ARTICLE
Radiotherapy was and is of great value in the treatment of a number of
malignant tumours. As a consequence, despite all the technical improvements,
the problem of acute and chronic radiation injury still exists. The incidence
of radiogenic damage to soft tissue has been reported as being up to 40%
[1]. Furthermore, as a result of the prolonged latency, we are often confronted
with the cutaneous consequences of radiotherapy from the past decade.
Radiation-induced fibrosis (RIF) as a chronic form of cutaneous radiation
syndrome (CRS) following the irradiation of breast carcinomas, is of particular
concern due to its high incidence. Effective treatment of RIF is extremely
difficult. The latissimus dorsi graft is a promising therapeutic approach
in cases of ulcerated RIF following Ablatio mammae and post-operative
irradiation. However, as the patients are usually elderly and frequently
multi-morbid, such an extensive operation is often not possible. A very
good response in an initially ulcerated RIF was seen under oral therapy
with pentoxifylline (PTX) and vitamin E. In the future, this method could
provide a well-tolerated drug therapy as an alternative to surgical intervention.
Case report
A left Ablatio mammae with axillary lymphadenectomy due to breast cancer
(T2, N0, M0) had been carried out on a 60 year-old patient 14 years previously.
After wound healing, radiotherapy was undertaken (orthovolt radiotherapy
after Hellriegel [2], total dose 40 Gy). Under this treatment, a bullous
manifestation of CRS developed. No evidence for a recurrence of the breast
cancer was found in any of the subsequent check-ups. Two years before
admission to our hospital (12 years post-operative), RIF arose over the
whole of the former irradiated area. Six months previously, a painful,
foetid ulceration developed on the left ventral thorax. On admission,
fibrosis with hypo- and hyperpigmentation and telangiectasis in the form
of a poikilodermia was found over the former irradiated area of the left
Regio pectoralis and in the left axilla. Two ulcers (3 x 3.5 and 5.5 x
3 cm) with adherent blackish necroses and raised borders (Fig.
1) were present on the ventral thoracic wall. The area surrounding
the ulcers was extremely painful. Furthermore, a lymphatic oedema was
present in the left arm.
Histologically, a deeply seated hyaline fibrosis and an inconspicuous
epidermis without keratinocytic dysplasia could be determined. The X-ray
examinations of the chest, bony hemi-thorax and the lumbar spine, and
the sonography of the abdomen showed no indication of metastasis of the
earlier breast cancer. Only degenerative osseous changes could be seen.
Although surgery would have been possible in
principle, the patient refused all operative procedures. A conservative
therapy with pentoxifylline 3 x 400 mg/day and vitamin E 2 x 200 mg/day
per os was therefore selected. The therapy produced no side effects and
was very well tolerated by the patient.
The effect of the therapy on perfusion was measured by laser Doppler
fluxmetry (Fig. 2). The
altered morphological conditions, in particular the thickness and structure
of the corium, were recorded by means of 20 MHz sonography (Fig.
3). The areas for measurement were defined as the left (affected
skin) and right (healthy skin) parasternal area at the level of the attachment
of the 5th rib, 4 cm from the lateral sternum edge.
Prior to therapy, an irregular amplitude configuration with low flux
levels was shown by laser Doppler fluxmetry. After one year of therapy,
the amplitudes had become more rhythmical and smooth and the flux had
increased. This can be assessed as an improvement in tissue perfusion.
Sonographically, a decrease in corium thickness from 5.6 to 2.6 mm could
be seen.
A clear subjective improvement in the feeling of tightness and pain
was recorded after 12 weeks. The ulcers healed almost completely within
18 months and adhering crusts became detached (Fig.
4). During this time, the loose necrotic areas were carefully
removed only twice. The local therapy was restricted to emollients.
Discussion
Radiation-induced fibrosis is characterised by a lower tolerance to
exogenous noxae (trauma, UV irradiation, bacterial infection). Despite
the clinically marked telangiectasis, which is common, the nutritive supply
to the tissues is clearly reduced. These factors make the treatment of
this chronic stage of CRS difficult. There is no "golden rule" for a suitable
therapy. The surgical methods of treatment, such as the latissimus dorsi
graft, are limited by general restrictions in the operability and anaesthesia
tolerance of the patients. Furthermore, an operation on such previously
severely damaged tissue is associated with a higher complication rate.
In addition to infections of the wound, graft necrosis and hypertrophic
scars, patients who have a second operation with the implantation of a
prosthesis are particularly at risk [3]. The surgical intervention is
also expensive because of the complexity of the operation and the long
period of post-operative hospitalisation [4].
Few investigations into the medicinal treatment of RIF are available.
Peter et al. described low-dose interferon gamma to be effective
in patients with RIF caused by the Chernobyl power plant accident [5].
Furthermore exogenous superoxide dismutase seems to be successful in superficial
RIF, but is not yet available [6]. The efficacy of PTX in the treatment
of RIF has been known since the start of the 90's [7]. The combined PTX
and vitamin E therapy, which was successfully applied in the present case,
has been previously described by Gottlöber et al. [8]. They
also first observed a subjective improvement in the feeling of tightness
of the skin. Subsequently, a sonographically documented reduction in the
thickness of the corium was found at six months. This observation is supported
by Futran et al. [1], who observed complete healing of necroses
in 75% and a reduction of the fibroses in 67% of patients with CRS under
treatment with 3 x 400 mg PTX. Delanian et al. recently presented
a controlled study of 43 patients with RIF showing a significant reduction
of the involved area under a combination therapy with PTX and vitamin
E [9]. However, the efficacy is obviously limited to chronic radiation
damage. In an animal experimental study, no reduction in acute radiation
damage under PTX was found [10].
The precise pharmacological mode of action is unclear. Rheological and/or
immunological effects are possible. PTX leads to more favourable tissue
nutrition as a result of an improvement in erythrocyte elasticity [11].
This is brought about by an increase in intra-erythrocytic adenosine triphosphate
(ATP) and a simultaneous reduction in intracellular calcium.
Furthermore, the immunological influence of
PTX appears to be of significance. For the most part, the radiation-induced
fibrosis is mediated by the transforming growth factor beta (TGF-beta)
[12]. In addition to the induction of a radiogenic fibrosis, a central
role in scleroderma has been ascribed to this substance [13]. In an in
vitro study, TGF-beta induced collagen biosynthesis could be reduced
by PTX [14]. Interestingly, a synergistic, TGF-beta reducing effect of
PTX and alpha-tocopherol (vitamin E) was found in animal experiments on
pigs after high-dose irradiation [15]. This leads to a functional reduction
in collagen biosynthesis [11]. In addition, fibroblast collagenases are
activated [11]. All these experimental data are supported by our clinical
observations and the observations of Gottlöber, Futran and Delanian
[1, 8, 9].
It is unclear whether or not the downregulation of TGF-beta expression
by PTX could also be an explanation for a decrease in radiation damage
of this substance in acute radiation damage described by Ward et al.
[10]. Because TGF-beta is known to be immunsuppressive by inhibiting the
production of several proinflammatory cytokines (e.g. TNF-alpha,
IL-1) and nitric oxide [16], it seems to be possible that a reduction
of this substance leads to inflammation. Though some of the cytokines
suppressed by TGF-beta (TNF-alpha, IL-1) are thought to be radioprotective
[17], the proinflammatory effect of reduced TGF-beta expression seems
to predominate.
Side effects of oral PTX therapy with a standard dose of 1,200 mg/day
are rare. Gastrointestinal complaints (nausea, vomiting and dyspepsia)
occur in less than 3% of cases [12]. Headaches and restlessness have been
observed at an incidence of between 1.2 and 1.9%; Angina pectoris in 0.3%
of patients. A disadvantage of the therapy described is certainly the
long treatment period of at least six months.
The oral application of PTX and vitamin E is an effective and inexpensive
medicinal therapy for RIF (daily therapy costs in Germany about 1.3 Euro).
In particular, those patients for whom surgical treatment is not possible
can be helped. Furthermore, the potential of early therapy of radiation-induced
fibrosis with PTX and vitamin E as an ulceration prophylaxis should be
investigated in the future.
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