ARTICLE
After the third week of a conventional radiotherapy course (1.8-2 Gy/day,
5 times/week) a spotted dermatitis often appears which tends to progress
unless the treatment is interrupted for some days [1-4]. Doses between
35 and 50 Gy induce confluent dry and moist desquamation [1, 2], occasionally
resulting in interruption of the radiation treatment [4]. The acute skin
changes produced macroscopically by irradiation are erythema, edema, dry
desquamation, pigmentation accompanied by vesicles and blisters, sometimes
leading to ulcerations [5, 6]. Histopathologically, the radiation-induced
skin damage is characterized by capillary dilatation and obstructive vitiation
of arterioles [3, 5]. The accompanying hypoplasia of the squamous epithelium
appears to be due to the apoptotic death of keratinocyte stem cells and
the inhibition of proliferation of transit amplifying cells [3, 5]. The
prevention and treatment of the dermatitis is important to allow the regular
administration of a complete radiotherapy course, the prolongation of
which has a negative impact on disease outcome [7-9].
Amifostine, formerly known as WR (Walter-Reed)-2721, was developed as
a radioprotectant during the Cold War by the Walter Reed Army Institute
[10-13]. It is rapidly dephosphorylated by alkaline phosphatase into its
active form free thiol or WR-1065 [14-17]. Six minutes after the intravenous
administration of amifostine less than 10% of the drug remains in plasma
[15, 18, 19]. This may be due to its rapid conversion into WR-1065, which
is also rapidly cleared from the circulation either by its fast uptake
in normal tissues or by its conversion into disulfides [15, 20, 21]. The
cytoprotective effect of WR-1065 is based on scavenging free radicals,
and donating hydrogen ions for DNA repair [10, 21]. The cytoprotective
effect of amifostine against radiation-induced toxicity has already been
estimated [23-25]. Despite the technological advances of radiation treatment,
the acute skin toxicity remains a problem in routine radiotherapy treatment
of the pelvis especially in the femur-inguinal and middle pygal fold [1-4].
The morbidity may be severe, with acute and long-term consequences. According
to our knowledge the specific impact of amifostine to acute skin reactions
has not yet been documented in terms of radiodermatitis as a primary endpoint.
The aim of this study was to evaluate the radioprotective efficacy of
amifostine against radiation dermatitis in pelvic areas.
Patients and methods
A total of 220 cancer patients with pelvic tumors (bladder, rectum,
prostate, or gynecological cancer) were reviewed in this study. Between
September 1999 and January 2001, 100 patients underwent radiotherapy supported
with intravenous administration of amifostine as a cytoprotective agent.
These patients constituted the amifostine group (group A). Another group
of 120 patients treated before September 1999 who had not undergone radioprotective
treatment represented the historical control (group B). The patients included
in group B had undergone radiotherapy from January 1998 until August 1999.
All bladder-cancer patients had T3-4/Nx-1 disease and were treated only
with radical radiotherapy. Patients with rectal cancer recruited postoperatively
into the study had surgical stage C1/C2 of disease. All patients with
prostate cancer had T1b-T3 stage of disease. Patients with corpus uteri
cancer had limited-stage disease and underwent postoperative radiotherapy.
All patients recruited for cervical cancer had stage IIb to IIIb disease.
Recruitment criteria
Patients recruited in the amifostine-group had a World Health Organization
performance status ¾ 2. They were referred either for radical radiotherapy
(cases of locally advanced inoperable cancer) or radical postoperative
radiotherapy (cases of residual mass or positive histologic margins without
evidence of distant metastases). According to the Helsinki declaration
of human rights, written informed consent was obtained from all patients.
Patients previously treated with radiotherapy or chemotherapy or with
haemoglobin levels less than 11 g/dL or with WBC counts less than 2,500/muL
and platelet counts less than 100,000/muL were excluded. Patients with
major heart, lung, liver, renal, or neurologic/psychiatric disease, and
patients with hematologic malignancies were also excluded. Patients with
hypertension controlled with medication were also eligible for inclusion
in the protocol. No modification of the antihypertensive regimen was performed.
Patients with clinically evident pulmonary insufficiency (exceptional
dyspnoea) were excluded. Patients with serum creatinine or liver enzyme
serum levels higher than 1.5 and 2.5 times the normal values, respectively,
were excluded.
In order to minimise the bias related to the investigator, the 120 patients
as historical control were randomly selected by a database in our hospital.
The random selection of the controls, described in the paragraph of randomisation
method, was performed by an independent external user of the medical database
in the Institute of Telecommunication and Computer Systems of National
Technical University of Athens. The selection of the historical control
was achieved without any access to the personal record of the patient.
Consequently, during the retrospective analysis of the data, the investigators
of this study were provided only with the code-numbers of the patients'
records in a worksheet-form being unaware of the administration of the
amifostine. Patients' characteristics for both groups (amifostine and
historical control) are listed in Table
I.
The procedure for the random selection was divided in three steps. In
step one, 387 patients were included from the database using the recruitment
criteria of the amifostine group (for the homogeneity of the study) as
well as the site of the tumor, the stage of disease and the dose-schedule.
In step two, a pseudorandom generator was used based on the deterministic
mathematical process of Ehrhardt [27]. According to the suggestions for
randomness described by Gleason [28], the uniformity of generated sequences
of numbers and the absence of intra-sequence serial correlation were also
checked. In step three, a second set of 120 random cases was used and
a comparative "off-study" statistical evaluation was performed with the
initial set in terms of radiation-induced dermatitis. By using this endpoint,
no statistical difference was detected between the initial and the second
potential group of cases (P > 0.05, Chi2 test).
Patients' evaluation and radiotherapy
Baseline studies included physical examinations, chest X-rays, blood
counts with differential and platelet counts, complete biochemical profiles,
ECGs and body-weight measurements. Complete blood cell count, serum urea
and creatinine levels, and liver enzyme levels were assessed every 2 weeks
during the radiotherapy period and for 4 weeks thereafter. Response to
treatment (in cases with measurable disease) was assessed with a CT scan
of the area of interest 60 days after completion of treatment.
The World Health Organization (WHO) scale was used to assess the amifostine-related
toxicity [23]. Acute radiation dermatitis related to pelvic radiotherapy
was assessed using the common toxicity criteria scale (CTC, version 2.0,
revised March 23 of 1998) [24]. Both of the latter mentioned toxicity-scales
are included in the routine clinical practice of the radiotherapy department
of Aretaieion University Hospital. Acute radiation dermatitis was assessed
during treatment twice per week and the most severe recorded grade was
evaluated as the final morbidity score for this patient. Mean gross dermatitis
score (MGDS) for every group of patients was the mean value of recorded
radiation induced dermatitis score (according to CTC scale) for all patients
included in each group. The outcome measure of the gross dermatitis scale
has been already used in a previous publication [25]. Radiotherapy treatment
planning was based on pretreatment computed tomography (CT) scans depending
on the site of disease. A standard fractionation regimen was used in all
cases (1.8-2 Gy/fraction, 5 fractions/week). A 6-MV linear accelerator
was used for the irradiation of all recruited patients.
Immediately after documentation of radiation induced severe dermatitis
(grade 2-3), the radiotherapy was interrupted until the grade of dermatitis
regressed to 1. The supportive care was homogeneous in the two groups.
Patients with severe dermatitis in both groups were treated with sitz
baths and steroid cream applications.
Amifostine administration
All patients were pretreated with 5 mg of oral tropisetron 1 hr before
the injection of amifostine. Amifostine (500-mg flat dose) was diluted
in 50 ml of normal saline and was injected intravenously with the patient
in a supine position. The patient's dose ranged from 250 to 330 mg/m2
related to the body-surface area. The injection was repeated daily, before
each radiotherapy fraction. Blood pressure was monitored before and during
IV administration, and at 2, 5 and 10 min after the injection. No further
measurement of blood pressure was performed since generally hypotension
was transient and returned to baseline after a median time of 5 min [26].
Comparative evaluations and statistical analysis
The calculations for the sample size included the following values:
alpha = 0.05, power = 0.9. The optimum sample size supported by power
calculation was performed in two steps. In step one, a primary descriptive
evaluation in a small sample of 33 cases (15 patients in group A and 18
in group B) showed a proportion of 33.3% of dermatitis in the amifostine
group and 55.5% in the historical control. In step two, by assuming a
ratio of 1.2 between the two groups, the required samples were 100 in
group A and 119 in group B, values that are similar to the final sample-sizes.
The above calculations incorporated a continuity correction as described
by Fleiss [29].
Interruption time (in days) due to radiation-induced dermatitis was
recorded. The mean value for interruption time was assessed for each group
(amifostine and historical control). Pearson Chi2 test and
Fisher's exact test for 2 x 2 tables were used to test relationships between
categorical variables [30]. Mann-Whitney U non-parametric test was used
for statistical comparisons between mean values [30]. A P value
< 0.05 was considered as significant. All tests were double-sided and
statistical analysis was performed using the SPSS 8.0 package (SPSS, Inc.,
Chicago, IL).
Results
Grade 2 nausea was noted in 8 of 100 patients (8%) and Grade 1 nausea
was noted in 13 of 100 patients (13%), lasting for nearly 6 hrs after
amifostine injection. Grade 2 vomiting was observed in 7 patients (7%).
Sixty-two patients (62%) complained of severe asthenia (grade 2/3) that
was cumulative. It occurred from the 2nd day of amifostine injection.
Dose reduction to 170-200 mg/m2 allowed the continuation of
amifostine delivery in these patients. In seven out of 100 patients (7%),
grade 2 hypotension was noted during amifostine administration. The IV
infusion was immediately stopped, and normal-saline fluid was administered.
After 3-5 min the pressure was normal again and the residual dose of amifostine
was administered without any further adverse event. Grade I hypotention
was noted in 92 of 100 patients (92%) during cytoprotective treatment
without requiring any therapy.
Four patients (4%) presented with fever (37.5° C to 38.5°
C) and a generalized pink-colored rash throughout their body 4 hrs after
the 4th or 7th injection of amifostine. The fever lasted nearly 10 hrs.
Amifostine interruption and oral therapy with antihistamines for 3 days
resulted in complete remission of the rash within 24 hrs from its onset.
This side effect was considered an allergic reaction to amifostine, and
after 4 days of interruption, cytoprotection was continued in these patients
in conjunction with corticosteroid treatment (250 mg hydrocortisone hemisuccinate)
without any further sign of allergic reaction. Mild xerostomia and a "metallic"
taste in the mouth reported by 16 patients (16%), were persistent throughout
the treatment. Headache was observed in 32 patients (32%) and sweats were
observed in 12 patients (12%). No hematologic toxicity related to amifostine
administration was noted.
Table II lists the radiation-induced
dermatitis observed separately for the two groups of patients scored according
to CTC scale. A significant reduction of incidence and severity of dermatitis
related to irradiation was noted in the group of patients treated with
amifostine compared to the historical control. The cumulative incidence
(i.e. risk) of radiodermatitis (grade 1, 2) was 15 out of 100 (15%)
in the amifostine group and 99 out of 120 (82%) in the control group.
Therefore, the relative risk of the outcome in the amifostime group compared
to the control group is 0.23 (95% CI: 0.15 to 0.34), meaning a 77% reduction
in the risk of radiation-induced dermatitis. Mean gross dermatitis score
(MGDS) for the group A was 0.18 ± 0.09 versus 1.0 ± 0.11 for
group B (P < 0.001, Mann-Whitney U test). A significant reduction
of interruption time related to radiation-induced dermatitis was noted
in group A patients treated with amifostine before radiotherapy as compared
to the historical control. Mean interruption time for the group A was
0.78 ± 1.71 days versus 1.89 ± 2.53 days for group B (P
< 0.001, Mann-Whitney U test). Concerning the age and total dose of
radiotherapy administered, no significant statistical difference was noted
between the two groups (P > 0.05, Mann-Whitney U test), confirming
the fact that the two groups were quite homogeneous in terms of the above-mentioned
parameters. That was also an indication of the adventive and non-biased
way of recruiting patients for the historical control. The mean value
of BMI was 27.0 (± 3.7) and 26.8 (± 3.9) for group A and B respectively,
without any significant difference (P > 0.05, Mann-Whitney test).
Due to the mixed type of tumors recruited in the present study, it was
difficult to compare response rates between the two treatment groups.
Discussion
A temporary treatment interruption and local care is needed for the
majority of patients suffering from acute radiation dermatitis [3, 5].
The period of interruption depends on the severity of dermatitis and this
on the treatment regimen (concurrent chemotherapy-radiotherapy, radiation
dose fractionation) as well as on the patient's skin sensitivity [3].
Amifostine has the unique ability to protect normal tissues but not
tumor cells from radiation or chemotherapy [12, 13, 31-34]. The selective
cytoprotection derives from several mechanisms. First: the concentration
of membrane-bound alkaline phosphatase (amifostine-activating enzyme)
is 275-fold greater in normal than in tumor tissues. Second: this drug
is absorbed by active transport in normal tissues but by passive diffusion
in tumor cells. Third: the lower blood supply especially in the hypoxic
centre of tumorous masses, as compared with normal tissues, may result
in minor delivery of the drug to tumor cells. Fourth: the neutral pH of
normal tissue results in a greater uptake of the drug [10, 32]. These
mechanisms cause higher (about 50-100 fold) drug concentrations in normal
organs than in tumor tissue. In general, preclinical studies demonstrated
that amifostine is anticarcinogenic, antimutagenic, anticlastogenic and
antitransforming [33-35].
Geng et al. [36] studied the topical or systemic prostaglandin
E2 or WR-2721 (WR-1065) administration in terms of protection against
murine alopecia produced by varying doses and schedules of fractionated
radiation. They concluded that application of amifostine enhanced hair
regrowth following radiation with a cytoprotection in the irradiated epidermis.
Further to the conclusion of Geng et al. conclusion, we may say
that since WR-2721 spreads efficiently in the hair follicles then in the
same way it may protect the basal membrane of the epidermis, resulting
in a reduction of skin erythema and desquamation as well. Already back
in 1994, Wasserman reported that skin is one of the favorite targets of
WR-2721 in terms of higher uptake while amifostine produces an up to 2.0-2.4
time greater protection rate against radiation [37]. Recently, Altmann
and Hoffmanns by reviewing 23 patients receiving radioprotection with
amifostine and comparing them with a historical control of 17 patients,
reported a significantly lower dermatologic toxicity of WHO Grade in the
amifostine group [38]. In a randomized study, Koukourakis et al.
[39] noticed only grade 1 toxicity of the perineal/vulvar area versus
a grade 2/3 toxicity noted in all gynecologic and rectal cancer patients
treated without amifostine (P < 0.0001). In another randomized
study with radiotherapy plus/no amifostine for rectal carcinoma, Dunst
et al. [40] reported that patients with additional amifostine had
less acute skin lesions (maximum erythema score: 1.47 ± 0.64 without
amifostine versus 0.87 ± 0.52 with amifostine, P = 0.009).
Our results are in accordance with the above observations. As shown in
Table II, the incidence
and severity of skin-toxicity after irradiation were significantly lower
in the amifostine group.
The impact of BMI on radiation-induced skin reactions is well-established
[3]. However, in our study BMI did not differ in the two groups, meaning
that the potential impact of obesity was homogeneous in the amifostine
and in the control group.
Our results also show that the interruption time due to gross radiation-induced
dermatitis was significantly lower in the amifostine group compared to
the historical control. This is an important advantage of amifostine administration
for patients undergoing radiation therapy. The interruption of radiotherapy
and its prognostic value as regards patients' overall survival rate has
already been associated with the loss of tumoral local control in vaginal
carcinomas and in head and neck tumors [7, 8]. In terms of response of
cervical tumors, no significant difference was found between the two groups.
This was also in agreement with several studies demonstrating the non-protective
role of amifostine in the tumorous tissues [13, 15]. It is also important
to mention that no changes in factors that might modify the administration
of the therapy (personnel, radiotherapy machinery, settings, procedures,
etc.) intervened between group A and group B treatment period.
Several factors in our study contribute to reduce the danger of bias
inherent to a retrospective analysis. Although the observers were not
"blinded" during the evaluation of radiodermatitis, it should be clarified
that they were not aware that they were recording observations for the
purpose of this study. At that time, the patients were entered in a phase
II study for radiation induced gastrointestinal mucositis that is still
on going, but according to the policy in our department, data concerning
dermatitis were also recorded thoroughly. The informed consent concerned
the administration of amifostine for the purpose of the initial study
(evaluation of mucositis and not dermatitis). One possible argument could
be that the quality of data collected for a specific purpose might be
higher than the information collected without a particular purpose in
mind. However, our 5 years daily practice in radiodermatitis assessment
according to CTC scale and previous experience in its treatment ensure
a homogeneous quality data collection [25, 41]. In short, the data for
radio-dermatitis were recorded by physicians with good knowledge of acute
dermatitis and unaware of the purpose of the current study, meaning that
the possible bias could be reduced to a minimum. In addition, we tried
to rule out the potential impact of biased data by performing a random
selection for historical controls.
Concerning the four patients who received intravenous corticosteroids
together with amifostine, the inflammatory process might represent a contributory
factor in radiodermatitis development and the systemic corticosteroid
treatment might be involved in the protection against erythema [42]. However,
these four subjects compared to the whole group of patients treated are
but a minimum number and, moreover, no exceptionally lower score of MGDS
was observed in these cases. In addition, the radiodermatitis desquamation
is not affected by anti-inflammatory treatments, such as the corticoid
administration.
CONCLUSION
In conclusion, the clinical use of amifostine as a radioprotector seems
to safeguard the epidermis lying within a radiation therapy field. This
topic warrants further investigation with randomised clinical trials.
Our results should also represent a starting point to define the dermo-protective
effects, if any, of amifostine. The answers will help to specify the role
of this drug in clinical practice. The possibility that amifostine might
offer skin protection against the solar radiation should also be considered.
Individual responses to radiation-induced DNA damage resulting in radiodermatitis
may be at least in part independent from the type of radiation: gamma-radiation,
UVA, UVB [43]. In addition, epidermal permeability barrier function is
impaired in patients who exhibit clinical signs of radiation dermatitis
and this barrier impairment is comparable to the changes observed with
UV radiation exposure [44]. These similarities in the patho-physiological
mechanisms involved in the dermatitis produced by gamma-radiation as well
as UV exposure suggest that amifostine might be used in the sun-block
pharmaceutical creams for protection against solar UV-radiation..
Article accepted on 10/7/02
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