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Review

Oxford, UK
International
IJD
Blackwell
1365-4632
45 Publishing,
Publishing
Journal Ltd,
of
Ltd.
Dermatology
2004

Risti
Radiation recall dermatitis
Radiation recall dermatitis
Review

Biljana RistiC, MD

From the Department of Dermatology, Clinical


Center Bezanijska kosa, Belgrade, Serbia

Correspondence
Biljana Risti, MD
Department of Dermatology
Clinical Center Bezanijska kosa
Autoput bb
11 080 Belgrade
Serbia
E-mail: biljara@ptt.yu

antituberculous drugs.11 Recall reactions are mainly seen


Introduction
in the skin.3 Other sites reported include the lungs,6 vaginal
Radiation recall dermatitis (RRD) is the development of an mucosa,12 laryngeal mucosa,13 central nervous system, bowel,
inflammatory reaction throughout a previously irradiated and esophagus.3
area, precipitated by the administration of certain drugs. So far, few published data have been reported on the incid-
Recall trigger drugs are usually, but not exclusively, intraven- ence of radiation recall reactions, as most information has
ous cytotoxics. The time period between radiation exposure been based on isolated case reports. The only available data
and the administration of a recall trigger drug may be from on incidence have been reported in a study by Tan et al.,14 in
several days to years. The recall usually occurs on first which 27 patients out of a total of 57, or 47%, developed RRD.
exposure to a particular recall trigger drug. Subsequent admin-
istrations of a trigger drug tend to produce either only a mild
Clinical Features
recurrence or no recurrence of recall. The main clinical features
are erythema, desquamation, edema, urticaria-like lesions, Clinical signs include erythema, desquamation, edema,
vesiculation, necrosis, ulceration, and hemorrhage. Patients urticaria-like lesions, vesiculation, necrosis, ulceration, and
usually complain of pruritus or pain. All clinical signs tend hemorrhage (Fig. 1a,b). Patients usually complain of pruritus
to resolve without any specific treatment over several weeks. or pain. Camidge and Price2 proposed a grading system for
Steroids, systemic or topical, and antihistamines control RRD (Table 1).
pruritus and/or pain. A number of different hypotheses have Usually, the most severe RRD is associated with a shorter
been proposed for the potential etiology and pathogenesis of time period between the end of radiotherapy and exposure to
RRD. These hypotheses have focused on vascular damage, the trigger drug. Interestingly, however, the same grade of RRD
epithelial stem cell inadequacy, epithelial stem cell sensitivity can be produced across a very wide range of radiotherapy
or drug hypersensitivity as the mechanism for RRD. drug time intervals.2 As the radiotherapydrug interval
decreases, there is a potential overlap of RRD with either
radiosensitization or impaired healing of ongoing skin
Definition
reactions. Radiosensitizers enhance the effect of radiation on
RRD is defined as a skin reaction, with all the clinical signs of normal and malignant tissues by increasing the initial damage
inflammation, in a previously irradiated field subsequent to produced by radiation, or by interfering with the subsequent
drug administration (usually cytotoxic drugs) days to years repair of this damage. According to a number of animal
after exposure to ionizing radiation. It was initially described and human studies, there is a defined sensitive period of about
in association with actinomycin-D by DAngio et al.1 Since 3 days after irradiation during which drug treatment produces
then, many other drugs have been associated with radiation enhanced radiation reactions.2 Camidge and Price2 have
recall reactions, most often chemotherapeutic agents.27 proposed that skin reactions brought about by drugs given
Other drugs reported as triggers include tamoxifen (nonster- less than 7 days after radiotherapy should be considered
oidal antiestrogen),8 interferon alfa-2b,9 simvastatin,10 and radiosensitization rather than RRD. Radiation, itself, may 627

2004 The International Society of Dermatology International Journal of Dermatology 2004, 43, 627631
628 Review Radiation recall dermatitis Risti

2
Table 1 Grading system for radiation recall dermatitis

Grade Clinical signs

1 mild Erythema pruritus dry desquamation


2 mild/moderate Grade 1+ pain, edema, urticaria-like, vesiculation
3 moderate Moist desquamation
4 severe Necrosis, ulceration, or hemorrhage

RRD from the other clinical entities which may cause dia-
gnostic difficulties. Erysipelatoid carcinoma and panniculitis
always have a chronic course with characteristic pathology.

Radiation Characteristics
Certain radiation characteristics are very important for the
development of RRD. The minimal required dose of radiation
for RRD has not been determined. The majority of published
case reports specify the radiation dose to the tumor, not to the
skin, and the minimal required dose for RRD is probably
lower than the therapeutic radiation dose for the tumor. The
time gap between radiation and drug exposure is also very
important. The radiation dose necessary for RRD when a drug
is given soon after radiotherapy may no longer be sufficient
if the drug is given days or weeks later.2 Stelzer et al.15 have
demonstrated that it is necessary to achieve a minimal
Figure 1 (a) Erysipelas-like erythema restricted to the area of
cumulative radiation dose for the development of RRD.
irradiation. Note the enlargement of the left arm and breast due They treated three similar skin lesions of Kaposis sarcoma
to impaired lymphatic drainage and (b) pale erythema extending in a human immunodeficiency virus (HIV)-positive patient
to the back (courtesy of D. Marisavljevic, md, Hematology with different radiation doses. After the administration of
Department, Clinical Center Beanijska kosa, Belgrade, bleomycin, cutaneous manifestations of RRD developed only
Serbia) in the area treated with the highest radiation dose. Yeo and
Johnson5 have observed a similar effect in one patient treated
with docetaxel. In contrast, Kuku et al.16 presented a case
provoke an acute radiation dermatitis with the same clinical report of gemcitabine-induced erysipelas-like skin lesions in a
manifestations as RRD. Severe skin reactions may take weeks patient with no previous history of radiotherapy or lymphe-
to heal. During that period, a trigger drug may provoke an dema at that site. There were no data available on whether the
exacerbation by interfering with the ongoing healing process. patient had received an injury or X-ray diagnostic procedure
This reaction is probably quite different from a recall phe- at that site that might have influenced the later development
nomenon, but is indistinguishable at that point. Camidge and of skin lesions. Valentin17 has suggested that, during certain
Price2 have suggested that all acute radiotherapy reactions interventional radiology procedures, skin doses approach
in the skin should be completely healed before any drug those experienced in some cancer radiotherapy fractions.
exposure can be assigned as producing RRD. The use of inappropriate equipment or poor operational
The differential diagnosis of RRD includes erysipelas, techniques may increase the absorbed dose. As we do not
herpes zoster, fixed drug eruption, erysipelatoid carcinoma, have reliable data on the minimal required dose for RRD, it
panniculitis, and other radiation reactions. The history of pre- would be of great benefit to exclude previous exposure to
vious exposure to radiation, the course of the disease (recurrent either diagnostic or therapeutic X-ray procedures.
course with milder clinical signs after each of the subsequent
administrations of the drug), laboratory tests (without any sign
Drug Characteristics
of inflammation), and the time gap between the end of radio-
therapy and exposure to the trigger drug (with subsequent Usually, RRD has been reported in association with chemo-
clinical features of RRD) are usually sufficient to distinguish therapeutic drugs, given as monotherapy. No particular

International Journal of Dermatology 2004, 43, 627 631 2004 The International Society of Dermatology
Risti Radiation recall dermatitis Review 629

reaction has been recorded in association with chemotherapy can produce certain stable cellular changes that increase
protocols (consisting of several drugs given at the same time). stem cell sensitivity. From several in vitro studies, there is
Interestingly, RRD is not a privilege of cytotoxics, as it has evidence that radiation can produce stable long-term changes
been reported in association with antiestrogen,8 interferon alfa- in the cell phenotype.2 The p53-mediated signal transduction
2b,9 simvastatin,10 and antituberculous drugs.11 On the other pathway activates the cellular response to DNA damage
hand, some commonly used cytotoxics, such as cyclophos- produced by ionizing radiation. Smith et al.21 have revealed,
phamide, have never been reported as trigger drugs in RRD. using immunohistochemical staining, that cumulative p53
RRD usually occurs on first exposure to a particular recall mutations may play some, but not the major, role in the patho-
trigger drug; however, there have been a few reports of genesis of RRD. In their opinion, mitochondrial dysfunction
presensitization in RRD. In several cases, particular recall probably has a more important role in these eruptions.21
trigger drugs have been given several times in one month Camidge and Price2 have suggested that RRD may be an
before eliciting RRD.18,19 The speed of onset of RRD varies example of a drug hypersensitivity reaction. Such a reaction
according to the different application of a trigger drug. The would probably not be immune (occurs on first exposure,
onset is faster with intravenous drugs (ranging from a few usually without reccurence), but would be more likely to
minutes to several days; median, 3 days) than with oral drugs involve direct nonimmune activation of inflammatory
(ranging from 3 days up to 2 months; median, 8 days).2 The pathways (like a fixed drug eruption).2
same is true for the time taken for RRD to resolve. With this Most of the accused drugs provoke a disruption of DNA
in mind, the previously mentioned presensitization can be and trigger the formation of free radicals. Radiation also
explained as a cumulative reaction triggered after the first cleaves DNA and makes it vulnerable to free radical attack.
exposure to a drug. Finally, the cellular recovery after radiation exposure is
Rechallenge with the recall trigger drug may provoke inhibited via the inhibition of DNA repair, and this could be
another recall reaction, but this is not the rule. Usually, the one possible mechanism for RRD.5 These findings correlate
recurrence of RRD presents with milder clinical signs than at with those of Smith et al.,21 who reported an acceleration of
the first instance. cell damage due to free radicals.
The review by Martin et al.22 has attracted our attention.
They showed that transforming growth factor-1 (TGF-1)
Pathology
protein was overexpressed in samples of postradiation fibrotic
Skin biopsies of RRD reveal signs of acute or chronic epidermal skin, in both scarred epidermis and fibrotic dermis. These
radiation injuries with a nonspecific, mixed, inflammatory fibrotic samples were surgically removed over a period from
infiltrate.2,12,20,21 Dermal changes include dermal fibrosis, 6 months to 20 years after radiation exposure. Moreover,
vasodilatation, and atypical fibroblasts. Immunohistochem- skin cells isolated from the tissue retained their dysregulated
ical staining for p53 in epidermal keratinocytes shows only secretion of TGF-1 in culture, especially keratinocytes. The
a modest increase compared with skin matched for similar same results were obtained for postradiation fibrosis in the
ultraviolet radiation exposure.21 intestinal tract, lung, bladder, and liver. TGF-1 is a multi-
functional cytokine. Apart from its immunosuppressive role
and activities in the remodeling of the extracellular matrix, it
Etiology and Pathogenesis
acts as a potent negative regulator of growth for most cell
A number of different hypotheses have been proposed for types, including epithelial, endothelial, and hematopoietic
the potential etiology and pathogenesis of RRD. These hypo- cells. Several studies have reported that TGF-1 mediates
theses have focused on vascular damage, epithelial stem cell mast cell chemotaxis.23,24 Gruber et al.23 have demonstrated
inadequacy, epithelial stem cell sensitivity or drug hyper- that femtomolar concentrations of TGF-1 induce rapid and
sensitivity as the mechanism of RRD.2 Bostrom et al.8 have pronounced mast cell chemotaxis. They also suggest that mast
suggested that local vascular permeability or proliferative cells can bind TGF-1 through at least two transmembrane
changes induced by radiotherapy may affect the subsequent proteins. Olsson et al.24 went further and compared the
pharmacokinetics of the trigger drug. Other authors have potency of different members of the TGF- family as human
proposed that radiation may decrease the number of epithelial mast cell chemotaxins. They demonstrated that TGF-3 was
stem cells in irradiated fields. In addition, the ability of stem a more effective chemotaxin than TGF-1 and TGF-2 at the
cells to proliferate may remain permanently impaired after same concentration. In contrast, TGF-3 was a less efficient
radiation exposure.2 Abadir and Leibmann10 have proposed inhibitor of proliferation of human mast cells than the other
that radiation may increase stem cell sensitivity by switching two TGF- factors. They also confirmed the expression of
the cell cycle at a faster rate. In this case, stem cells still maintain TGF- receptors on human mast cells. Even though TGF-1
an adequate functional role, but become more susceptibile to is capable of inhibiting mast cell proliferation, it does not
drug damage.10 Other hypotheses have proposed that radiation affect the degranulation and release of histamine directly.23,25

2004 The International Society of Dermatology International Journal of Dermatology 2004, 43, 627631
630 Review Radiation recall dermatitis Risti

RRD is usually seen in cancer patients treated previously or pain, but the time to the resolution of cutaneous mani-
with radiation therapy. The accumulation of mast cells festations remains the same with or without steroid or
around tumor areas is well known. On the other hand, a few antihistamine treatment.2,3
studies on animal models have demonstrated increased TGF-
immunoreactivity and mast cell hyperplasia,26 with high
Conclusions
levels of mast cell amines, histamine, and serotonin greatly
exceeding those of any normal tissue,27 in radiation-induced With the increasing use of combination radiotherapy and
enteropathy26 or pulmonary fibrosis.27 These measurements chemotherapy in the treatment of malignant disease, a better
were recorded 226 weeks26 or 48 weeks27 after radiation knowledge of the pathogenesis of RRD and its appropriate
exposure (dose, 30 50 Gy; single dose or fractions). management have become necessities. The main question is
Recent studies2830 have demonstrated that mast cells may whether chemotherapy should be continued after the first
be a source of nitric oxide (NO). NO is readily diffusible in manifestation of RRD. The decision should consider the
body fluids and tissues and freely crosses the cell membrane. benefit on the one hand and the potential risk of rechallenge
Inside a cell, NO undergoes numerous oxidative reactions, with the same drug.
generating the highly reactive peroxynitrite.31 Peroxynitrite is As anticipated from the previously mentioned data,
a potent DNA oxidant and can inhibit DNA repair mechan- pretreatment with antioxidants and/or inhibitors of mast cell
isms. It also irreversibily inhibits mitochondrial respiration, degranulation may be of some help in the prevention of the
which can induce cell death.32 Finally, NO upregulates the clinical manifestations of RRD.
expression of the p53 gene, which is involved in the induction
of cell apoptosis.32 Smith et al.21 reported similar observations.
Acknowledgment
To our knowledge, there have been no studies on mast cells
as possible mediators in RRD. From all the previously The author thanks R. D. Zeevic, a dermatologist from the
mentioned results and experimental models, we believe that Military Medical Academy, Belgrade, Serbia, for his thought-
further investigations should reveal whether mast cells have a ful comments on the manuscript.
role in the pathogenesis of RRD.
The clinical symptoms of erythema, edema, and pruritus
correspond with the well-known signs of mast cell degranu- References
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2004 The International Society of Dermatology International Journal of Dermatology 2004, 43, 627 631