ARTICLE
Auteur(s) : Maria Cristina Leonardi 1, Silvia Gariboldi 2, Giovanni Battista
Ivaldi1, Annamaria Ferrari1, Flavia
Serafini1, Florence Didier3, Luigi
Mariani4, Simona Castiglioni5, Roberto
Orecchia1,6
1Division of Radiation Oncology, European Institute
of Oncology, via Ripamonti, 435, Milan, Italy
2Department of Human Morphology, Università degli Studi
di Milano, via Mangiagalli, 31, Milan, Italy
3Division of Psyconcology, European Institute of
Oncology, via Ripamonti, 435, Milan, Italy
4Unit of Medical Statistics and Biometry, National
Cancer Institute, via Venezian, 1, Milan, Italy
5Casa di Cura Santa Maria Holding Multimedica, viale
Piemonte, 70, Castellanza (VA), Italy
6Institute of Radiological Sciences, Università degli
Studi di Milano, via Di Rudinì, 8, Milan, Italy
accepté le 25 Decembre 2007
Acute radiation dermatitis (RD) is a common side effect of
radiotherapy in many forms of cancer (e.g. head and neck, breast
and low pelvic carcinomas). The intensity of the reaction depends
on the radiotherapy fraction schedules, the total dose, the treated
skin area, and also individual variations [1]. The appearance of
the skin is often described as resembling severe sunburn (erythema)
with peeling (dry desquamation). The reaction may become more
severe with varying degrees of epidermal loss (moist desquamation)
and, very rarely, necrosis [2]. Trans-epidermal water loss (TEWL)
escalates with the progression of these symptoms [3]. Although
relatively short lived, skin reactions are uncomfortable and itchy,
can be painful and are sometimes dose-limiting [4].
Overall, however, there is no gold-standard approach in the
prevention and management of radiation dermatitis; practice seems
to be varied across countries and between centres in each country.
Clinical studies of varying quality have been carried out to assess
the efficacy of a range of treatments. These include simply washing
with water and mild soap, use of aqueous cream, aloe vera, topical
corticosteroids of varying potency, gentian violet, sucralfate
cream and hyaluronic acid cream. Reviews of these studies concluded
that only the last two preparations reduce the severity of skin
reactions experienced by patients [5-7]. However, a recent clinical
trial compared the use of either aqueous or sucralfate cream with
no cream, to establish whether either of these creams could reduce
acute skin toxicity during radiotherapy (RT) [8]. It was concluded
that neither of the creams prevented radiation skin reactions.
Although hydrocortisone cream can provide some symptom relief,
steroid creams may mask superficial infection and should be used
with caution.
MAS065D (Sinclair Pharmaceuticals Ltd, Godalming, UK) is a
non-steroidal medical device registered in the US and EU for the
symptomatic treatment of RD. MAS065D is a water-in-oil cream with
barrier-forming, hydrating and anti-inflammatory properties that
can minimize the side effects of RT on the skin. Here we report the
results of a randomised, double-blind, vehicle-controlled clinical
study, that evaluated the efficacy of MAS065D in minimizing acute
skin reactions and associated symptoms during and after RT for
breast cancer.
Materials and methods
Study population
Following signature of the informed consent approved by the
relevant Ethic Committee (EC), 40 adult women diagnosed with breast
cancer, scheduled to receive post-operative radiotherapy, were
enrolled in the study. Patients had to observe a washout period of
7 days and refrain from using other topical medications for the
entire study period; patients with tumour involvement of the skin
were excluded from the study; pregnant and lactating women were
also excluded, as were women with known allergies to any of the
ingredients present in MAS065D, with a history of substance or
alcohol abuse, or any other physiological condition that could, in
the investigator’s opinion, adversely affect patients’ adherence to
the protocol.
Study design
This randomised, double-blind, vehicle-controlled, clinical study
was conducted at the European Institute of Oncology (IEO), in
Milan. The clinical volume for radiotherapy was to the breast with
a field size of at least 12 × 12 cm. RT was delivered daily to
the whole breast with tangential fields (2.25 Gy/fraction) and
concomitantly to the surgical bed in the same session
(0.25 Gy/fraction via variously-angled photon beams) in 20
fractions over 4 weeks, using a 6 MV linear accelerator. Patients
were examined at the baseline and at consecutive weekly intervals
during RT and 3 weeks after its completion.
Treatments
Patients were randomised to receive tubes of study medication or
vehicle. The randomization was generated by computer and both
patients and investigators remained blind to it throughout the
study. The randomisation codes were only opened at the time of
statistical analysis. Vehicle was an emollient base cream similar
in colour and consistency to MAS065D, but without the key
ingredients. Patients were instructed to apply the study cream on
the irradiated area three times daily, starting on the first day of
irradiation and continuing until 3 weeks after completion of RT.
The use of other topical medications for the treatment of RD was
not permitted during the study.
Study endpoints
The primary efficacy endpoint was the maximum degree of radiation
dermatitis experienced during RT and the follow-up period. Skin
reaction was visually assessed and recorded with reference to
erythema, desquamation, oedema, moist desquamation and ulceration,
using the skin toxicity criteria of the National Cancer Institute
(NCI) [9]. Secondary endpoints of the study were the patient’s
evaluation of itch, pain and burning within the radiation field,
assessed with a 0-10 cm visual analogue scale (VAS), where 0
corresponded to “none”, and 10 to the “worst severity possible”.
Patient fatigue, the severity of symptoms from the patient’s
perspective, and compliance with study medication were also
investigated.
Evaluations were carried out at baseline, at weekly intervals
for 28 days of RT, and 3 weeks after completion of RT.
Statistical methods
All study endpoints were summarized appropriately by variable;
categorical data by counts and percentages and continuous variables
by mean, standard deviation, median, minimum, maximum and number of
patients. Baseline characteristics of the two groups of patients
were compared by Student’s t-test or Chi-square test, as
appropriate. Differences in the maximum degree of RD between
treatment arms were assessed using the Wilcoxon (Mann-Whitney)
Ranks-sum test. For clinical symptoms, severity of symptoms from
the patient’s perspective, and compliance with study medication the
Wilcoxon (Mann-Whitney) Ranks-sum test or the Chi-square test were
applied.
The analysis was performed as an ITT (Intention To Treat)
analysis and missing values were substituted by the Last
Observation Carried Forward (LOCF) method.
All significant tests were two-sided and performed at the 5%
significance level.
Results
Study patients
40 Caucasian female patients, with a mean age of 57.26 years, were
enrolled in the study between June 2004 and May 2005: 22 (55%) were
randomised to MAS065D and 18 (45%) to vehicle. Thirty-five patients
(87.5%) completed the study. One patient (4.5%) in the MAS065D and
4 patients (22.2%) in the vehicle group were withdrawn from the
study, at the investigator’s decision, due to a worsening of the
skin reaction, resulting in a 1 point increase on the NCI scale for
skin toxicity.
Baseline characteristics
Baseline characteristics are summarized in table
1. The Karnofsky performance score, tobacco use, breast
size, breast condition and skin pigment, were recorded at baseline
for each patient. Breast size was “medium” in 50% of the patients,
and skin colouring was “white” or “light brown” in about 90%. 24
patients (60%) reported never having smoked; of these 11 (27.5%)
were randomised to MAS065D, and 13 (35.8%) to the vehicle; 3
patients in each group reported having quit smoking more than 6
months before surgery, while 8 (20%) patients in the MAS065D and 2
(5%) in the vehicle group were smokers. Skin condition at baseline
was “well healed” for all but 1 patient, for whom this was not
specified. No statistically significant difference was found
between the groups as for the aforementioned baseline
characteristics.
Table 1 Patients’ characteristics
|
MAS065D
|
Vehicle
|
- MAS065D vs vehicle
- p-value*
|
|
N of patients
|
22
|
18
|
|
|
Ethnic origin
|
|
Caucasian
|
22 (100%)
|
18 (100%)
|
-
|
|
Age
|
|
Mean
|
59
|
55
|
0.28
|
|
Range
|
43.5-76.9
|
33.1-75.4
|
|
|
Karnofsky performance
|
|
|
|
|
Score
|
|
|
|
|
100
|
22 (100%)
|
18 (100%)
|
-
|
|
Skin colouring
|
|
White
|
7 (31.8%)
|
11 (61.1%)
|
0.164
|
|
Light brown
|
12 (54.5%)
|
5 (27.7%)
|
|
|
Brown
|
3 (13.6%)
|
2 (11.1%)
|
|
|
Affected breast
|
|
Right
|
11 (50.0%)
|
11 (61.1%)
|
0.537
|
|
Left
|
11 (50.0%)
|
7 (38.8%)
|
|
|
Condition of the breast
|
|
Well healed
|
21 (95.4%)
|
18 (100%)
|
1.00
|
|
Not specified
|
1 (4.5%)
|
-
|
|
|
Tobacco use
|
|
Never used
|
11 (50%)
|
13 (72.2%)
|
0.182
|
|
Yes quit > 6 months
|
3 (13.6%)
|
3 (16.6%)
|
|
|
Yes currently
|
8 (36.3%)
|
2 (11.1%)
|
|
|
Breast size
|
|
Small
|
7 (31.8%)
|
5 (27.7%)
|
0.151
|
|
Medium
|
13 (59.0%)
|
7 (38.8%)
|
|
|
Large
|
2 (9.0%)
|
6 (33.3%)
|
|
Efficacy
Primary endpoint – Maximum degree of radiation dermatitis (NCI
grading index)
A statistically significant difference (p < 0.0001) between the
two groups was found for the maximum degree of RD: 20 (91%)
patients in the MAS065D group reported a grade 0 or 1 (faint
erythema or dry desquamation) on the NCI skin toxicity scale,
compared with 16 (89%) patients treated with vehicle, who reported
a grade higher or equal to 2 (moderate to brisk erythema). The only
2 cases that reached a grade 3 were recorded in the vehicle group,
during the follow-up visit. The most significant differences
between the two groups were recorded after three weeks of treatment
(table 2).
Table 2 Maximum degree of radiation dermatitis (NCI
grading index). MAS065D vs vehicle – Wilcoxon Rank-Sums test: p
< 0.0001
|
NCI grade
|
MAS065D
|
Vehicle
|
|
0
|
1 (4.5%)
|
-
|
|
1
|
19 (86.3%)
|
2 (11.1%)
|
|
2
|
2 (9.0%)
|
14 (77.7%)
|
|
3
|
-
|
2 (11.1%)
|
|
≥ 4
|
-
|
-
|
Secondary endpoints – burning, itching, pain within radiation
field (VAS 0-10 cm)
A statistically significant difference (p = 0.039) was registered
for burning within the radiation field, in favour of MAS065D. The
mean value (± SD) registered for the increase in burning sensation
was 1.27 (± 2.14) in patients treated with vehicle, compared with
0.13 (± 1.32) in patients treated with MAS065D. Although better
results were evident in the MAS065D group with respect to pain [0.4
(± 1.76) vs 0.9 (± 1.86)] and itch [0.8 (±1.99) vs 1.05 (± 2.01)],
no statistically significant differences between the two groups
were recorded for these symptoms (table
3; median = 0, for all the parameters).
Table 3 Degree of pain, itching and burning in the
irradiated territory. VAS - 0 (no symptom) to 10 (worst possible
symptom)
|
Treatment
|
Visit/Changes
|
Mean VAS score
|
Std Dev
|
|
PAIN
|
MAS065D
|
Baseline
|
0.59
|
1.368
|
|
(P = 0.43)
|
(N = 22)
|
Week 4
|
1.00
|
1.511
|
|
Changes vs baseline
|
0.40
|
1.763
|
|
Vehicle
|
Baseline
|
0.55
|
1.199
|
|
(n = 18)
|
Week 4
|
1.50
|
2.255
|
|
Changes vs baseline
|
0.94
|
1.862
|
|
ITCHING
|
MAS065D
|
Baseline
|
0.27
|
0.935
|
|
(P = 0.96)
|
(N = 22)
|
Week 4
|
1.04
|
1.703
|
|
Changes vs baseline
|
0.77
|
1.998
|
|
Vehicle
|
Baseline
|
0.16
|
0.514
|
|
(n = 18)
|
Week 4
|
1.22
|
2.129
|
|
Changes vs baseline
|
1.05
|
2.013
|
|
BURNING
|
MAS065D
|
Baseline
|
0.22
|
0.751
|
|
(p = 0.039)
|
(N = 22)
|
Week 4
|
0.36
|
1.135
|
|
Changes vs baseline
|
0.13
|
1.320
|
|
Vehicle
|
Baseline
|
0
|
0
|
|
(n = 18)
|
Week 4
|
1.27
|
2.136
|
|
Changes vs baseline
|
1.27
|
2.136
|
Secondary endpoints – fatigue, severity of symptoms from the
patient’s perspective and compliance with study medication
As regards the symptoms assessed by the patients, a significant
difference between treatments was observed for desquamation during
the fourth-week visit of the study (figure 1): only 13.5% (3
of 22) of patients reported mild to moderate desquamation, compared
with 50% (9 of 18) in the vehicle group. (Chi square test p =
0.02). By contrast, no statistically significant difference between
the two arms was observed for dryness, itching, pain or
difficulties in wearing underclothing.
Both study creams were well tolerated, for their cosmetic
acceptability, with no statistical differences between groups.
Safety
No adverse events were observed or reported in either group.
Discussion
Despite the common occurrence of radiation-induced skin toxicity,
there have been very few trials that have formally evaluated the
usefulness of topical therapy and, to date, there is no universally
accepted standard approach. It would therefore be of interest to
investigate the role of new compounds that could reduce the
incidence and severity of acute skin reactions caused by ionising
radiation, thus improving patients’ quality of life and compliance
to treatment constraints.
Although limited by the small number of patients, this study
registered a statistically significant difference between vehicle
and MAS065D groups regarding the maximum severity of skin toxicity
(p < 0.0001), symptoms of burning within the radiation field (p
= 0.039) and desquamation (p = 0.02). Baseline characteristics were
well balanced, although a higher proportion of women with fair skin
was allocated to the vehicle group. Although the relationship
between skin type and the response to exposure to ultraviolet light
is well known, the potential prognostic factor of skin phenotype
for radiation-induced dermatitis is uncertain and to date there are
no studies that show a systematic correlation. Other factors
presumed to have an impact on the severity of radiation-induced
dermatitis, such as breast size and smoking, failed to reach
statistical significance in our study, probably due to the small
cohort of patients.
This interim analysis showed that MAS065D can have a beneficial
role in the management of patients undergoing RT for breast cancer.
In this study, the topical application of MAS065D from the first
day of RT until 2 weeks after its completion was associated with a
significant reduction in the severity of erythema (p < 0.0001)
and a significant reduction in burning sensation (p = 0.039), two
conspicuous and widely-encountered symptoms of radiation
dermatitis. No adverse events were observed or reported and none of
the patients randomized to MAS065D was required to stop RT as a
consequence of the effects of radiation dermatitis. No significant
differences were observed concerning pain, itching and dryness.
Notwithstanding this, patients expressed an overall appreciative
opinion of the effectiveness of MAS065D.
MAS065D is a water-in-oil formulation containing hyaluronic acid
(HA), shea butter, glycyrrhetinic acid (GrA), Vitis vinifera and
telmesteine, which are believed to contribute, synergistically and
independently, to the minimization of radiation induced skin
reactions. HA is a major component of the extracellular matrix of
the skin. It has demonstrated remarkable hygroscopic properties
which are relevant to wound healing [10]. HA is also the most
powerful moisturizing agent known, being able to attract and retain
1,000 times its weight in water. Shea butter is an excellent source
of saturated fatty acids, mono-unsaturated fatty acids and linoleic
acid and resembles sebum in its composition. It is these fatty
acids that help restore skin barrier function, by supporting the
elasticity and turgidity of the skin [11]. GrA has demonstrated the
ability to inhibit 11β-hydroxysteroid dehydrogenase, an enzyme
responsible for metabolizing hydrocortisone. Inhibition of this
enzyme results in an accumulation of endogenous hydrocortisone, a
natural steroid with anti-inflammatory properties [12, 13]. The
anti-inflammatory action of GrA is reinforced by the presence of
bisabolol (chamomile extract) [14]. Vitis vinifera extract in the
formulation exerts a natural antioxidant activity, a property that
may be very helpful against radiation-induced skin damage [15, 16].
MAS065D also contains telmesteine, which has shown anti-elastase
and anti-collagenase activity in vitro [17]. Given the results of
this interim analysis, and those of a recently published
randomised, double-blind pilot clinical study [18], MAS065D can be
regarded as one of the available treatment regimens effective in
the prevention of radiation skin reactions and the promotion of
symptomatic relief.
Acknowledgments
Sponsor: Sinclair Pharmaceuticals Ltd, Godalming Business Centre,
Woolsack way, Godalming, GU7 1XW Surrey, UK. We thank Dr. Antonio
Colantoni for the statistical analysis of data. Conflicts of
interest: none declared.
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