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
Radiation recall dermatitis (RRD) is the development of an
inflammatory reaction throughout a previously irradiated
area, precipitated by the administration of certain drugs.
Recall trigger drugs are usually, but not exclusively, intraven-
ous cytotoxics. The time period between radiation exposure
and the administration of a recall trigger drug may be from
several days to years. The recall usually occurs on first
exposure to a particular recall trigger drug. Subsequent admin-
istrations of a trigger drug tend to produce either only a mild
recurrence or no recurrence of recall. The main clinical features
are erythema, desquamation, edema, urticaria-like lesions,
vesiculation, necrosis, ulceration, and hemorrhage. Patients
usually complain of pruritus or pain. All clinical signs tend
to resolve without any specific treatment over several weeks.
Steroids, systemic or topical, and antihistamines control
pruritus and/or pain. A number of different hypotheses have
been proposed for the potential etiology and pathogenesis of
RRD. These hypotheses have focused on vascular damage,
epithelial stem cell inadequacy, epithelial stem cell sensitivity
or drug hypersensitivity as the mechanism for RRD.
Definition
RRD is defined as a skin reaction, with all the clinical signs of
inflammation, in a previously irradiated field subsequent to
drug administration (usually cytotoxic drugs) days to years
after exposure to ionizing radiation. It was initially described
in association with actinomycin-D by DAngio et al.1 Since
then, many other drugs have been associated with radiation
recall reactions, most often chemotherapeutic agents.27
Other drugs reported as triggers include tamoxifen (nonster-
oidal antiestrogen),8 interferon alfa-2b,9 simvastatin,10 and
in the skin.3 Other sites reported include the lungs,6 vaginal
mucosa,12 laryngeal mucosa,13 central nervous system, bowel,
and esophagus.3
So far, few published data have been reported on the incid-
ence of radiation recall reactions, as most information has
been based on isolated case reports. The only available data
on incidence have been reported in a study by Tan et al.,14 in
which 27 patients out of a total of 57, or 47%, developed RRD.
Clinical Features
Clinical signs include erythema, desquamation, edema,
urticaria-like lesions, vesiculation, necrosis, ulceration, and
hemorrhage (Fig. 1a,b). Patients usually complain of pruritus
or pain. Camidge and Price2 proposed a grading system for
RRD (Table 1).
Usually, the most severe RRD is associated with a shorter
time period between the end of radiotherapy and exposure to
the trigger drug. Interestingly, however, the same grade of RRD
can be produced across a very wide range of radiotherapy
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
reactions. Radiosensitizers enhance the effect of radiation on
normal and malignant tissues by increasing the initial damage
produced by radiation, or by interfering with the subsequent
repair of this damage. According to a number of animal
and human studies, there is a defined sensitive period of about
3 days after irradiation during which drug treatment produces
enhanced radiation reactions.2 Camidge and Price2 have
proposed that skin reactions brought about by drugs given
less than 7 days after radiotherapy should be considered
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
Figure 1 (a) Erysipelas-like erythema restricted to the area of
irradiation. Note the enlargement of the left arm and breast due
to impaired lymphatic drainage and (b) pale erythema extending
to the back (courtesy of D. Marisavljevic, md, Hematology
Department, Clinical Center Beanijska kosa, Belgrade,
Serbia)
provoke an acute radiation dermatitis with the same clinical
manifestations as RRD. Severe skin reactions may take weeks
to heal. During that period, a trigger drug may provoke an
exacerbation by interfering with the ongoing healing process.
This reaction is probably quite different from a recall phe-
nomenon, but is indistinguishable at that point. Camidge and
Price2 have suggested that all acute radiotherapy reactions
in the skin should be completely healed before any drug
exposure can be assigned as producing RRD.
The differential diagnosis of RRD includes erysipelas,
herpes zoster, fixed drug eruption, erysipelatoid carcinoma,
panniculitis, and other radiation reactions. The history of pre-
vious exposure to radiation, the course of the disease (recurrent
course with milder clinical signs after each of the subsequent
administrations of the drug), laboratory tests (without any sign
of inflammation), and the time gap between the end of radio-
therapy and exposure to the trigger drug (with subsequent
clinical features of RRD) are usually sufficient to distinguish
International Journal of Dermatology 2004, 43, 627 631
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
cumulative radiation dose for the development of RRD.
They treated three similar skin lesions of Kaposis sarcoma
in a human immunodeficiency virus (HIV)-positive patient
with different radiation doses. After the administration of
bleomycin, cutaneous manifestations of RRD developed only
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
report of gemcitabine-induced erysipelas-like skin lesions in a
patient with no previous history of radiotherapy or lymphe-
dema at that site. There were no data available on whether the
patient had received an injury or X-ray diagnostic procedure
at that site that might have influenced the later development
of skin lesions. Valentin17 has suggested that, during certain
interventional radiology procedures, skin doses approach
those experienced in some cancer radiotherapy fractions.
The use of inappropriate equipment or poor operational
techniques may increase the absorbed dose. As we do not
have reliable data on the minimal required dose for RRD, it
would be of great benefit to exclude previous exposure to
either diagnostic or therapeutic X-ray procedures.
Drug Characteristics
Usually, RRD has been reported in association with chemo-
therapeutic drugs, given as monotherapy. No particular
2004 The International Society of Dermatology
Risti
reaction has been recorded in association with chemotherapy
protocols (consisting of several drugs given at the same time).
Interestingly, RRD is not a privilege of cytotoxics, as it has
been reported in association with antiestrogen,8 interferon alfa-
2b,9 simvastatin,10 and antituberculous drugs.11 On the other
hand, some commonly used cytotoxics, such as cyclophos-
phamide, have never been reported as trigger drugs in RRD.
RRD usually occurs on first exposure to a particular recall
trigger drug; however, there have been a few reports of
presensitization in RRD. In several cases, particular recall
trigger drugs have been given several times in one month
before eliciting RRD.18,19 The speed of onset of RRD varies
according to the different application of a trigger drug. The
onset is faster with intravenous drugs (ranging from a few
minutes to several days; median, 3 days) than with oral drugs
(ranging from 3 days up to 2 months; median, 8 days).2 The
same is true for the time taken for RRD to resolve. With this
in mind, the previously mentioned presensitization can be
explained as a cumulative reaction triggered after the first
exposure to a drug.
Rechallenge with the recall trigger drug may provoke
another recall reaction, but this is not the rule. Usually, the
recurrence of RRD presents with milder clinical signs than at
the first instance.
Pathology
Skin biopsies of RRD reveal signs of acute or chronic epidermal
radiation injuries with a nonspecific, mixed, inflammatory
infiltrate.2,12,20,21 Dermal changes include dermal fibrosis,
vasodilatation, and atypical fibroblasts. Immunohistochem-
ical staining for p53 in epidermal keratinocytes shows only
a modest increase compared with skin matched for similar
ultraviolet radiation exposure.21
Etiology and Pathogenesis
A number of different hypotheses have been proposed for
the potential etiology and pathogenesis of RRD. These hypo-
theses have focused on vascular damage, epithelial stem cell
inadequacy, epithelial stem cell sensitivity or drug hyper-
sensitivity as the mechanism of RRD.2 Bostrom et al.8 have
suggested that local vascular permeability or proliferative
changes induced by radiotherapy may affect the subsequent
pharmacokinetics of the trigger drug. Other authors have
proposed that radiation may decrease the number of epithelial
stem cells in irradiated fields. In addition, the ability of stem
cells to proliferate may remain permanently impaired after
radiation exposure.2 Abadir and Leibmann10 have proposed
that radiation may increase stem cell sensitivity by switching
the cell cycle at a faster rate. In this case, stem cells still maintain
an adequate functional role, but become more susceptibile to
drug damage.10 Other hypotheses have proposed that radiation
2004 The International Society of Dermatology
Radiation recall dermatitis Review 629
can produce certain stable cellular changes that increase
stem cell sensitivity. From several in vitro studies, there is
evidence that radiation can produce stable long-term changes
in the cell phenotype.2 The p53-mediated signal transduction
pathway activates the cellular response to DNA damage
produced by ionizing radiation. Smith et al.21 have revealed,
using immunohistochemical staining, that cumulative p53
mutations may play some, but not the major, role in the patho-
genesis of RRD. In their opinion, mitochondrial dysfunction
probably has a more important role in these eruptions.21
Camidge and Price2 have suggested that RRD may be an
example of a drug hypersensitivity reaction. Such a reaction
would probably not be immune (occurs on first exposure,
usually without reccurence), but would be more likely to
involve direct nonimmune activation of inflammatory
pathways (like a fixed drug eruption).2
Most of the accused drugs provoke a disruption of DNA
and trigger the formation of free radicals. Radiation also
cleaves DNA and makes it vulnerable to free radical attack.
Finally, the cellular recovery after radiation exposure is
inhibited via the inhibition of DNA repair, and this could be
one possible mechanism for RRD.5 These findings correlate
with those of Smith et al.,21 who reported an acceleration of
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)
protein was overexpressed in samples of postradiation fibrotic
skin, in both scarred epidermis and fibrotic dermis. These
fibrotic samples were surgically removed over a period from
6 months to 20 years after radiation exposure. Moreover,
skin cells isolated from the tissue retained their dysregulated
secretion of TGF-1 in culture, especially keratinocytes. The
same results were obtained for postradiation fibrosis in the
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
acts as a potent negative regulator of growth for most cell
types, including epithelial, endothelial, and hematopoietic
cells. Several studies have reported that TGF-1 mediates
mast cell chemotaxis.23,24 Gruber et al.23 have demonstrated
that femtomolar concentrations of TGF-1 induce rapid and
pronounced mast cell chemotaxis. They also suggest that mast
cells can bind TGF-1 through at least two transmembrane
proteins. Olsson et al.24 went further and compared the
potency of different members of the TGF- family as human
mast cell chemotaxins. They demonstrated that TGF-3 was
a more effective chemotaxin than TGF-1 and TGF-2 at the
same concentration. In contrast, TGF-3 was a less efficient
inhibitor of proliferation of human mast cells than the other
two TGF- factors. They also confirmed the expression of
TGF- receptors on human mast cells. Even though TGF-1
is capable of inhibiting mast cell proliferation, it does not
affect the degranulation and release of histamine directly.23,25
International Journal of Dermatology 2004, 43, 627631
630 Review Radiation recall dermatitis
RRD is usually seen in cancer patients treated previously
with radiation therapy. The accumulation of mast cells
around tumor areas is well known. On the other hand, a few
studies on animal models have demonstrated increased TGF-
immunoreactivity and mast cell hyperplasia,26 with high
levels of mast cell amines, histamine, and serotonin greatly
exceeding those of any normal tissue,27 in radiation-induced
enteropathy26 or pulmonary fibrosis.27 These measurements
were recorded 226 weeks26 or 48 weeks27 after radiation
exposure (dose, 30 50 Gy; single dose or fractions).
Recent studies2830 have demonstrated that mast cells may
be a source of nitric oxide (NO). NO is readily diffusible in
body fluids and tissues and freely crosses the cell membrane.
Inside a cell, NO undergoes numerous oxidative reactions,
generating the highly reactive peroxynitrite.31 Peroxynitrite is
a potent DNA oxidant and can inhibit DNA repair mechan-
isms. It also irreversibily inhibits mitochondrial respiration,
which can induce cell death.32 Finally, NO upregulates the
expression of the p53 gene, which is involved in the induction
of cell apoptosis.32 Smith et al.21 reported similar observations.
To our knowledge, there have been no studies on mast cells
as possible mediators in RRD. From all the previously
mentioned results and experimental models, we believe that
further investigations should reveal whether mast cells have a
role in the pathogenesis of RRD.
The clinical symptoms of erythema, edema, and pruritus
correspond with the well-known signs of mast cell degranu-
lation. The fact that the recurrence of RRD is rare, or
manifested by only mild clinical signs, can be explained as a
result of either interaction with other secretagogues and/or
cytokines that inhibit mast cell degranulation, or vacancies
in mast cell depots. The synergistic effect of an increased
number of mast cells and high levels of mast cell amines and
cytokines in postradiation fibrous tissue and around tumor
areas, tentatively documented a few months to several years
after radiation exposure, may explain the development of
RRD several years after radiotherapy. The reason why many
patients do not develop RRD for several years even though
they have been treated with cytotoxics after radiotherapy
remains unclear. Possibly, tissue tolerance evolves the first
time after radiotherapy, or tissue sensitivity is increased
later. This phenomenon could be genetically determined. The
observation that only cytotoxic drugs given as monotherapy,
rather than concurrently with others, can trigger radiation
recall can be explained as the cessation of their effect on target
cells due to a direct, pharmacologic interaction with particular
drugs, or the interaction of certain mediators released from
malignant tissue after polychemotherapy.
Treatment
RRD tends to resolve without specific treatment. Steroids,
systemic or topical, and antihistamines control pruritus and/
International Journal of Dermatology 2004, 43, 627 631
Risti
or pain, but the time to the resolution of cutaneous mani-
festations remains the same with or without steroid or
antihistamine treatment.2,3
Conclusions
With the increasing use of combination radiotherapy and
chemotherapy in the treatment of malignant disease, a better
knowledge of the pathogenesis of RRD and its appropriate
management have become necessities. The main question is
whether chemotherapy should be continued after the first
manifestation of RRD. The decision should consider the
benefit on the one hand and the potential risk of rechallenge
with the same drug.
As anticipated from the previously mentioned data,
pretreatment with antioxidants and/or inhibitors of mast cell
degranulation may be of some help in the prevention of the
clinical manifestations of RRD.
Acknowledgment
The author thanks R. D. Zeevic, a dermatologist from the
Military Medical Academy, Belgrade, Serbia, for his thought-
ful comments on the manuscript.
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