Acute and Chronic Cutaneous Reactions to Ionizing Radiation Therapy

Abstract

Ionizing radiation is an important treatment modality for a variety of malignant conditions. However, development of radiation-induced skin changes is a significant adverse effect of radiation therapy (RT). Cutaneous repercussions of RT vary considerably in severity, course, and prognosis. When they do occur, cutaneous changes to RT are commonly graded as acute, consequential-late, or chronic. Acute reactions can have severe sequelae that impact quality of life as well as cancer treatment. Thus, dermatologists should be informed about these adverse reactions, know how to assess their severity and be able to determine course of management. The majority of measures currently available to prevent these acute reactions are proper skin hygiene and topical steroids, which limit the severity and decrease symptoms. Once acute cutaneous reactions develop, they are treated according to their severity. Treatments are similar to those used in prevention, but incorporate wound care management that maintains a moist environment to hasten recovery. Chronic changes are a unique subset of adverse reactions to RT that may develop months to years following treatment. Chronic radiation dermatitis is often permanent, progressive, and potentially irreversible with substantial impact on quality of life. Here, we also review the etiology, clinical manifestations, pathogenesis, prevention, and management of late-stage cutaneous reactions to radiotherapy, including chronic radiation dermatitis and radiation-induced fibrosis.

Introduction

Ionizing radiation (IR) is used to treat a variety of malignant conditions and is used to palliate metastatic disease. However, the development of radiation-induced skin changes is a significant adverse effect of radiation therapy (RT). Skin reactions to radiation are largely a function of technique, total dose, volume, and individual variations in treatment [1, 2]. While advances in technology and changes to therapeutic regimens have reduced the burden of cutaneous reactions to RT, radiation dermatitis remains a significant adverse effect of radiotherapy.

Cutaneous repercussions of RT vary considerably in severity, course, and prognosis. When they do occur, cutaneous changes to RT are commonly graded as acute, consequential-late, or chronic [3]. Acute changes include erythema and pain and occur within 90 days [3]. Even with modern radiotherapy techniques, approximately 85% of patients will experience a moderate to severe acute skin reaction in exposed areas [4]. Severe acute reactions may lead to blistering, erosions, and ulceration [5], which can lead to premature interruption of RT and potentially negatively influence cancer control and prognosis. Alternatively, the skin may appear relatively normal for months to years following RT, when chronic radiation dermatitis develops [3]. Chronic radiation dermatitis is permanent, progressive, and irreversible and has substantial impact on quality of life [5]. Thus, it is important for dermatologists to be able to recognize the adverse reactions to IR in order to assess the severity of disease and to assist in the management of these conditions. This review of cutaneous repercussions of RT is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by the authors.

Clinical Manifestations

Acute Radiation Dermatitis

Acute radiation dermatitis is one of the most common reactions to RT and usually occurs within 90 days of exposure. The severity of reaction ranges from mild erythema to moist desquamation and ulceration (Table 1) [6, 7]. The reaction typically starts within 1–4 weeks after starting radiation treatment and persists during the radiation treatment period [8]. Acute radiation dermatitis is likely to heal with mild cutaneous changes.

Table 1.

Dose-dependent acute cutaneous findings after local radiation exposure [7]

Observed acute skin reaction	Radiation dose (Gy)	Onset of findings
Transient erythema	2	Hours
Faint erythema and epilation	6–10	7–10 days
Defined erythema and hyperpigmentation	12–20	2–3 weeks
Dry desquamation	20–25	3–4 weeks
Moist desquamation	30–40	4 weeks or more
Ulceration	>40	6 weeks or more

The severity of disease can be graded on a scale of 1–4 according to the National Cancer Institute (Table 2). Acute reactions start with erythema, edema, pigmentary changes and depilation that correlate with the amount of radiation exposure. Grade 1 changes include dry desquamation with a generalized erythema (Fig. 1). Pruritus, epilation, scaling and depigmentation can also occur. With grade 2, there is brisk erythema or localized focal sloughing of the epidermis (Fig. 2). These reactions lead to moist desquamation confined to the skin folds once the cumulative radiation dose reaches 40 Gy or more [9]. With moist desquamation, the epidermal layer is lost and there is a high propensity for infection. The reaction peaks in 1–2 weeks with subsequent healing. Patients can experience increased pain due to exposure of nerve endings. Grade 3 presents with extensive moist desquamation outside of skin folds (Fig. 3). With grade 4, ulcerations, hemorrhage and skin necrosis occur that in some cases does not resolve, leading to the late-consequential changes of acute dermatitis that include ulcerations and fibrosis.

Table 2.

Classification of acute radiation dermatitis

Grade
1	2	3	4
Faint erythema or dry desquamation	Moderate to brisk erythema or patchy moist desquamation, mostly confined to skin folds and creases; moderate erythema	Moist desquamation other than skin folds; pitting edema, bleeding from minor trauma or abrasion	Skin necrosis or ulceration of full-thickness dermis; may have spontaneous bleeding from affected area

According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 3

Fig. 1.

Grade 1 acute radiation dermatitis. Reproduced from Mesía et al. [132] under open-access article distributed under the terms of the creative commons attribution license.

Copyright 2009

Fig. 2.

Grade 2 acute radiation dermatitis. a Radiation dermatitis of the breast with moist desquamation limited to the inframammary fold. b Radiation dermatitis with moderate erythema and scaly dry desquamation. a Reprinted from Journal of the American Academy of Dermatology, 54, Sharon R. Hymes, Eric A. Strom, Caroline Fife, Radiation dermatitis: Clinical presentation, pathophysiology, and treatment 2006, 28–46, Copyright (2006), with permission from Elsevier

Fig. 3.

Grade 3 acute radiation dermatitis with confluent moist desquamation. Reprinted from Journal of the American Academy of Dermatology, 54, Sharon R. Hymes, Eric A. Strom, Caroline Fife, Radiation dermatitis: Clinical presentation, pathophysiology, and treatment 2006, 28–46, Copyright (2006), with permission from Elsevier

Reepithelialization usually starts within 10 days, but can be prolonged with exposure to radiosensitizing drugs especially platinum based chemotherapy. Additional findings that may occur with acute radiation dermatitis include comedo reactions of whiteheads and blackheads in head and neck cancers. Pseudorecidives (keratosis-like lesions) and transient hair loss may progress to permanent hair loss if follicular fibrosis occurs [10].

Radiation Burns

Radiation burns, although rare with current treatment modalities, can occur with high-dose exposure to x-rays during interventional radiology procedures or with RT [11]. Management of these lesions is difficult because of the inability to differentiate injured tissue from uninjured tissue [12, 13], the unpredictable inflammatory waves that can come weeks to years after tissue injury, and the occurrence of opiate-resistant pain. [9].

Radiation Recall

Radiation recall is an acute inflammatory reaction confined to an area previously exposed to radiation after a chemotherapeutic agent or other medication. Clinically, radiation recall manifests with maculopapular eruptions, dry desquamation, pruritus, swelling and ulcerations. The incidence has been reported to occur in up to 6% of individuals undergoing RT, but reactions are drug-specific and can occur weeks to months after the original RT and subsequent chemotherapeutic administration [14]. However, the majority of reactions occur when the drug has been administered within 2 months of RT [15]. Radiation recall is most frequently associated with traditional chemotherapeutic agents including anthracyclines, taxanes, and antimetabolites [14], but reactions have been reported with EGFR inhibitors, BRAF tyrosine kinase inhibitors [16] and other non-chemotherapeutic agents (see Table 3) [14, 15].

Table 3.

Common chemotherapeutic agents that induce radiation recall [14, 15]

Chemotherapeutic agent
Doxorubicin
Docetaxel
Paclitaxel
Gemcitabine
Capecitabine
Trimetrexate
Methotrexate
Hydroxyurea
Tamoxifen
Dactinomycin
Vimblastine
Vemurafenib
Cetuximab

Chronic Radiation Dermatitis

Rarely, acute radiation fails to heal and consequential-late changes of RT may develop, which include chronic wounds and skin necrosis [3]. In contrast, chronic radiation dermatitis is a true late-stage reaction that develops months to years after exposure to IR. The condition may develop in patients who only experienced minimal acute radiation dermatitis and so may develop in near-normal-appearing skin. Unlike acute radiation dermatitis, chronic radiation dermatitis is unlikely to self-repair and may remain indefinitely [3]. The defining features of the late-stage are fibrosis, atrophy, hypo- or hyperpigmentary changes and the development of cutaneous malignancies (Table 4).

Table 4.

Clinical manifestations of chronic radiation dermatitis and radiation-induced fibrosis

Late reaction or complication	Clinical manifestations
Textural changes	Xerosis
	Scale
	Hyperkeratosis
Persistent poikilodermatous changes (indicate severe RT damage)	Dyspigmentation
	Atrophy
	Telangiectasia
Absence of hair follicles and sweat glands	Alopecia
	Decreased or absent sweating
Destruction or permanent loss of nail appendages	Friable nails
	Longitudinal striations
Cutaneous breakdown	Epidermal atrophy
	Slow-healing, painful erosions and ulcerations
	Necrosis of soft tissue, cartilage, and bone
Cutaneous and subcutaneous tissue fibrosis	Pain, limited range of motion, contractures
Secondary malignancy	Primarily SCC and BCC

Post-inflammatory dyspigmentation is common, and, depending on the skin type of the patient and severity of the reaction, may slowly resolve or worsen over time [3]. The skin may become xerotic, scaly, and hyperkeratotic. Significant cutaneous injury is characterized by persistent dyspigmentation, atrophy, and telangiectasia (Fig. 4) [3]. Telangiectasia commonly results from boost dosing, acute radiation grade 3 injury, and moist desquamation [17, 18]. With severe cutaneous injury, there may be permanent loss of nail and skin appendages, absence of hair follicles and sebaceous glands with resultant alopecia, and absent or reduced sweating [3]. Small arteries and arterioles predisposed to thrombosis or obstruction may lead to skin breakdown and ulceration [3, 9]. Further, atrophied skin is fragile and is predisposed to erosions and ulcerations that are painful and slow to heal [3, 19].

Fig. 4.

Chronic radiation dermatitis at the site of radiation beam entry. The lesion is an 8 × 6 well-demarcated erythematous atrophic plaque with telangiectasias and ulceration. Reprinted from The American Journal of Cardiology, 110, Alison Spiker, Zachary Zinn, William H. Carter, Roxann Powers, Rodney Kovach, Fluoroscopy-Induced Chronic Radiation Dermatitis, 1861–1863., Copyright (2012), with permission from Elsevier

Radiation-induced Fibrosis

When skin and subcutaneous tissue develops fibrosis, there can be a limited range of motion, contractures, and pain [3]. Radiation-induced fibrosis of the skin and subcutaneous tissues may develop at any RT treatment site; however, fibrosis most commonly occurs in breast cancer patients who were formerly treated with a combination of surgical intervention and RT. These patients may experience pain, skin retraction and induration, restricted arm and neck movement, lymphedema, and skin necrosis and ulcerations [20]. Boost dosing is an added risk factor for the development of fibrosis [21]. Fibrosis in the skin and subcutaneous tissue is usually diagnosed by palpation and inspection. Radiation-induced fibrosis is limited to the region treated with RT. If tumor recurrence is suspected, MRI may be obtained to differentiate [22, 23]. However, biopsy should be obtained to confirm fibrosis.

Secondary Cutaneous Malignancies

Individuals treated with IR are also at risk for the long-term development of secondary cutaneous malignancies. Increased risk for skin cancers may last a lifetime following radiation, is dose-related, and increases over the patient’s lifespan [24–26]. Patients who are exposed to radiation at younger ages are at greater risk for the development of basal cell carcinoma (BCC) than those who are exposed as adults [24, 25, 27, 28]. BCCs that do present following RT are often more aggressive or unusual variants [3]. The link between cancer treatment with RT and the development of melanoma and other non-melanoma skin cancers later in life is less clear [24, 28].

Pathophysiology

Acute Cutaneous Reactions

Radiation-induced tissue injury occurs on a functional, cellular, and gross level [3]. The susceptibility of the skin to radiation is due to the rapid rate of proliferation and maturation of cells, so that the basal keratinocytes, hair follicle stem cells and melanocytes are the most susceptible [29]. RT interferes with normal production and maturation of epithelial and hair matrix cells and also leads to the development of atypical fibroblasts and cutaneous vasculature [30]. With the first dose of RT, there is immediate tissue damage, generation of short-lived free radicals, irreversible breaks in cellular DNA, and generation of an inflammatory response [3, 31–33]. The early inflammatory response to radiation is principally caused by a proinflammatory cytokine cascade (IL-1, IL-3, IL-5, IL-6, TNF-a), chemokines (IL-8, eotaxin, CCR receptor), receptor tyrosine kinase, and adhesions molecules (ICAM-1, VCAM, E-selectin). These factors create a local inflammatory reaction of eosinophils and neutrophils that leads to self-perpetuating tissue damage and loss of the protective barrier [34]. Wound healing is impaired by the destruction of the basal keratinocytes, so that repeated exposures do not allow time for tissue or cellular repair. Each additional exposure to RT results in further direct tissue injury, inflammation, and impaired epithelial regeneration, all of which contribute to the development of acute radiation injury [35].

Chronic Cutaneous Reactions

The development of chronic radiation dermatitis is intricately related to the cytokine TGF-β [3, 36]. TGF-β is a regulatory protein that controls proliferation and differentiation of many cell types, wound healing, and synthesis of extracellular matrix proteins in the normal tissue inflammatory response [37]. Importantly, TGF-β activates fibroblasts, which are key cells in the development of late radiation-induced fibrotic changes [36]. TGF-β has been found to be upregulated in fibrotic tissue of irradiated patients, but not in non-irradiated controls [38].

Once the skin has had sufficient opportunity to “heal” from radiation-induced injury, long-lasting cellular dysfunction and stromal changes remain that impair cutaneous integrity [3, 35]. Permanently atypical fibroblasts may lead to cutaneous atrophy, contraction, and fibrosis [39, 40]. These late effects are more dependent on the type of radiation, area, volume, fraction size and schedule rather than total radiation dose [41]. The pathogenesis of telangiectasia development is unknown; however, it is thought to be in part due to acutely damaged microvasculature and production of platelet-derived growth factor (PDGF) and fibroblast growth factor by damaged cells [35]. Leukocyte infiltration at sites of irradiation is also likely to lead to atrophy, fibrosis, and necrosis in surrounding normal tissues [42].

The development of radiation-induced fibrosis is mediated by inflammation that begins immediately following RT and continues for months to years. TNF-α, IL-6, and IL-1 have been implicated in the inflammatory response, while TGF-β and PDGF modulate and enhance fibroblast activity and encourage production of extracellular matrix proteins [36, 43–45]. These changes in addition to radiation-induced alterations of the vascular system contribute significantly to late toxicity of RT.

Epidemiology

Skin injuries occur in about 95% of patients who receive RT [4]. Any body site treated with RT is susceptible to cutaneous injury; however, the face, neck, trunk, and extremities are particularly vulnerable [46]. Patients with breast cancer, head and neck cancer, lung cancer, and sarcoma are most often affected because of the higher radiation doses to the skin [4, 29, 41, 47]. RT was formerly used by dermatologists in the treatment of benign conditions such as acne, eczema and psoriasis [3]. These patients are also at risk for the development of chronic radiation dermatitis. In addition to RT, radiation dermatitis may occur as a result of accidental or occupational exposures to radiation [5].

Risk Factors

A variety of factors that increase the risk of developing acute cutaneous reactions to IR have been identified (see Table 5). The severity of the reaction is related to both intrinsic and extrinsic factors. Extrinsic factors include the total dosage of radiation, fractioned delivery schedules, volume of irradiated tissue and the intrinsic radiosensitivity of the involved tissue [48]. However, in general, moist intertriginous skin folds of the body are most susceptible. These areas include the skin under the breast, axilla, head and neck, and the groin due to the “bolus effect”, i.e. the propensity for higher doses of radiation to reach the skin folds [49].

Table 5.

Risk factors for development of acute skin reactions to radiation

Extrinsic
Total radiation dose
Fractionation schedule
Type of radiation
Quality of radiation beam
Concurrent chemotherapy
Antibiotics
Anti-tuberculosis medications

Intrinsic
Advanced age
Female sex
Obesity
Comorbidities (diabetes mellitus, connective tissue disease)
Chronic sun exposure
Radiosensitive disorders
Ataxia telangiectasia
Xeroderma pigmentosa
Previous breast reconstruction/implants
Nutritional status
Immunocompromised
Smoking

Extrinsic Factors

The total dose, dose/fraction, characteristics of the beam, volume and surface area of exposure to radiation all influence the degree of tissue damage [2, 3, 50–53]. For example, the total radiation dose is an important factor in the development of skin toxicity. However, the total dose that leads to cutaneous skin reactions varies depending on the dosing schedule. For instance, single doses of 16–22 Gy can result in the development of skin toxicity. However, if the dose is fractionated into 2-Gy fractions the total dose can be increased to 30–40 Gy before skin toxicity develops [54]. Thus, there is an increase in radiation tolerance with hyperfractionated treatments. This strategy allows for delivery of a higher total radiation dose with similar cutaneous toxicity to lower single-dose treatments. Interestingly, the time before clinical manifestations present is independent of the radiation dose, and is actually related to the timing of normal cell turnover. However, the total dose does affect the time required for the skin to clinically heal [55]. The use of boost doses, which intentionally create overlapping treatment fields, as well as bolus material are methods of RT that increase radiation dose and therefore increase risk of cutaneous reactions [53, 56].

The quality of radiation beam also influences the development of acute skin toxicity. In general, modern RT techniques have improved substantially so that normal tissue should be spared [57, 58]. New external beam radiation modalities such as intensity-modulated radiotherapy (IMRT) reduce radiation hot spots in the skin by delivering more homogenous radiation than traditional wedge beam radiation. Studies have shown as much as a 20% reduction in the development of moist desquamation from this modality alone [59, 60]. IMRT also shows promising reduction in the incidence of late radiation-induced cutaneous effects, such as induration and telangiectasia, in breast cancer patients [61–63]. Additionally, the type of particle that is emitted by the radiation source affects the depth of penetration and extent of damage that can occur (Table 6). The volume of the area being treated is proportional to the risk of developing skin reactions due to the higher radiation doses needed to treat larger areas.

Table 6.

Radiation particle and effect on skin [11]

Particle type	Penetration	Effect on skin
Alpha	Large amount of ionization, but minimal skin penetration	Not able to penetrate stratum corneum when emitted
Beta	Greater penetration than alpha particle, but less ionization	Shallow penetration of skin
Gamma	Low ionization, but high penetration	More penetration in skin with damage inversely proportional to the energy
X-ray	Similar to Gamma ray; longer wave length providing more penetration	Effect on skin is proportional to energy of X-ray
Neutron	High penetration due to size and neutral charge	Can be lethal; high energy transfer destroying basal layer of skin leading to necrosis

Certain drugs increase sensitivity to RT, so that the timing and dose of these agents is critical [3]. These drugs increase cellular damage that occurs with RT and hinder tissue repair. Conventional chemotherapeutic agents as well as anticancer therapies with EGFR inhibitors increase the risk of developing severe radiation dermatitis [64]. Commonly cited agents include dactinomycin, doxorubicin, methotrexate, 5-fluorouracil, hydroxyurea and bleomycin [56, 65]. New BRAF inhibitors such as vemurafenib have also produced severe skin and oral mucosal reactions when given with concurrent radiotherapy [66]. In the treatment of breast cancers, paclitaxel and docetaxel in conjunction with RT synergistically create cutaneous damage [67, 68]. Timing of adjuvant drugs also influences the development of chronic cutaneous changes to RT. In an RCT comparing sequential versus concurrent chemotherapy with RT in breast cancer patients, the risk for the development of late subcutaneous fibrosis was greater in those receiving both therapies at the same time [69]. Tamoxifen is also suspected to increase subcutaneous fibrosis when used in conjunction with RT [70].

Intrinsic Factors

Intrinsic factors such as general skin condition, nutritional status, age, comorbid disease (diabetes mellitus and connective tissue disorders) and ethnicity all modulate the risk of acute skin reactions [71, 72]. Moreover, smoking, actinic damage, and obesity have also been implicated [73]. In addition, patients with implants and breast reconstruction have a higher risk of radiation dermatitis due to the skin’s inability to dissipate heat [74, 75]. Furthermore, patients who are immunocompromised secondary to HIV infection who are treated with IR for cancers of the head and neck, abdomen, or pelvis have an increased risk of developing mucosal reactions [76].

Genetics influences the development of acute cutaneous reactions from radiation, particularly conditions resulting from mutations in DNA repair mechanisms. The most well-known example is ataxia telangiectasia, a rare autosomal-recessive disorder that results from mutations in both ATM genes. Patients with this disorder have a high propensity to develop severe complications after RT due to the inability to repair DNA. An estimated 1% of the population is heterozygous for the ATM gene [77], which predisposes patients to develop cutaneous reactions [78]. Modified treatment protocols with lower radiation dose and volumes can be utilized in these patients to avoid skin reactions and decrease the risk of skin toxicity. Other conditions that lead to chromosomal breakage includes Fanconi’s anemia, Bloom syndrome and xeroderma pigmentosum. Patients with these conditions develop gaps in skin fibroblasts after irradiation [79]. Moreover, specific genetic polymorphisms have been identified in DNA repair and oxidative stress response genes that confer a higher risk for acute skin reactions after radiotherapy [80].

Prevention

General Preventive Measures

Prevention of radiation dermatitis is an important consideration in the pre- and post-RT period. General measures, such as maintaining proper skin hygiene by washing with lukewarm water and mild soaps, and the use of unscented, lanolin-free water-based moisturizers, decreases the risk for acute radiation dermatitis [81, 82]. Avoiding metallic and/or oil based topical products, wearing loose-fitting clothes, and avoiding sun exposure may help prevent post-RT complications. However, to date, there are few randomized controlled trials (RCTs) that assess preventive measures for acute radiation-induced skin toxicity (Table 7). Topical moisturizers, gels, emulsions, or dressings can cause a bolus effect and so should not be applied shortly before radiation [83]. Careful positioning of the patient and appropriate placement of skin shields may decrease radiation-induced skin problems. Following RT sessions, exposure to ultraviolet light in treatment areas and temperature extremes should be avoided [3]. Patients undergoing RT treatment should avoid metallic compounds including magnesium in talcs and aluminum in antiperspirants [19].

Table 7.

Preventions and treatments for acute cutaneous skin reactions to radiotherapy

Prevention	Level of evidence
Proper skin hygiene	Wash with mild soaps and lukewarm water to help maintain skin barrier
Protection of skin from additional trauma	Use of topical steroids; use before development of radiation dermatitis to slow progression to radiation dermatitis (Grade B) Oral Wobe-Mugus can decrease odds of developing radiation dermatitis (Grade C) Wear loose fitting clothing, avoid sun exposure, avoid metallic based topical products, use water based lanolin-free moisturizers

Treatment of	Level of evidence
Dry desquamation	Low- to mid-potency topical steroids; decrease progression and severity of itching, burning and irritation (Grade C) Use of hydrophilic moisturizers
Moist desquamation	Wound care management with hydrogel and hydrocolloid dressings
Radiation burns	Removal of necrotic debris and mesenchymal stem cell injections to area to increase healing Mesenchymal stem cell injections around lesions to enhance wound healing (Grade D)

Topical Corticosteroids

Topical corticosteroids have long been used for the prevention and treatment of RT-induced skin toxicity due to the underlying inflammatory pathophysiology. However, the efficacy of topical corticosteroids in reducing the frequency and severity of radiation dermatitis has been evaluated in several small clinical trials, with inconsistent results [3]. Some studies show no statistically significant difference between steroid (mometasone furoate 0.1% cream [84]; 0.2% hydrocortisone valerate [85]) versus placebo, whereas other groups demonstrated decreased severity or frequency of acute radiation dermatitis in the topical steroid group [86–88]. Advocates of corticosteroid use recommend application of low to medium potency steroid to the treatment field 1–2 times a day after each RT session to reduce the severity of acute radiation dermatitis and decrease the severity of symptoms, including decreased itching, irritation, burning, and discomfort. Whether or not application of corticosteroids during periods of RT can impact the frequency or severity of eventual chronic radiation dermatitis remains to be seen. It is also not known whether corticosteroids may increase the incidence of infection, telangiectasia, or skin atrophy [3].

Other Adjuvants

Oral Wobe-Mugus (a proteolytic enzyme mixture of 100 mg papain, 40 mg trypsin and 40 mg chymotrypsin) has been shown in two nonblinded RCTs versus no medication to decrease the odds for developing RT-induced skin toxicity by as much as 87% [89, 90]. However, dosages and treatment schedule varied between studies. Other agents, including aloe vera, trolamine, sucralfate, and hyaluronic acid, do not have supportive evidence for use in the prevention of radiation dermatitis [91–96].

Management

Acute Cutaneous Reactions

Grade 1

Management is based principally on the severity of damaged skin. Patients with grade 1 radiation dermatitis are treated with nonspecific treatment similar to the aforementioned general prevention measures. Dry desquamation can be treated with hydrophilic moisturizers, while pruritus and irritation can be treated with low to mid potency steroids.

Grades 2 and 3

With more severe reactions involving moist desquamation (grades 2 and 3), treatment should be directed toward preventing secondary infection and dressing the areas of moist desquamation. Dressings are used in moist desquamation to maintain a wet environment over de-epithelialized skin, which allows for a higher rate of wound healing [97]. A variety of dressings have been employed in the treatment of these lesions, but results to date are inconclusive [98–100].

Two types of dressings commonly used in moist desquamation are hydrogel and hydrocolloid dressings. Hydrogel dressings do not adhere to wounds and allow for ease of cleaning and reapplication. Hydrocolloid dressings are absorbent, self-adhering, and can be left in place for several days to simplify wound care [101]. These dressings have been shown to speed wound healing and improve patient comfort, but no high-powered RCTs exist to date comparing these treatments [102].

Grade 4

In severe skin reactions to RT (grade 4), there is significant full-thickness skin necrosis and ulceration. Treatment requires a multidisciplinary approach and discontinuation of RT. In addition, surgical debridement of necrotic tissues and the utilization of full-thickness skin grafts or pedicle flaps may be indicated. These high-grade cutaneous skin toxicity reactions can lead to late-consequential changes including fibrosis and non-healing ulcers, which have potential for malignant transformation. Moreover, waves of inflammation can occur with radiation burns leading to the need for successive surgical excisions, reconstruction, and potential need for amputation [12, 13].

Chronic Cutaneous Reactions

Unlike the majority of cases of acute cutaneous reactions to RT, chronic radiation dermatitis and radiation-induced fibrosis are unlikely to be self-repairing. Management of late cutaneous reactions of RT is reviewed in Table 8.

Table 8.

Management of chronic radiation dermatitis and radiation-induced fibrosis

Late reaction or complication	Management
Ulcers and erosions	Non-specific, follows general wound care guidelines, including
	Hydrophilic or lipophilic barrier creams with or without hydrogel or hydrocolloid dressings
	Careful and selective debridement, eschar removal
	For infected or at-risk wounds, antibacterial agents as needed and silver-based dressings
	Surgical intervention for nonhealing ulcers with skin flaps, less commonly with staged skin-muscle or axial-pedical flaps
	Grade D
	Artificial or bioengineered skin
	Low-intensity helium laser
Fibrosis	Supportive measures: physical therapy, massage, and pain management
	Grade 2C
	Pentoxifylline with or without tocopherol
	Grade D
	Superoxide dismutase
	Interferon gamma (IFNγ)
	Hyperbaric oxygen therapy
	Laser therapy with epidermal grafting
Telangiectasias	Grade D  Pulse dye laser
Secondary skin cancers and radiation-induced keratoses	Surgical excision preferred for skin cancers
	Grade 2C
	Radiation-induced keratoses:
	Cryosurgery
	Mechanical destruction (peel, laser, or dermabrasion)
	Grade D
	Topical 5-fluorouracil
	Diclofenac
	Photodynamic therapy
	Imiquimod

Chronic Ulcerations and Wounds

As in acute radiation dermatitis, the care of ulcerations and wounds resulting from chronic radiation dermatitis is non-specific and follows general wound care guidelines. Wound dressings protect the injured skin from environmental damage and infection and also serve to contain wound secretions [3]. Moisture helps with re-epithelialization of tissue as well as removal of necrotic tissue and bacteria [3, 9, 103, 104]. Hydrophilic and lipophilic creams and ointments may be used alone or with dressings to enhance barrier function. Similar to management of moist desquamation, hydrogel or hydrocolloid dressings may be utilized.

Chronic ulcers may require careful and selective debridement. Persistent eschars may be removed manually, or treated with enzymatic debridement or autolytic dressings [3]. Chronic, nonhealing ulcers are poorly vascularized, and may require surgical intervention with skin flaps or sometimes staged skin-muscle or axial-pedical flaps [105]. Less commonly, artificial and bioengineered skin have been used for nonhealing ulcerations [104]. Case reports show that laser therapy with low-intensity helium laser has benefitted some patients with chronic ulcerations [106]. For infected or at-risk wounds, antibacterial agents should be considered. Silver-based dressings may be effective for this purpose [3]. Chronic nonhealing ulcers and suspected lesions may need to be biopsied for histopathologic examination to exclude secondary skin cancers [3].

Radiation-induced Fibrosis

Radiation-induced fibrosis is one of the most difficult skin complications to treat [3]. A team approach with wound care, physical therapy, and pain management is needed to preserve quality of life [3]. Physical therapy may include active and passive range of motion exercises, which may help to improve range of motion and reduce contractures. Massage may also be beneficial [107]. Adequate pain control should be provided as pain from fibrosis can be significant.

Pentoxifylline (PTX) may be used alone or in combination with tocopherol (vitamin E) to treat radiation-induced fibrosis as well as to prevent pulmonary fibrosis. PTX is a methylxanthine derivative that is commonly used as an inhibitor of platelet aggregation, while vitamin E is a scavenger of reactive oxygen. PTX is thought to modulate the immune response by increasing polymorphonuclear leukocyte and monocyte phagocytic activity, antagonizing TNF-α and TNF-β [3], decreasing granulocyte–macrophage colony-stimulating factor and interferon gamma (IFNγ), among other effects [108, 119]. Combination with tocopherol may downregulate TGF-β expression and may even reverse alter the abnormal fibroblasts that perpetuate fibrosis [20, 110–112]. Multiple small randomized trials have suggested that PTX and/or tocopherol may reduce fibrosis [113–116]. However, the results of the largest of these trials have met with mixed results. In these studies, patients treated with PTX in combination with vitamin E demonstrated marginal improvement in their condition, but treatment had little to no benefit over placebo [115, 116]. However, longer-term therapy may be an important element in the treatment of fibrosis. In a study of 44 women with superficial radiation-induced fibrosis treated with PTX and tocopherol over a range of 6–48 months, regression of superficial fibrosis was seen [117]. An average of 68% regression of the radiation-induced fibrosis required an average of 24 months of treatment. Those who stopped treatment prior to 12 months saw a rebound in the fibrotic area after treatment. PTX and vitamin E can reverse superficial radiation-induced fibrosis, but the optimal dose and duration of therapy are unknown at this time.

Additional therapeutic agents that have been attempted in the treatment of fibrosis include superoxide dismutase (SOD), IFNγ, hyperbaric oxygen therapy, and laser therapy with epidermal grafting [3, 118]. Liposomal SOD is thought to downregulate TGF-β expression by myofibroblasts as well as function as an anti-inflammatory agent and anti-oxidant [3, 36]. In a clinical trial of 34 patients treated with 6 intramuscular injections of SOD over a 3-week period, clinical regression of fibrosis was seen at 2-month follow up [119]. IFNγ is an inflammatory cytokine that is thought to inhibit collagen production by fibroblasts [3]. Treatment with IFNγ in 5 patients over a 1-year period was shown to be useful in the treatment of cutaneous fibrosis [120].

Hyperbaric oxygen has been evaluated as a treatment for radiation-induced fibrosis; however, there is insufficient evidence to show efficacy at this time [121–123]. Treatment may result in less pain, swelling, redness, or lymphedema, but no effect on fibrosis has been found [3, 124]. However, hyperbaric oxygen improves neutrophil function and has anti-bacterial effects, and thus may be considered as a guard against infection [3].

Laser therapy with epidermal grafting has also been explored as a novel approach to the treatment of radiation-induced fibrosis. In one case series, three Vietnamese children who had developed significant chronic radiation dermatitis and fibrosis from RT for infantile hemangiomas were treated with pulse-dye laser and/or fractional laser with epidermal skin grafting. The study authors reported skin softening, increased flexibility, repigmentation of the skin, and improvement of the telangiectasias, suggesting that this treatment modality should be explored further [118].

Quercetin is a bioflavenoid with anti-inflammatory effects. A study performed in a mouse model of radiation-induced fibrosis demonstrated that oral administration reduced hind limb contracture, collagen expression, and TGF-β in irradiated skin [125]. However, quercetin has not yet been tested as a therapeutic agent for radiation-induced fibrosis in human trials.

Telangiectasias

Treatments of telangiectasias resulting from chronic radiation dermatitis are limited. Treatment with pulse dye laser has been shown in case series to be beneficial [126]. In a retrospective study of breast cancer patients with radiation-induced telangiectasias, all 11 patients experienced clinical improvement with pulse dye laser, with an average clearance of 72.7% [127].

Secondary Skin Cancers

Squamous cell carcinomas that arise in radiation fields exhibit aggressive behavior and more frequently metastasize, so surgical excision is the preferred modality for management [3]. Radiation-induced keratoses are pre-malignant and may be treated with cryosurgery when localized or with mechanical destruction with peels, laser, or dermabrasion when diffuse [3]. Topical 5-fluorouracil, diclofenac, photodynamic therapy, and imiquimod have also been used in the treatment of skin cancers and precancerous lesions [3, 128, 129].

Future Directions

The current advances in reducing cutaneous reactions have been primarily in the technological advancements of delivering increasingly targeted, homogenized RT utilizing fractionated schedules. The future will combine these advancements with targeted therapies for reducing the underlying inflammatory cascade, such as superoxide dismutase/catalase mimetics [130], to decrease reactive oxygen species and interleukin inhibitors. Anti-oxidant properties of curcumin could be used to reduce radiation skin toxicity [131]. In addition, stem cell treatments to replace necrotic tissue after radiation burns [12] and high-grade radiation dermatitis may become more readily available options.

Conclusions

Acute cutaneous skin reactions are common side effects of RT. Preventive measures for acute cutaneous skin reactions have proven elusive. However, progression and severity of reaction can be mitigated. After acute reactions to RT develop, they should be treated according to grade of severity, and RT treatment may be interrupted if necessary to allow for re-epithelialization and healing to occur. Moreover, proper wound management should be started promptly to decrease healing time and the risk of secondary infections. Similarly, therapeutic advancements in the treatment of chronic radiation dermatitis and radiation-induced fibrosis have been promising, however there is still great need for novel and developing therapies. Supportive care and appropriate wound care continue to be mainstays of treatment at this time.