INTRODUCTION
Radiation therapy is a commonly used and clinically important
treatment for a variety of malignancies. The limiting factor in radiation
treatment is often skin tolerance, as radiation injury to
healthy skin is a frequent complication.1 Although it is not the primary
therapeutic target, the skin undergoes molecular, gross, and
functional changes as a result of radiation therapy,2-4 resulting in adverse
events. Radiation confers significant, dose-dependent acute
and chronic cutaneous sequelae,1,5 including erythema, desquamation,
ulceration, alopecia, decreased skin elasticity, thickened and
fibrotic skin,1 and delayed wound healing.6 These cutaneous side
effects are painful, aesthetically unpleasant, affect quality of life,
and may influence treatment adherence, tolerance, and schedule.5,7
The Scope of Dermatologic Side Effects in Oncologic Therapies
Cancer treatment confers a plethora of toxicities and affects most organ systems. Oncologic therapy targets rapidly dividing cells, and because the skin is characterized by rapid cell proliferation, it is often affected by such treatment.3 With the development of new oncologic therapeutic strategies, the scope of dermatologic side effects has evolved: greater than 50 cutaneous side effects are associated with more than 30 anti-cancer drugs. Such side effects include chemotherapy-induced alopecia, acral erythema, subungual hemorrhages, and other nail toxicities, erythema multiforme, and radiation dermatitis, among others.8 Additionally, the development of targeted anti-cancer medications has elicited class-specific cutaneous toxicities. For example, epidermal growth factor receptor (EGFR) inhibitors cause cutaneous side effects in 50% to 90% of patients.9 Most commonly, EGFR inhibitors induce a papulopustular eruption, as well as xerosis cutis, hyperpigmentation, hair and nail changes,9 and augmentation of radiation dermatitis symptoms.10,11
Radiation dermatitis is a well-established entity in the medical
literature. It was first detailed in 1896 in the British Medical
Journal, which published one of the earliest reports of the
cutaneous side effects of ionizing radiation presenting on the
hands. Radiation dermatitis continues to be a common side effect
of radiation exposure today: as many as 90% of patients
treated for breast or head and neck cancers demonstrate symptoms
of acute radiation dermatitis.8,12
Radiation Dermatitis: Pathophysiology
Ionizing radiation incites a cascade of molecular events with subsequent development of radiation dermatitis symptoms. The pathophysiology is multifactorial, and includes the generation of reactive oxygen species and cytokine release (Figure 1).
Ionizing radiation induces a burst of free radicals which react with
intracellular components, ultimately causing alterations in lipids,
proteins and carbohydrates, as well as DNA damage.4,13 Irradiated
cells are stimulated to release a variety of cytokines, which activate
an inflammatory cascade.14 Cytokine expression begins immediately
following irradiation and is maintained for months, and even
years, until late pathologic findings and chronic radiation dermatitis
symptoms are clinically apparent.14,15 Implicated cytokines
include IL-1, IL-6, IL-8, CCL4, CXCL10, CCL2, eotaxin, tumor necrosis
factor- (TNF) α, and transforming growth factor- (TGF) β.3,14
Cytokine release results in increased vascular permeability, permitting
activated inflammatory cells to extravasate from the
vasculature and migrate into irradiated tissue.14 This influx of inflammatory
cells and specifically, macrophages,1,14 is a hallmark
of radiation-induced cutaneous damage3 and results in clinically
apparent inflammation and erythema that can manifest within
hours of exposure.2 The coagulation system becomes activated
secondary to radiation-induced endothelial damage; this further
promotes the inflammatory reaction with additional cytokine
production.2 Additionally, radiation decreases, in a dose-dependent
manner, nitric oxide (NO) synthesis,6 an important regulator
of immune function and wound healing. The combined effect
