Review Article
Skin Toxicity During Breast Irradiation:
Pathophysiology and Management
Jennifer L. Harper, MD, Lynette E. Franklin,
and Eric G. Aguero, MD
Abstract: Radiotherapy is a critical component in the treatment of
breast cancer, a disease that is estimated to have affected 203,500
US women in 2002. According to the data from some series, an
estimated 90% of patients treated with radiotherapy for breast cancer
will develop a degree of radiation-induced dermatitis. This review
describes the indications and techniques of radiotherapy for breast
cancer. The pathophysiology, clinical presentation, and contributing
factors of radiation-related skin injury are discussed. A review of
recent clinical research addressing skin toxicity is provided.
Key Words: breast cancer, breast radiotherapy, radiation-induced
dermatitis, skin care
R adiotherapy is a critical component in the treatment of
breast cancer, a disease estimated to have affected
203,500 women in 2002.1 Many women with early stage
breast cancer are candidates for breast conservation therapy
(BCT), which combines conservative surgery and radiother-
apy.2 In more advanced breast cancer requiring mastectomy,
adjuvant radiotherapy has been shown to improve overall
survival.3,4
Before the development of modern megavoltage x-ray
capability, skin toxicity limited the doses that could be safely
delivered to the breast.5 The dose of megavoltage x-rays
builds up at a depth below the skin.6 This characteristic dose
distribution spares the skin and allows tumoricidal doses to be
delivered to cancers within the breast. Despite these advances,
in some series, greater than 90% of patients treated with
radiotherapy for breast cancer will develop a degree of radi-
ation-induced dermatitis.7 With so many patients at risk, it is
From the Department of Radiation Oncology and the Wound, Ostomy, and
Continence Nursing Department, Medical University of South Carolina,
Charleston, SC.
Reprint requests to Jennifer L. Harper, MD, Department of Radiation On-
cology, Medical University of South Carolina, 169 Ashley Avenue,
Charleston, SC. Email: harrper@radonc.musc.edu
Accepted June 14, 2004.
Copyright © 2004 by The Southern Medical Association
0038-4348/04/9710-0989
Southern Medical Journal • Volume 97, Number 10, October 2004
MSN, Joseph M. Jenrette, MD,
important for the clinician to become familiar with the pre-
sentation and management of radiation-induced skin reac-
tions.
Introduction to Radiotherapy for Breast
Cancer
The goal of radiotherapy is to precisely target a tumor
volume with megavoltage x-rays while limiting the volume of
normal tissue exposed to radiation. The intracellular target for
these x-rays is deoxyribonucleic acid, DNA. Damage to DNA
can be sufficient to disrupt replication, resulting in cell death.
Ionizing radiation also produces DNA damage that can be
repaired, known as sublethal damage, and cells remain viable.
The therapeutic ratio of radiotherapy is achieved by the greater
capacity of normal tissue to repair radiation-induced sublethal
DNA damage as compared with rapidly proliferating tumor
cells. However, normal tissues that also rapidly proliferate,
such as skin, gastrointestinal mucosa, and hematopoietic cells
are also relatively radiosensitive.8
Breast irradiation following lumpectomy or chest wall
irradiation following mastectomy is commonly delivered
through medial and lateral tangential x-ray beams for 6 to 7
weeks of daily treatment (Fig. 1). The tangential beam ar-
rangement minimizes the volume of normal lung and cardiac
tissue that is irradiated.
The severity of skin reactions during and following breast
irradiation is influenced by both treatment-related factors and
patient-related factors. Treatment-related factors include the
fraction size (the dose delivered with each treatment), the
Key Points
• Radiotherapy is a modality commonly incorporated in
breast cancer therapy.
• Radiation-related skin injury frequently occurs, and is
related to both treatment and patient factors.
• While there is a paucity of data to support the pro-
phylactic use of topical agents during therapy, ad-
vances in radiation techniques hold promise for pre-
venting severe injury.
989
Harper et al • Skin Toxicity During Breast Irradiation
Fig. 1 Medial and lateral tangential beams used for whole-
breast irradiation.
total dose delivered, the volume of tissue treated, the type of
radiation,8 and the addition of chemotherapy.9 Patient-related
factors include breast size, smoking, axillary lymphocele
drainage before treatment (suggesting poor lymphatic drain-
age), age, and infection of surgical wound.10 A patient’s
genomic constitution also influences their risk of normal tis-
sue toxicity. Recent data suggests that carrying a single mu-
tated copy of the DNA repair gene, ATM, can predispose
patients to late tissue effects following breast radiotherapy.11
ATM heterozygosity occurs in approximately 1% of the gen-
eral population12 and may be more common in breast cancer
patients.13
Characteristic distributions of skin injury result from fea-
tures of breast topology and beam arrangement that increase
the skin’s dose of radiation. The axilla and inframammary
fold, commonly sites of the most severe skin injury, receive
higher skin doses because these are sites where redundant
skin produces a bolus effect and pulls the higher doses up to
the skin surface. Thus, large-breasted women and obese pa-
tients are at increased risk of skin toxicity.10 With the tan-
gential beam arrangement used in breast radiotherapy, there
are some regions of the breast, such as the axilla, in which the
beam is incident to the skin at nearly a glance angle. At these
angles, the skin-sparing effect of megavoltage x-rays is lost,
and patients experience greater skin reactions.14
Pathophysiology and Sequence of
Radiation-induced Skin Changes
The skin is composed of an outer layer, the epidermis,
and an underlying connective tissue layer, the dermis. The epi-
dermal layer is 30 to 300 um, and is derived from a basal layer
990
of stem cells. These cells proliferate and migrate to the surface
to be sloughed. This migration occurs over a period of approx-
imately fourteen days. The dermal layer is 1 to 3 mm thick and
is composed of a papillary level and a deeper, reticular dermis.
The dermis is composed of collagen bundles, fibroblasts, and
microvessels that sustain the epidermis.15
The sequence of gross skin changes occurring with stan-
dard schedules and doses of radiotherapy to the breast have
been described.16 These reactions are categorized as early
effects or late effects, as determined by the time at which they
present.
Early effects are those that occur within 90 days of the
initiation of radiation. Those skin reactions occurring during the
second to fourth week of therapy include dryness, epilation,
pigmentation changes, and erythema.16 Dryness and epilation
result from destruction of the sebaceous glands and hair follicles
of the dermal layer.8 The skin becomes hyperpigmented due to
stimulation of epidermal melanocytes.8 Cytokines mediate in-
flammatory reactions that cause acute erythema.17
During the third to sixth week of therapy, populations of
basal-layer stem cells become depleted in the treated area,
and dry desquamation can develop.18 Dry desquamation is
clinically characterized by scaling and pruritus. Moist des-
quamation results if all stem cells are eradicated from the
basal layer, and is characterized by serous oozing and expo-
sure of the dermis. Moist desquamation may occur following
four to five weeks of therapy.16
Late effects are those that present more than 90 days after
the completion of radiotherapy, and are associated with injury
to the dermis. Following the acute skin changes, the skin
appears “normal” for a variable interval of time ranging from
months to years. The late effects of atrophy and fibrosis are
directly related to dermal fibroblast response to radiotherapy.
Atrophy results from the decreased population of dermal fi-
broblast and the reabsorption of collagen fibers. The remain-
ing atypical fibroblasts are stimulated by growth factors pro-
duced in response to injury. The proliferation of these atypical
fibroblasts in response to growth factors such as TBF-B re-
sults in the deposition of dense fibrous tissue.19 Radiation-
induced fibrosis is characterized by progressive induration,
edema formation, and thickening of the dermis.16
Pigmentation changes can also occur as a late reaction.
These changes are quite variable. Some patients experience
gradual hyperpigmentation, while others with more darkly
pigmented skin may develop depigmentation due to complete
eradication of all melanocytes.8
Telangiectasias can develop 6 months to multiple years
following the completion of radiotherapy. Telangiectasias are
areas in which multiple, prominent, dilated, and thin-walled
vessels are visible in the skin. In these areas, microvessels
have lost endothelial cells, shortened, and become visible
through an atrophied dermal layer.16
Dermal necrosis also can occur months to years follow-
ing radiotherapy. Necrosis is associated with doses higher
© 2004 Southern Medical Association

than those used to treat the breast.16 This form of skin injury
is related to microvascular changes that result in dermal isch-
emia.18
Generally, external beam radiotherapy is a well-tolerated
treatment. A clinical trial by Fisher et al,20 which prospec-
tively assessed skin toxicity over the course of breast irradi-
ation using Radiation Therapy Oncology Group (RTOG) tox-
icity criteria, found less than 3% of patients developed grade
III toxicity.
Preventing and Managing Radiation-
related Skin Toxicity
Skin injury incurred during breast irradiation can pro-
duce significant discomfort, limit daily activities, and result
in breaks from treatment. Some of the commonly held beliefs
regarding preventing skin toxicity have recently been inves-
tigated in randomized trials.
Washing the irradiated skin with soap and water was felt
to exacerbate radiation dermatitis during the orthovoltage era.
Roy et al21 evaluated the impact of skin washing with soap
and water on acute skin toxicity during breast irradiation
using modern megavoltage radiotherapy. In this trial, 99 pa-
tients undergoing breast irradiation were randomized to skin
washing with soap and water or no skin washing. Moist des-
quamation developed in 33% of those that did not wash the
skin as compared with 14% of those that washed the skin. A
multivariate analysis of this small trial showed acute skin
toxicity correlated with patient’s weight, concomitant chemo-
radiotherapy and regions of higher dose, while there was a
trend toward increased toxicity in the nonwashing arm. It is
hypothesized that washing may reduce moist desquamation
by removing skin microbes which act as inflammatory stimuli
at the basal layer of the skin. The authors concluded that
washing the skin does not increase skin toxicity.
The efficacy of aloe vera gel, a therapy commonly used
to prevent radiation skin toxicity, has been evaluated recently
in two randomized trials. Williams et al22 conducted two
trials involving women receiving breast irradiation, and which
compared skin toxicity between those receiving aloe vera gel
and a control group. The first trial was a double-blinded trail
in which 194 women were randomized to receive topical aloe
vera gel or a placebo. In the second trial, 108 patients were
randomized to aloe vera or no treatment. The scoring of skin
toxicity was similar for both arms of the two trials. This
suggests that aloe vera has no protective effect for those
receiving breast irradiation.
Biafine (Medix Pharmaceuticals, Tampa, FL), a wound-
healing product from France, has been touted to reduce radi-
ation-related skin toxicity.23 The wound-healing properties of
Biafine are a result of its capacity to recruit macrophages to
epidermal wounds and promote granulation tissue forma-
tion.24 Biafine was compared with best supportive care, which
consisted of Aquaphor (Biersdorf, Lindenhurst, NY) and aloe
Southern Medical Journal • Volume 97, Number 10, October 2004
Review Article
vera, in a randomized trial of women receiving breast irradi-
ation. This trial demonstrated no statistical difference in skin
toxicity between those receiving Biafine and those treated
with best supportive care.20
Topical steroids are commonly used to treat radiation-
induced skin inflammation. Corticosteroids have been shown
to inhibit the upregulation of the proinflammatory cytokine
IL-6 in response to ionizing radiation.25 The efficacy of the
corticosteroid cream mometasone furoate (MMF) as a pro-
phylactic and therapeutic intervention was investigated in a
randomized trial. Forty-nine patients receiving breast radio-
therapy were randomized in a double-blinded placebo con-
trolled trial to receive MMF and an emollient cream or a
placebo emollient cream during their radiotherapy and for
three weeks following. This trial demonstrated that prophy-
lactic application of MMF combined with an emollient cream
significantly decreased acute radiation dermatitis compared
with emollient cream alone.26
While there is little empirical evidence to support the use
of prophylactic topical therapies, advances in radiotherapy
techniques are addressing treatment-related causes of skin
injury. The contour of the breast and its varying thickness
produces inhomogeneous distribution of the radiation dose.
The regions of higher dose are at increased risk of skin injury.
The use of three-dimensional (3D) planning systems, which
incorporate computerized tomography-based images, allow
for more accurate calculation of dose throughout the breast.
Aref27 compared the simple radiotherapy plan utilizing a sin-
gle contour to a 3D plan using dose-based compensators and
lung inhomogeneity corrections. The use of 3D planning,
which allowed more accurate dose calculations and dose-
based compensators, significantly decreased the volumes of
breast that received doses that exceeded 100% of the pre-
scribed dose. Intensity-modulated radiotherapy (IMRT) is a
technique that further increases the homogeneity of dose in
the breast. IMRT uses the dose calculations obtained from 3D
planning and then decreases the transmission of radiation to
regions of excessively high doses. In the initial clinical ex-
perience with IMRT at William Beaumont Hospital, none of
the 32 patients receiving breast irradiation experienced RTOG
grade III or greater skin toxicity.28
Although not evidence-based, the following practice guide-
lines to prevent skin injury during and after breast irradiation are
recommended by many radiation oncology centers.
• Avoidance of metallic-based topical agents is advised, as
these may increase skin dose. Metallic agents include zinc
oxide-based creams and deodorants with aluminum bases.
• Avoiding traumatic shear and friction injuries by wearing
loose cotton clothing is advised.
• Use of nonadhesive wraps or securing devices allows for
wound examination and exposure of the treatment site,
without surrounding skin trauma. SNUG wraps (Assurity
991
Harper et al • Skin Toxicity During Breast Irradiation
Medical, Atlanta, GA) are cotton wraps available in var-
ious sizes, used to protect wounds without skin adhesives.
Unfortunately, many women will experience some de-
gree of skin injury during breast irradiation. Current therapies
used in the treatment of dry and moist desquamation are
reviewed below.
Dry Desquamation
Dry desquamation clinically presents as scaling and pru-
ritus of irradiated skin. The goal of therapy for this skin
damage is to provide moisture to injured areas, and to de-
crease patient discomfort. The choice of topical therapy
should be hydrophilic, with a neutral pH to avoid excess
irritation. There is also evidence, as discussed above, that
topical corticosteroids have been shown to decrease the acute
dermatitis that may proceed dry desquamation associated with
breast irradiation.26
Moist Desquamation
Sloughing of the epidermis and exposure of the dermal
layer clinically characterize moist desquamation. Manage-
ment of these partial-thickness wounds has been influenced
by the Winter principle of moist wound healing, which sug-
gests that wounds heal more rapidly in a moist environment.29
Hydrocolloid dressings applied directly to these wounds pre-
vent the evaporation of moisture from the exposed dermis and
create a moist environment at the wound site that promotes
cell migration.
In a randomized prospective trial, hydrocolloid dressings
were compared with gentian violet, a compound with anti-
fungal and antiseptic properties used in some institutions to
treat moist desquamation. Unlike the hydrocolloid dressings,
gentian violet produces a dry wound bed. Thirty-nine patients
who developed a total of 60 wounds during radiotherapy were
randomized to treatment with either a hydrocolloid dressing
or gentian violet. There were no significant differences in
wound healing time. However, patients reported higher sat-
isfaction with the hydrocolloid dressing based on its comfort
and aesthetic factors. Gentian violet produced skin discolor-
ation and drying affects that limited mobility.30 Patient com-
fort should determine the best clinical practice, and at our
institution hydrocolloid dressings are commonly prescribed
for moist desquamation.
Conclusion
The skin reactions resulting from breast irradiation can
range from mild to severe, and are related to both treatment-
and patient-related factors. Guidelines for skin care during
radiotherapy are often aimed at preventing further exacerba-
tion of radiation dermatitis that has already developed. There
is a paucity of evidence that topical agents are effective in
preventing skin reactions. However, advances in radiation
planning and delivery, such as IMRT, may dramatically de-
992
crease the incidence of severe reactions. Finally, as our un-
derstanding of genetic sensitivity to radiotherapy increases,
we may be able to predict those at risk for greater skin tox-
icity and use this information to tailor therapy.
References
1. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer
J Clin 2002;52:23– 47.
2. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a ran-
domized trial comparing total mastectomy, lumpectomy, and lumpec-
tomy plus irradiation for the treatment of invasive breast cancer. N Engl
J Med 2002;347:1233–1241.
3. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy
in high-risk premenopausal women with breast cancer who receive ad-
juvant chemotherapy. Danish Breast Cancer Cooperative Group 82b
Trial. N Engl J Med 1997;337:949 –955.
4. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemo-
therapy in node-positive premenopausal women with breast cancer.
N Engl J Med 1997;337:956 –962.
5. Shimm D. The skin, in Cox J (ed): Moss’ Radiation Oncology: Rational,
Techniques, Results. St. Louis, Mosby-Year Book, 1994, ed 7, pp 99 –
118.
6. Velkley DE, Manson DJ, Purdy JA, et al. Buildup region of megavoltage
photon radiation sources. Medical Physics 1975;2:14 –19.
7. Porock D, Kristjanson L. Skin reactions during radiotherapy for breast
cancer: the use and impact of topical agents and dressings. Eur J Cancer
Care (Engl) 1999;8:143–153.
8. Mettler F. Medical Effects of Ionizing Radiation. Philadelphia, W.B.
Saunders Co., 1995, ed 2.
9. Bentzen SM, Turesson I, Thames HD. Fractionation sensitivity and la-
tency of telangiectasia after postmastectomy radiotherapy: a graded-
response analysis. Radiother Oncol 1990;18:95–106.
10. Porock D, Kristjanson L, Nikoletti S, et al. Predicting the severity of
radiation skin reactions in women with breast cancer. Oncol Nurs Forum
1998;25:1019 –1029.
11. Iannuzzi CM, Atencio DP, Green S, et al. ATM mutations in female
breast cancer patients predict for an increase in radiation-induced late
effects. Int J Radiat Oncol Biol Phys 2002;52:606 – 613.
12. Swift M, Morrell D, Cromartie E, et al. The incidence and gene fre-
quency of ataxia-telangiectasia in the United States. Am J Hum Genet
1986;39:573–583.
13. Swift M, Morrell D, Massey RB, et al. Incidence of cancer in 161
families affected by ataxia-telangiectasia. N Engl J Med 1991;325:1831–
1836.
14. Jackson W. Surface effect of high-energy x-rays at oblique angles. Br J
Radiol 1971;44:109 –115.
15. Archambeau J. Relative radiation sensitivity in the integumentary sys-
tem dose response of the epidermal, microvascular, and dermal popula-
tions, in Lett J (ed): Advances in Radiation Biology Vol 12. San Diego,
Academic Press, 1987, pp 147–203.
16. Archambeau JO, Pezner R, Wasserman T. Pathophysiology of irradiated
skin and breast. Int J Radiat Oncol Biol Phys 1995;31:1171–1185.
17. Kupper TS. The activated keratinocyte: a model for inducible cytokine
production by non-bone marrow-derived cells in cutaneous inflamma-
tory and immune responses. J Invest Dermatol 1990;94:146S–150S.
18. Hopewell JW. The skin: its structure and response to ionizing radiation.
Int J Radiat Biol 1990;57:751–773.
19. Canney PA, Dean S. Transforming growth factor beta: a promotor of late
connective tissue injury following radiotherapy? Br J Radiol 1990;63:
620 – 623.
20. Fisher J, Scott C, Stevens R, et al. Randomized phase III study com-
paring best supportive care to Biafine as a prophylactic agent for radi-
© 2004 Southern Medical Association

ation-induced skin toxicity for women undergoing breast irradiation:
Radiation Therapy Oncology Group (RTOG) 97–13. Int J Radiat Oncol
Biol Phys 2000;48:1307–1310.
21. Roy I, Fortin A, Larochelle M. The impact of skin washing with water
and soap during breast irradiation: a randomized study. Radiother Oncol
2001;58:333–339.
22. Williams MS, Burk M, Loprinzi CL, et al. Phase III double-blind eval-
uation of an aloe vera gel as a prophylactic agent for radiation-induced
skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345–349.
23. Spitalier J, Amalric M. Value of Biafine in the prevention and treatment
of skin reactions following radiotherapy. 1973. Located at: Centre Re-
gional Delutte Centre Le Cancer, Marsille, France, submitted for pub-
lication.
24. Coulomb B, Friteau L, Dubertret L. Biafine applied on human epidermal
wounds is chemotactic for macrophages and increases the IL-1/IL-6
ratio. Skin Pharmacol 1997;10:281–287.
When you do the common things in life in an
uncommon way, you will command the attention
of the world.
Southern Medical Journal • Volume 97, Number 10, October 2004
Review Article
25. Beetz A, Messer G, Oppel T, et al. Induction of interleukin 6 by ionizing
radiation in a human epithelial cell line: control by corticosteroids. Int J
Radiat Biol 1997;72:33– 43.
26. Bostrom A, Lindman H, Swartling C, et al. Potent corticosteroid cream
(mometasone furoate) significantly reduces acute radiation dermatitis:
results from a double-blind, randomized study. Radiother Oncol 2001;
59:257–265.
27. Aref A, Thornton D, Youssef E, et al. Dosimetric improvements fol-
lowing 3D planning of tangential breast irradiation. Int J Radiat Oncol
Biol Phys 2000;48:1569 –1574.
28. Kestin LL, Sharpe MB, Frazier RC, et al. Intensity modulation to im-
prove dose uniformity with tangential breast radiotherapy: initial clinical
experience. Int J Radiat Oncol Biol Phys 2000;48:1559 –1568.
29. Winter G. Formation of the scab and the rate of epithelialization of
superficial wounds in the skin of the domestic pig. Nature 1962;193:
293–294.
30. Mak SS, Molassiotis A, Wan WM, et al. The effects of hydrocolloid
dressing and gentian violet on radiation-induced moist desquamation
wound healing. Cancer Nurs 2000;23:220 –229.
––George Washington Carver
993