patients had an average of 1.7 BCC lesions, 89% of which were
primary lesions and 11% were recurrent lesions (table 1). The mean number of sBCC and nBCC was 1.9
and 1.1 lesions per patient respectively. The mean lesion size
(length × width) was 17.8 × 13.1 mm for sBCC and 18.9 ×
13.5 mm for nBCC. This diameter is rather large, compared to
the data mentioned by Rhodes et al. [17], where about 80% of the
patients had a lesion diameter of less than 15 mm.
Treatment
The average number of pre-treatment consultations to the
dermatologist was 0.68 (table 2). Some
patients had no pre-treatment consultations because their study
start was equal to the start of treatment. In total, 28% of the
patients had a biopsy after inclusion in the study (and before
MAL-PDT-treatment): AK: 18%, BCC: 37%. The average number of
biopsies was 0.29 (AK: 0.18, BCC: 0.38) (table
2).
Patients had an average of 2 MAL-PDT sessions. On average 8.0
pricing units of MAL-PDT were used over the treatment sessions (AK:
9.6, BCC: 6.7 pricing units). Lesion preparation (debulking,
curettage, etc.) before MAL-PDT treatment was performed in 93% of
the lesions. Mean time between first and second treatment session
was 22 days. Mean time between second and third treatment session
(when applicable) was 33 days. The average duration of application
time of MAL-PDT was 3 hours. Average illumination time after
MAL-PDT application was 9 minutes. Patients had on average 1
follow-up visit during the 6 months after the first MAL-PDT session
(table 2).
Table 2 Frequency of consultations and diagnostic
biopsies, number of pricing units used, application time for
MAL-PDT and illumination time (N = 247)
|
AK
|
BCC
|
Total study
|
|
Mean ± SD
|
Mean ± SD
|
Population Mean ± SD
|
|
Consultations
|
|
|
|
|
No. of pre-treatment consultations
|
0.7 ± 0.8
|
0.7 ± 0.7
|
0.7 ± 0.8
|
|
No. of diagnostic biopsies
|
0.2 ± 0.4
|
0.4 ± 0.5
|
0.3 ± 0.5
|
|
No. of consultation during treatment
|
2.0 ± 0.8
|
2.3 ± 0.7
|
2.1 ± 0.8
|
|
No. of consultation in follow up period
|
1.3 ± 0.9
|
1.4 ± 0.8
|
1.3 ± 0.9
|
|
Treatment
|
|
|
|
|
No. of pricing units
|
9.6 ± 8.0
|
6.7 ± 5.0
|
8.0 ± 6.8
|
|
Application time MAL-PDT (hours)
|
3.3 ± 0.6
|
3.4 ± 0.7
|
3.3 ± 0.7
|
|
Illumination time (minutes)
|
9.1 ± 2.5
|
9.1 ± 2.6
|
9.1 ± 2.6
|
Clinical response
Figure 1 shows
the clinical response for both the observational study and the
Randomized Clinical Trials (RCT) data used for the model [12, 16,
17]. The average duration between the first MAL-PDT session and the
first follow-up visit was 2.5 months. During the follow-up period,
83.3% of the patients with AK obtained a complete clinical
response, compared to 80.7% in the RCT [12]. For BCC, a slightly
lower response rate was observed in the study compared to the RCTs
[16, 17]. In total, 85.2% of sBCC patients and 77.8% of nBCC
patients obtained a complete clinical response in the observational
study. For the model, the data used for BCC originated from two
RCTs in which complete clinical response was observed in 88.7% [16]
and 86.5% [17] for sBCC and nBCC respectively.
Cosmetic outcome
The cosmetic outcome to MAL-PDT is shown in figure 2.
In the observational study, 95% of the patients obtained good or
excellent cosmetic outcome after MAL-PDT treatment for AK compared
to 98% patients in the RCT [12].
For BCC, the cosmetic outcome results obtained from the present
observational study were slightly better than those from the RCTs;
94% of the patients with sBCC and 89% of the patients with nBCC had
a good to excellent cosmetic outcome in the observational study
compared to 89% and 82% respectively in the two RCTs [16, 17].
Subsequent therapies
Subsequent therapy was reported to be initiated in cases of non
complete lesion response (clinical and/or cosmetic) in 22% of the
patients. Table 3 shows the subsequent
therapies used for AK and BCC. For AK, the most frequent subsequent
therapy was cryotherapy (62%) followed by MAL-PDT (31%), whilst for
BCC, the most common was MAL-PDT (55%) followed by cryotherapy
(14%) and excision therapy (14%).
Table 3 Subsequent therapy used in cases of
non-complete response with MAL-PDT in AK and BCC
|
AK
|
BCC
|
|
N = 26
|
N = 29
|
|
N (%)
|
N (%)
|
|
Cryotherapy
|
16 (61.53)
|
4 (13.79)
|
|
MAL-PDT
|
8 (30.77)
|
16 (55.17)
|
|
Cryotherapy, imiquimod
|
1 (3.85)
|
-
|
|
Mohs surgery
|
1 (3.85)
|
1 (3.45)
|
|
Excision surgery
|
-
|
4 (13.79)
|
|
Curettage
|
-
|
1 (3.45)
|
|
Electrosurgery
|
-
|
1 (3.45)
|
|
5-Fluorouracil
|
-
|
1 (3.45)
|
|
Unknown
|
-
|
1 (3.45)
|
Concomitant therapy
A total of 58% of patients used analgesics during MAL-PDT treatment
(64% of AK patients and 52% of BCC patients). Of these, the most
common was water spray (55%) followed by water spray + oral
analgesics (24%), oral analgesics (9%), local infiltration (4%),
analgesic spray (4%), water spray + local infiltration (1%), oral
analgesic + local infiltration (1%). The remaining patients used
analgesics of unknown type.
Adverse events
Skin discomfort was experienced by 139 (56%) patients in total (62%
of AK patients and 51% of BCC patients). Other adverse events were
reported by 18 (7%) patients, and included pain (3%), oedema and
erythema (1%), skin necrosis with severe crust forming (1%). Only
two patients discontinued treatment because of adverse event: one
patient because of oedema, erythema and severe crust forming and
pain, the other patient because of severe crust forming.
Cost of MAL-PDT
Table 4 shows the cost of care for AK
and BCC calculated from the observational study data. Table 5 compares the costs calculated in this
real-life study with the predictions obtained from the model.
Cost for actinic keratoses treatment
The total cost of AK care with MAL-PDT in this real-life study was
€380.66, compared with €248.86 predicted by the model (table 5). The number of lesions for AK in the
observational study was higher than the number of lesions assumed
in the model (7.1 per patient in the observational study compared
to 4.1 in the model).
The cost per lesion was calculated for both the model and the
observational data (table 5). The total
cost per AK lesion was calculated to be €58.16 in the real-life
study and €58.70 from the model.
Table 4 Cost of care AK, BCC, nBCC and sBCC in Euros
(health care insurance perspective)
|
AK
|
BCC
|
nBCC
|
sBCC
|
|
Mean N
|
Unit cost
|
Cost
|
Mean N
|
Unit cost
|
Cost
|
Mean N
|
Unit cost
|
Cost
|
Mean N
|
Unit cost
|
Cost
|
|
Pre-treatment
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Consults
|
0.65
|
19.76
|
12.83
|
0.70
|
19.76
|
13.83
|
0.86
|
19.76
|
16.93
|
0.66
|
19.76
|
13.11
|
|
Diagnostic techniques*
|
-
|
-
|
2.42
|
-
|
-
|
5.19
|
-
|
-
|
7.24
|
-
|
-
|
4.68
|
|
Treatment
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Consults
|
1.95
|
19.76
|
38.50
|
2.31
|
19.76
|
45.59
|
2.43
|
19.76
|
47.98
|
2.28
|
19.76
|
44.99
|
|
Pricing units**
|
9.56
|
31.45
|
300.60
|
6.65
|
31.45
|
209.22
|
6.98
|
31.45
|
219.60
|
6.60
|
31.45
|
207.45
|
|
Concomitant therapy
|
-
|
-
|
0.02
|
-
|
-
|
0.00
|
-
|
-
|
0.00
|
-
|
-
|
0.00
|
|
Follow up
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Consults
|
1.32
|
19.76
|
26.17
|
1.35
|
19.76
|
26.59
|
1.32
|
19.76
|
26.11
|
1.36
|
19.76
|
26.80
|
|
Diagnostic techniques*
|
-
|
-
|
0.12
|
-
|
-
|
0.77
|
-
|
-
|
0.90
|
-
|
-
|
0.90
|
|
Total cost
|
|
|
380.66
|
|
|
301.20
|
|
|
318.16
|
|
|
297.92
|
*For diagnostic techniques, no separate mean n and unit
cost is presented since two differently quoted biopsies were
performed. Cost was calculated based on the mix of both.
**1 unit = 200 mg.
For concomitant therapy, only total cost is presented. Only a
small part of the concomitant therapy was reimbursable which
explains the low amount.
Table 5 Total cost of care and cost per lesion for
observational study and model data for AK, nBCC and sBCC
|
Cost of care (euros)
|
|
AK
|
nBCC
|
sBCC
|
|
Total cost of care
|
|
Observational study
|
380.66
|
318.16
|
297.92
|
|
Model
|
248.86
|
278.01
|
227.49
|
|
ARRAY(0x325588)
|
|
Cost per lesion
|
|
Observational study
|
|
|
|
|
MAL-PDT cost/lesion
|
42.35
|
197.77
|
111.60
|
|
Medical cost/lesion
|
15.81
|
117.91
|
66.02
|
|
Total cost/lesion
|
58.16
|
315.69
|
177.62
|
|
Model
|
|
|
|
|
MAL-PDT cost/lesion
|
35.75
|
138.20
|
86.14
|
|
Medical cost/lesion
|
22.95
|
122.07
|
123.69
|
|
Total cost/lesion
|
58.70
|
260.28
|
209.83
|
Cost for basal cell carcinoma treatment
The total cost of care calculated from the real-life study data was
€318.16 for nBCC and €297.92 for sBCC. The model showed a cost of
care for nBCC of €278.01 and a cost of care for sBCC of €227.49
(table 5).
The cost per lesion for nBCC and sBCC was calculated from both
the model data and the observational data (table
5). The total cost per lesion for nBCC predicted by the
model (€260.28) was 17.5% lower than that calculated using the
real-life data (€315.69). The total cost per lesion for sBCC
predicted by the model (€209.83) was 18.1% higher than in the
real-life study (€177.62).
In order to assess the impact of sBCC lesion size on treatment
cost, we calculated the cost per lesion and per lesion size on a
sub-group of patients with only one sBCC lesion and for whom
lesion size was available (64/101, 63.4%). The cost per lesion,
irrespective of lesion size, was 284.29 €, which is
unsurprisingly higher than in the whole sBCC population, where the
mean sBCC number per patient is 1.9, given that some sub-costs
(e.g. consultation costs) are spread out among several lesions. The
cost per lesion was 250.57 € for lesions in which the size
(largest diameter) is < 15 mm (38/64, 53.4%), 332.18 € for
lesions in which the size is comprised between 15 mm and
20 mm (15/64, 23.4%) and 335.47€ for lesions in which the size
is > 20 mm (11/64, 17.2%).
Discussion
Previous clinical trials showed that MAL-PDT had comparable
efficacy to the standard of care (cryotherapy for AK and sBCC and
excision surgery for nBCC), but with improved cosmetic outcomes
[12, 16, 17]. The clinical results of the present real-life
practice study were similar to those of the previous RCTs. The
clinical response and cosmetic outcomes of our study were within 5%
of the results from the RCTs, with the exception of the cosmetic
outcome for BCC where 7% more patients had an excellent cosmetic
outcome in this study than in the RCTs [16, 17]. The comparability
of the results found in this real-life practice study and the
clinical trials can be explained by the fact that MAL-PDT treatment
is a highly standardised, physician-controlled treatment, with the
major advantage of a high compliance.
This study also confirmed that MAL-PDT is well tolerated for
both AK and BCC. The fact that only 2 of the 247 patients withdrew
from this study due to adverse events shows that MAL-PDT is well
tolerated in real-life practice, whereas it has been shown that a
high rate of non-compliance is associated with the onset of
undesirable adverse events for other topical treatments of AK [24].
Fewer AEs were reported in patients with AK in the present study
than in the RCT [12] (62% compared to 73% respectively), which
indicates that for AK treatment, tolerability in real-life practice
is slightly better than that suggested by clinical trials. For BCC,
the number of AEs reported in this real-life study was closely
comparable to the RCTs [16, 17].
For both this study and the model, cost calculations were based
upon 2 sessions of MAL-PDT treatment for AK. However, based on
recent data [25], in Belgium the recommended dose is now one
initial treatment followed by a subsequent treatment 3 months later
if the clinical response is incomplete. The real-life treatment
cost for AK could thereby be lower than that calculated from this
study and could compare even more favourably with comparator
treatments e.g. cryotherapy, on condition that the effectiveness is
not compromised by the new schedule.
The treatment cost per AK lesion of MAL-PDT in this real-life
study was almost identical to that predicted by the model data
(€58.16 and €58.70 respectively). For nBCC and sBCC, costs per
lesion calculated from the real-life data were within 20% of the
models predicted costs. Thus, in terms of cost per lesion, the
real-life data confirmed the predictions made by the model, adding
to the predictive validity of the model.
However, the total cost of care calculated for AK was notably
higher in the real-life study (€380.66) than the model (€248.86).
One explanation is that the patients in the real-life study had an
average of approximately 7 AK lesions, compared to an average of
only 4 lesions in patients in the RCT from which the model cost was
derived [14]. It should also be noted that, for the purpose of cost
calculations, the patients described as having >10 lesions by
investigators (55% of AK patients) were assumed to have 11 lesions.
This estimate is likely to have been conservative as at least some
of these patients are likely to have had more than 11 lesions.
In addition, the Belgian reimbursement criteria, which were used
as inclusion criteria for the real-life study, required that
eligible AK patients should have had more than 10 lesions,
recurrent lesions or have been unsuccessfully treated with
cryotherapy. Considering that recurrent AK lesions are harder to
treat than primary lesions and that 67% of AK lesions were
recurrent, one can conclude that the Belgian reimbursement criteria
only allow “difficult-to-treat” AK patients to receive MAL-PDT.
The total cost of treatment and the cost per lesion were higher
for nBCC than for sBCC in both the model and this real-life study.
This can be explained by a greater number of consultations and a
greater quantity of MAL-PDT used for treating nBCC than sBCC.
The real-life cost of care was €40 higher than the model
prediction for nBCC, and €70 higher for sBCC. However, the MAL-PDT
cost per full responder being lower than the cost of the comparator
for treatment of nBCC and sBCC, excision surgery [14], it still
remains cost effective.
One issue with pharmacoeconomic evaluations is the problem of
how results can be extrapolated to be relevant in different
countries and to different healthcare providers. In order to allow
generalisation of results, the major factors to be considered are
the unit costs of treatment, the volume of drug used (dependent on
the recommended treatment regimen) and the resource use (e.g.
physician time vs nurse time, specialist vs GP). Considering that
in Belgium MAL-PDT can only be administered by a dermatologist
within a hospital setting, and that the AK lesions treated with
MAL-PDT are, by their nature, harder to treat, it could be
considered that costs elsewhere in the world are likely to be
similar to, or lower than, those found in this study. The fact that
this real-life study has confirmed the predictions of the model
means that the same model could be used to evaluate the
cost-effectiveness of MAL-PDT in other healthcare settings,
provided that the appropriate clinical information is
available.
Conclusion
The clinical response, cosmetic outcome, and tolerability results
of this real-life practice study confirm the efficacy and safety of
MAL-PDT demonstrated in previous clinical trials.
The costs calculated from this real-life practice study confirm
the predicted cost-effectiveness shown in the original model for
MAL-PDT in the management of AK and BCC.
Acknowledgements
We would like to thank Antonia Pickup (SciNopsis, France) and Zeina
Saab for medical writing services. Financial support: This study
was funded by Galderma Belgium. Conflicts of interest: All authors
were investigators of the study and received payments for this
study.
References
1 Frost CA, Green AC. Epidemiology of solar keratoses. Br
J Dermatol 1994; 131(4): 455-64.
2 Lebwohl M. Actinic keratosis: epidemiology and
progression to squamous cell carcinoma. Br J Dermatol 2003;
149(Suppl.66): 31-3.
3 Halpern AC, Kopp LJ. Awareness, knowledge and
attitudes to non-melanoma skin cancer and actinic keratosis among
general public. Int J Dermatol 2005; 44: 107-11.
4 Bernard P, Derancourt C, Arnoult-Coudoux E,
Picot R. Etude prospective de l’incidence des cancers cutanés
dépistés en pratique dermatologique dans la région de
Champagne-Ardenne. Ann Dermatol Venereol 2001; 128: 883-7.
5 Gold MH, Nestor MS. Current treatments of actinic
keratosis. J Drugs Dermatol 2006; 5(2 Suppl): 17-25.
6 Nikkels AF, Pierard-Franchimont C,
Nikkels-Tassoudji N, et al. Photodynamic therapy and
imiquimod immunotherapy for basal cell carcinomas. Acta Clin Belg
2005; 60(5): 227-34.
7 Braathen LR, Szeimies RM, Basset-Seguin N,
Bissonnette R, Foley P, Pariser D, Roelandts R,
Wennberg AM, Morton CA, International Society for
Photodynamic Therapy in Dermatology. Guidelines on the use of
photodynamic therapy for nonmelanoma skin cancer: an international
consensus. International Society for Photodynamic Therapy in
Dermatology, 2005. J Am Acad Dermatol 2007; 56(1): 125-43.
8 Stockfleth E, Kerl H, Guideline Subcommittee of the
European Dermatology Forum. Guidelines for the management of
actinic keratoses. Eur J Dermatol 2006; 16(6): 599-606.
9 Babilas P, Landthaler M, Szeimies RM.
Photodynamic therapy in dermatology. Eur J Dermatol 2006; 16(4):
340-8.
10 Bath-Hextall F, Perkins W, Bong J,
Williams H. Interventions for basal cell carcinoma of the
skin. Cochrane Database Syst Rev 2007(1); (CD003412).
11 Szeimies RM, Karrer S, Radakovic-Fijan S,
et al. Photodynamic therapy using topical methyl
5-aminolevulinate compared with cryotherapy for actinic keratosis:
A prospective, randomized study. J Am Acad Dermatol 2002; 47(2):
258-62.
12 Freeman M, Vinciullo C, Francis D, et al.
A comparison of photodynamic therapy using topical methyl
aminolevulinate (Metvix) with single cycle cryotherapy in patients
with actinic keratosis: a prospective, randomised study. J
Dermatolog Treat 2003; 14: 99-106.
13 Morton C, Campbell S, Gupta G, et al.
AKtion Investigators. Intraindividual, right-left comparison of
topical methyl aminolaevulinate-photodynamic therapy and
cryotherapy in subjects with actinic keratoses: a multicentre,
randomized controlled study. Br J Dermatol 2006; 155(5):
1029-36.
14 Foley P, Pariser D, Tarstedt M, et al.
Patient satisfaction after treatment with MAL-PDT of basal Cell
carcinoma and actinic keratoses with MAL-PDT compared to previous
other therapies. J Eur Acad Dermatol Venereol 2005; 19(Suppl 2):
240.
15 Surrenti T, De Angelis L, Di Cesare A,
Fargnoli MC, Peris K. Efficacy of photodynamic therapy
with methyl aminolevulinate in the treatment of superficial and
nodular basal cell carcinoma: an open-label trial. Eur J Dermatol
2007; 17(5): 412-5.
16 Basset-Seguin N, Ibbotson S, Emtestam L,
et al. Photodynamic therapy using methyl aminolevulinate is as
efficacious as cryotherapy in superficial BCC, with better cosmetic
results: results of a European randomized and multicenter study.
Eur J Dermatol 2008; 18(5): 547-53.
17 Rhodes LE, de Rie M, Enstrom Y, et al.
Photodynamic therapy using topical methyl aminolevulinate vs
surgery for nodular basal cell carcinoma: results of a multicenter
randomized prospective trial. Arch Dermatol 2004; 140(1):
17-23.
18 Caekelbergh K, Annemans L, Lambert J,
et al. Economic evaluation of methyl amniolaevulinate-based
photodynamic therapy in the management of actinic keratosis and
basal cell carcinoma. Br J Dermatol 2006; 155: 784-90.
19 Higashi MK, Veenstra DL, Langley PC. Health
Economics Evaluation of non-melenoma skin cancer and actinic
keratosis. Pharmacoeconomics 2004; 22(2): 83-94.
20 Warino L, Tusa M, Camacho F, et al.
Frequency and cost of actinic keratosis treatment. Dermatol Surg
2006; 32(8): 1045-9.
21 Weston A, Fitzgerald P. Discrete choice experiment
to derive willingness to pay for methyl aminolevulinate
photodynamic therapy versus simple excision surgery in basal cell
carcinoma. Pharmacoeconomics 2004; 22(18): 1195-208.
22 Murphy GM. Skin diseases with high public health impact.
Eur J Dermatol 2007; 17(6): 559-62.
23 Horn M, Wolf P, Wulf HC, et al. Topical
methyl aminolaevulinate photodynamic therapy in patients with basal
cell carcinoma prone to complications and poor cosmetic outcome
with conventional treatment. Br J Dermatol 2003; 149(6):
1242-9.
24 Spencer JM, Hazan C, Hsuing SH, et al.
Therapeutic decision making in the therapy of actinic keratoses. J
Drugs Dermatol 2005; 4(3): 296-301.
25 Tarstedt M, Rosdahl I, Berne B, et al. A
randomised multicentre study to compare two treatment regimens of
topical metyl aminovulinate (Metvix)-PDT in actinic keratosis of
the face and scalp. Acta Derm Venereol 2005; 85(5): 424-8.
1 http://www.registreducancer.be.
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