Ionizing Radiation: the Good, the Bad, and the Ugly Julie L

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Ionizing Radiation: The Good, the Bad, and the Ugly Julie L. Ryan1

Skin changes caused by ionizing radiation have been the human body (Wolbarst et al., 2010). The degree of scientifically documented since 1902. Ionizing radia- radiation injury is related to the total radiation dose, tion is a widely accepted form of treatment for various proportion of body irradiated, volume of tissues irradiated, types of cancer. Despite the technological advances, and the time interval of the radiation dose received (Hall and radiation skin injury remains a significant problem. Giaccia, 2006; Cox and Ang, 2010). The most radiosensitive This injury, often referred to as radiation dermatitis, cells in the body are those that are highly proliferative and occurs in about 95% of patients receiving radiation sufficiently oxygenated. The most radiosensitive organ therapy for cancer, and ranges in severity from mild systems are bone marrow, reproductive and gastrointestinal erythema to moist desquamation and ulceration. systems, skin, muscle, and the brain (Hall and Giaccia, 2006; Ionizing radiation is not only a concern for cancer Cox and Ang, 2010). Organ systems are more tolerant to low- dose radiation exposure over a long period of time, as used in patients, but also a public health concern because fractionated radiotherapy, compared with high local radia- of the potential for and reality of a nuclear and/or tion exposure or total body irradiation (Hall and Giaccia, radiological event. Recently, the United States has 2006; Cox and Ang, 2010). For example, radiotherapy for increased efforts to develop medical counter- breast cancer involves fractionated radiation doses of B2Gy measures to protect against radiation toxicities from for 6 weeks for a total radiation dose of X50 Gy. A total body acts of bioterrorism, as well as cancer treatment. irradiation dose of 100 Gy would result in 100% chance of Management of radiation dermatitis would improve death within hours of radiation exposure (Hall and Giaccia, the therapeutic benefit of radiation therapy for cancer 2006; Cox and Ang, 2010). The total body irradiation dose at and potentially the mortality expected in any ‘‘dirty which death will occur in 50% of individuals (LD50)is3–4Gy bomb’’ attack. Currently, there is no effective treat- (Hall and Giaccia, 2006; Cox and Ang, 2010). Although the ment to prevent or mitigate radiation skin injury. kinetics of the clinical signs of radiation exposure may differ This review summarizes ‘‘the good, the bad, and the between cancer radiotherapy and a ‘‘dirty bomb’’ attack, the ugly’’ of current and evolving knowledge regarding symptoms and syndromes in exposed organ systems are mechanisms of and treatments for radiation skin similar (Williams and McBride, 2011). injury. Journal of Investigative Dermatology (2012) 132, 985–993; doi:10.1038/ Radiation skin injury jid.2011.411; published online 5 January 2012 The main function of skin is to establish an effective physical and immunological barrier against the surrounding environment. The epidermis, the outermost layer of the skin, primarily composed of stratifying layers of keratinocytes, CURRENT UNDERSTANDING: PERCEPTION OF functions as the primary barrier and biosensor to the external RADIATION SKIN INJURY environment. The dermis is immediately underneath the Radiation exposure epidermis, providing structural strength to the skin. It is Radiation injury involves morphological and functional primarily composed of connective tissue produced by dermal changes that occur in noncancerous or ‘‘normal’’ tissue as fibroblasts. Skin is susceptible to radiation damage because it a direct result of ionizing radiation (Mendelsohn et al., 2002). is a continuously renewing organ containing rapidly prolif- b-radiation can penetrate several centimeters into the skin, erating and maturing cells. The basal keratinocytes, hair whereas g-radiation can penetrate through the skin and into follicle stem cells, and melanocytes are highly radiosensitive (Mendelsohn et al., 2002; McQuestion, 2011). Radiation skin injury involves immediate damage to basal keratinocytes 1Departments of Dermatology and Radiation Oncology, Center for Medical Countermeasures against Radiation, University of Rochester Medical Center, and hair follicle stem cells, followed by a burst of free Rochester, New York, USA radicals, irreversible double-stranded breaks in nuclear and Correspondence: Julie L. Ryan, Departments of Dermatology and Radiation mtDNA, and inflammation (Mendelsohn et al., 2002; Eide Oncology, University of Rochester Medical Center, 601 Elmwood Avenue, and Weinstock, 2005; Lopez et al., 2005; Hymes et al., 2006; Box 697, Rochester, New York 14642, USA. E-mail: [email protected] McQuestion, 2011). During radiation therapy, the first fractionated dose of radiation destroys a percentage of basal Abbreviations: DC, dendritic cell; LC, Langerhans cell; TGFb, transforming growth factor-b keratinocytes, resulting in a disruption in the self-renewing Received 30 June 2011; revised 30 September 2011; accepted 29 October property of the epidermis (McQuestion, 2011). These 2011; published online 5 January 2012 repeated exposures do not allow time for cells to repair

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tissue or DNA damage. Although the remaining keratinocytes changes, and depilation. Although histological analyses are stimulated to proliferate, these cells are continually of irradiated skin show hyperproliferation of the epidermis destroyed with each fractionated radiation treatment. There- and thickening of the stratum corneum, transepidermal water fore, it is not surprising that cancer patients undergoing loss, a measure for skin barrier integrity, is significantly radiation therapy experience skin reactions, as well as other increased (Schmuth et al., 2001; Jensen et al., 2011). Severe symptoms (Hickok et al., 2005). Radiation skin injury occurs radiation injury results in complete loss of the epidermis and in about 95% of patients receiving radiation treatment for in persistent fibrinous exudates and edema. Re-epithelializa- cancer (Salvo et al., 2010; McQuestion, 2011). Radiation skin tion begins within 10–14 days after radiation exposure in the injury has also been reported in over 70 cases of fluorosco- absence of infection (McQuestion, 2011). About a year after pically guided procedures because of the lack of awareness radiation exposure, the skin is thin, hypovascularized, tight, of radiation exposure to skin during the procedure (Brown and susceptible to trauma or infection (Mendelsohn et al., and Rzucidlo, 2011). Reported entrance doses from fluoro- 2002). Chronic radiation skin injury includes delayed ulcers, scopically guided procedures have ranged from 2 to 58 Gy fibrosis, and telangiectasias that present weeks to years after (Brown and Rzucidlo, 2011). Radiation skin toxicities can radiation exposure (Mendelsohn et al., 2002; Bridges et al., negatively affect the quality of a patient’s life because of pain 2009; Brown and Rzucidlo, 2011). and premature interruption of radiation treatment, which in For many years, radiation burns (i.e., radiation skin injury) turn may impair control of disease (Duncan et al., 1996; have been treated using the same therapeutic measures Robertson et al., 1998; Salvo et al., 2010; McQuestion, applied to thermal burns. However, the pathophysiology of 2011). Despite substantial improvements in radiation tech- radiation burns differs from thermal burns in three major nology, such as intensity-modulated radiation therapy, ways (Lataillade et al., 2007; Bey et al., 2010). First, radiation radiation skin injury is still a concerning problem (Pignol burns have a dose-dependent clinical pattern, which includes et al., 2008; Salvo et al., 2010; McQuestion, 2011). dry desquamation at 12–20Gy, moist desquamation at Radiation skin injury can be categorized as acute or late X20 Gy, and necrosis at 435 Gy (Mendelsohn et al., 2002; (i.e., chronic) injuries (Table 1). Acute injury occurs within Hymes et al., 2006; Bey et al., 2010; Wolbarst et al., 2010; hours to weeks after radiation exposure, whereas late injury Brown and Rzucidlo, 2011). Second, radiation burns are presents months to years after radiation exposure (Mendel- associated with opiate-resistant chronic pain (Lataillade et al., sohn et al., 2002; Salvo et al., 2010; Wolbarst et al., 2010; 2007; Bey et al., 2010). The most complicating factor of McQuestion, 2011). Individuals who experience severe acute radiation burns is the unpredictable successive inflammatory injury are not more susceptible to severe late injury (Meyer waves occurring weeks to years after radiation exposure et al., 2011). Acute radiation skin injury primarily involves (Lataillade et al., 2007; Bey et al., 2010). These uncontrolled cellular alterations and inflammation in the epidermis and the inflammatory waves make it difficult to delineate the dermis. Acute effects begin with erythema, edema, pigment radiation-injured tissue from noninjured tissue. Conventional treatment for severe radiation burns combines surgical excision of damaged tissue and reconstructive surgery, such as full-thickness skin grafts (Lataillade et al., 2007; Bey et al., Table 1. Acute skin changes with localized radiation 2010). However, successive inflammatory waves often lead dose to impairment and necrosis of the newly grafted skin. Acute skin effect Dose (Gy) Onset Therefore, the majority of severe radiation burns require Early transient erythema 2 Hours successive surgical excisions and reconstructions, as well as amputation (Lataillade et al., 2007; Bey et al., 2010). Overall, Faint erythema; epilation 6–10 7–10 Days the healing of radiation burns is extensive and unpredictable. Definite erythema; 12–20 2–3 Weeks hyperpigmenation Risk factors Dry desquamation 20–25 3–4 Weeks Both treatment- and patient-related factors can contribute to Moist desquamation 30–40 X4 Weeks the risk of developing severe radiation skin injury. Technical Ulceration 440 X6 Weeks factors with radiotherapy that influence the degree of radiation skin injury include radiation dose to skin, irradiation site, fractionation timing, total exposure time, and angle Late skin effect of radiation beam (Brown and Rzucidlo, 2011; McQuestion, Delayed ulceration 445 Weeks after radiation 2011). The dose of radiation on the skin is directly related to Dermal necrosis/atrophy 445 Months after radiation the severity of injury. Different skin areas of the body have Fibrosis 445 6 Months to X1 year different sensitivities to radiation. The most sensitive skin after radiation regions of the body are the anterior of the neck, extremities, chest, abdomen, and face (Brown and Rzucidlo, 2011). In Telangiectasia 445 6 Months to X1 year after radiation addition, hair follicles on the scalp and breast tissue are both radiosensitive compared with other regions of the body Information compiled from Mendelsohn et al., 2002; Hymes et al., 2006; Bey et al., 2010; Wolbarst et al., 2010; and Brown and Rzucidlo, 2011. (Brown and Rzucidlo, 2011). Patient-related factors include preexisting conditions such as obesity, age, gender, chronic

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sun exposure, and smoking (Hymes et al., 2006; Salvo et al., IL-1a and tumor necrosis factor-a (Takashima and Bergstres- 2010; Brown and Rzucidlo, 2011; McQuestion, 2011). ser, 1996). The LCs, along with dermal dendritic cells (DCs), Individuals with ataxia telangiectasia and hereditary nevoid are essential antigen-presenting cells and are responsible basal cell carcinoma syndrome (Gorlin Syndrome) require for the uptake of antigens that may breach the skin barrier dose alterations or avoidance of radiation exposure (Hymes (Kupper and Fuhlbrigge, 2004). The dermis also contains et al., 2006). Individuals with ataxia telangiectasia, a rare mast cells and T cells, which are also important factors autosomal-recessive disorder resulting in mutations in the in radiation-induced immune response (Kalesnikoff and ATM gene, are highly susceptible to severe radiation Galli, 2008; Stelekati et al., 2009; Muller and Meineke, dermatitis. Irradiation of individuals with Gorlin Syndrome 2011). Furthermore, the dermis is richly supplied with blood could produce widespread cutaneous tumors. Other dis- vessels and lymphatic vessels, which serve as the conduits by orders that increase the risk of radiation skin injury include which migrating DCs can traffic to the draining lymph nodes connective tissue disorders (lupus, scleroderma), chromo- and present antigens to T cells (Kupper and Fuhlbrigge, somal breakage syndromes (Fanconi’s anemia, Bloom syn- 2004). drome), xeroderma pigmentosa, Gardner’s syndrome, Ionizing radiation incites signaling between the epidermis hereditary malignant melanoma, and dysplastic nevus and dermis (Figure 1). Keratinocytes, fibroblasts, and endo- syndrome (Hymes et al., 2006). Older female patients have thelial cells in the skin stimulate resident (i.e., LCs, DCs, mast increased risk of radiation skin injury (Hymes et al., 2006; cells, T cells) and circulating immune cells (Muller and Salvo et al., 2010; Brown and Rzucidlo, 2011; McQuestion, Meineke, 2007, 2011). Numerous cytokines and chemokines 2011). A recent study in head and neck cancer patients are produced in response to these activation signals, which reported that women were at higher risk for acute and late act on the endothelial cells of local vessels, causing the radiation–induced toxicities (odds ratios ¼ 1.72 and 3.96, upregulation of adhesion molecules (Muller and Meineke, respectively) compared with men (Meyer et al., 2011). 2007). Adhesion molecules that have been implicated Other risk factors for severe radiation skin injury are include intercellular adhesion molecule-1, vascular cell increased transepidermal water loss and infiltration of patho- adhesion molecule-1, and E-selectin (Yuan et al., 2005; gens or bacteria into the skin (Elliott et al., 1990; Ledney Holler et al., 2009). Transendothelial migration of immune et al., 1991; Hill et al., 2004; Martin et al., 2010). Severe cells, such as neutrophils, macrophages, and leukocytes, radiation dermatitis for localized radiation has previously from circulation to irradiated skin is considered a ‘‘hallmark’’ been linked to Staphylococcus aureus infection (Hill et al., of radiation-induced skin injury (Muller and Meineke, 2007; 2004). Host antimicrobial defenses are severely compro- Holler et al., 2009). Acute radiation skin toxicity has been mised by radiation and/or skin trauma combined with radi- correlated with increased formation of various cytokines ation (Ledney et al., 1991). Even mice exposed to sublethal and chemokines, most notably IL-1a, IL-1b, tumor necrosis total body radiation have increased susceptibility to bacterial factor-a, IL-6, IL-8, CCL4, CXCL10, and CCL2 (Okunieff infections in wounds (Elliott et al., 1990; Ledney et al., 1991; et al., 2006; Xiao et al., 2006; Holler et al., 2009). Research Konchalovsky et al., 2005; Williams and McBride, 2011). demonstrated that both the epidermal LCs and the dermal It appears that ionizing radiation damage in the skin is DCs are depleted from the skin following local irradiation somewhat similar to atopic dermatitis. Atopic dermatitis, a (Cummings et al., 2009). This is time dependent and common form of eczema, affects up to 20% of children in the radiation-dose dependent for both subsets of cells (Cummings United States, and is widely accepted to have a profound et al., 2009). An important question, which has not yet been effect on the stratum corneum function, and increased trans- addressed, is whether this depletion is due to death of the epidermal water loss (Murata et al., 1996; Laughter et al., cells or by migration to the draining lymph node. The effects 2000; Imokawa, 2001; Pilgram et al., 2001; Choi and of ionizing radiation on DCs are largely unknown, and in Maibach, 2005; Jungersted et al., 2008). Atopic dermatitis humans they are limited to studies on populations of DCs patients are far more susceptible to skin infections by generated in vitro from peripheral blood mononuclear cells. organisms such as Staphlococcus aureus and Herpes simplex A recent study on DC populations has revealed that they do virus (Scott et al., 2007; Kedzierska et al., 2008; Lebre et al., not undergo apoptosis after as much as 30 Gy and maintain 2008; Niebuhr et al., 2008). It has been speculated that their ability to ingest particles and to migrate. However, their atopic dermatitis individuals would be more susceptible to antigen-presenting capabilities, as measured by their ability severe radiation skin injury; however, the definitive answer to induce T-cell responses, were found to be slightly impaired has yet to be elucidated. (Merrick et al., 2005). Merad et al. (2002) demonstrated that DCs were replaced by donor cells within 2 months in Skin immune response following radiation lethally irradiated C57BL/6-CD45.2 þ mice that received In addition to being the physical barrier, the skin provides a a bone marrow transplant from C57BL/6-CD45.1 þ donor system of immune surveillance that maintains homeostasis mice. In contrast, the host LCs persisted in the recipient mice and is poised to respond to environmental insults. Key cells for up to 18 months following irradiation (Merad et al., 2002). within the epidermal layer involved in this surveillance are Interestingly, in this same study, it was demonstrated that the Langerhans cells (LCs; Valladeau and Saeland, 2005). an additional injury (UVR) resulted in rapid disappearance Keratinocytes also have an important role because they are of LCs and replacement by circulating LC precursors. These capable of producing large amounts of cytokines, particularly studies suggest that LCs are quite radioresistant.

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Keratinocytes Langerhans cells Basal cells = radiosensitive Fairly radioresistant Recruit immune cells Antigen presentation Maintain skin barrier integrity Migration to/from lymphatic system Epidermis

IL-1α, IL-1β, IL-6, IL-8, CCL4, CXCL10, CCL2

RNS Oxidative stress and Superoxide dismutases ROS antioxidant imbalance Glutathione peroxidases Peroxides Thioredoxin reductases Superoxides Catalase Glutathiones Epidermal and dermal damage

Dendritic cells Endothelial cells Mast cells Fibroblasts T cells Express ICAM-1, Histamine, Acute: CCL8, IL-4, IL-5, IL-13, Antigen presentation VCAM-1, E-selectin tryptase, CCL13, CXCL4, TSLP, IFNγ, Migration for sertonin, TNFα CXCL6, CCL11, TNFα T-cell recruitment transendothelial Dermis migration of Signal to Late: TGFβ, VEGF, IL-12, IL-1α, IL-1β, leukocytes fibroblasts CCL11 IIL-6, IL-8, CCL4, CXCL10, CCL2 Wound healing: bFGF, EGF, KGF

Figure 1. Schematic identifying the key cells and mediators involved in radiation skin injury. Ionizing radiation incites signaling between the epidermis and dermis through resident skin cells. In the epidermis, immediate damage to the basal keratinocytes and burst of free radicals result in the increased formation of various cytokines and chemokines, most notably IL-1a, IL-1b, TNFa, IL-6, IL-8, CCL4, CXCL10, and CCL2. Keratinocytes, along with fibroblasts and endothelial cells in the dermis, stimulate resident skin cells and recruit circulating immune cells, such as neutrophils and macrophages. In addition, Langerhans cells in the epidermis and dendritic cells in the dermis migrate to lymph nodes for antigen presentation and immune cell stimulation. Degranulation of mast cells releases histamine, serotonin, TNFa, and tryptase. Fibroblast stimulation is involved in acute skin injury, late skin injury, and healing of radiation skin injury. Oxidative stress is generated at the time of radiation exposure, as well as days after irradiation, because of propagation of free radicals and inflammatory cell recruitment, creating an antioxidant imbalance. bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; ICAM-1, intercellular adhesion molecule-1; KGF, keratinocyte growth factor; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNFa, tumor necrosis factor-a; TSLP, thymic stromal lymphopoietin; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.

Recently, Muller and Meineke (2011) demonstrated that propagation of free radicals (Benderitter et al., 2007). ionizing radiation results in degranulation of mast cells in the Radiation skin injury also involves imbalances in antioxidant dermis. Mast cell–derived histamine, serotonin, tumor necro- status and redox control of wound healing (Benderitter sis factor-a, and tryptase significantly alter the release of et al., 2007; Holler et al., 2009; Muller and Meineke, 2007, CCL8, CCL13, CXCL4, and CXCL6 by dermal fibroblasts 2011; Williams and McBride, 2011). The immediate damage (Muller and Meineke, 2011). Research to date suggests that caused by ionizing radiation is a result of robust, but fibroblasts are responsible for fibrosis and other late-radiation transient, production of reactive oxygen species (Williams injury (Brown and Rzucidlo, 2011; Muller and Meineke, and McBride, 2011). However, inflammatory cell recruitment 2007, 2011). Transforming growth factor-b (TGFb), Smad3, and cytokine generation also lead to chronic generation of vascular endothelial growth factor, and CCL11 (eotaxin) have reactive oxygen species. Specific genes that have been been identified as key mediators of radiation-induced late implicated in oxidative stress following radiation exposures injury (Okunieff et al., 2006; Xiao et al., 2006; Muller and include superoxide dismutases, glutathione peroxidases, Meineke, 2007; Anscher, 2010). TGFb is a potent chemo- thioredoxins, heme-oxygenases, and heat-shock protein-27 attractant for various inflammatory cells and a stimulant for (Benderitter et al., 2007; Williams and McBride, 2011). extracellular matrix production by fibroblasts (Anscher, 2010; Superoxide dismutase-1, glutathione peroxidase-1, thio- Lee et al., 2010). TGFb initiates a fibrotic response through its redoxins-1, -2, and heat-shock protein-27 were upregulated receptor Smad3 on fibroblasts (Anscher, 2010; Lee et al., in healing skin after irradiation. However, these genes were 2010). Reduction in radiation-induced fibrosis in Smad3 downregulated, whereas heme-oxygenases-1 and -2 were knockout mice has demonstrated its link to late-radiation skin upregulated in nonhealing skin after irradiation (Benderitter injury (Ashcroft et al., 1999; Flanders et al., 2002, 2003; Lee et al., 2007). Benderitter et al. (2007) further implicated et al., 2010). a T helper type-2-mediated immune response for nonresolu- Oxidative stress is generated at the time of radiation tion of inflammatory response and delayed wound healing exposure, as well as days after irradiation, because of the following irradiation. Catalase has also been identified as

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a potential mitigator for radiation skin injury because Table 2. Comparison of acute radiation skin injury of its ability to reduce tumor necrosis factor-a-induced scoring systems production of cytokines and reactive oxygen species Score Observation (Doctrow et al., 1997; Young et al., 2008; Rosenthal et al., 2011). Radiation Therapy Oncology Group 0 No change over baseline AREAS NEEDING INVESTIGATION: WEAKNESSES IN 1 Erythema; dry desquamation; epilation MEASUREMENT AND TREATMENT Measuring severity of radiation skin injury 2 Bright erythema; moist desquamation; edema A gold standard for clinically rating the severity of radiation 3 Confluent moist desquamation; pitting edema skin injury does not exist (Table 2). The most commonly used 4 Ulceration, hemorrhage, necrosis scoring systems are the National Institutes of Health Common Toxicity Criteria-Adverse Event (CTCAE) and the Radiation NIH CTCAE Therapy Oncology Group toxicity scoring system (Salvo et al., 2010). However, other scoring scales, such as the 0 None Oncology Nursing Society, Douglas & Fowler, and Radiation 1 Faint erythema or dry desquamation Dermatitis Severity scales, have been developed to more 2 Moderate to brisk erythema accurately represent the varying levels of the actual skin 3 Confluent moist desquamation reaction. In contrast to the CTCAE and Radiation Therapy Oncology Group scoring systems, the newer scales have 4 Skin necrosis or ulceration smaller defined increments to represent subtle, yet critical, changes in the skin. The CTCAE and Radiation Therapy Oncology Nursing Society Oncology Group scales range from 0 to 4 with increments 0 No change of 1, whereas the Oncology Nursing Society, Douglas & 1.0 Faint or dull erythema Fowler, and Radiation Dermatitis Severity scales range from 0 to 4 or 1 to 5 with increments of 0.5. Table 2 shows the 1.5 Bright erythema various scoring systems used to measure acute radiation- 2.0 Dry desquamation with or without erythema induced skin reactions. Radiation-induced late effects in the 2.5 Small to moderate amount of moist desquamation skin are primarily rated by the Radiation Therapy Oncology 3.0 Confluent moist desquamation Group/European Organization for Research and Treatment of Cancer or Late Effects Normal Tissue Task Force/Subjective, 3.5 Ulceration, hemorrhage, or necrosis Objective, Management, and Analytic classifications, which range from Grade 1 to 4 (Hoeller et al., 2003). Both scales Douglas & Fowler measure late skin changes and subcutaneous tissue changes, 0 Normal but the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, and Analytic scale also incorporates 0.25 50/50, Doubtful if any difference from normal pain intensity. 0.5 Very slight reddening Over the past few years, patient-reported outcomes have 0.75 Definite but slight reddening become common instruments to aid in accurate assessment 1 Severe reddening of various symptoms (Neben-Wittich et al., 2010). Recently, 1.25 Severe reddening with white scale; ‘‘papery’’ appearance Neben-Wittich et al. (2010) reported that the Skindex-16 and of skin Skin Toxicity Assessment Tool, two patient-report outcome 1.5 Moist breakdown in one very small area with scaly or crusty instruments, did not correlate with the CTCAE scoring system. appearance Both patient-report outcome instruments provided a more complete measure of toxicity compared with the CTCAE 1.75 Moist desquamation in more than one small area scores. The importance of patient-report outcome instruments 2 Moist desquamation in 25% of irradiated area in radiation skin toxicity is further supported by a compara- 2.25 Moist desquamtion in 33% of irradiated area tive study conducted in 2007 (Ryan et al., 2007). Ryan 2.5 Moist desquamation in 50% of irradiated area et al. (2007) demonstrated a disconnect between clinically 2.75 Moist desquamation in 66% of irradiated area reported and patient-reported radiation-induced skin reaction. The study showed that African Americans reported 3 Moist desquamation in most of irradiated area more severe posttreatment skin reactions compared with 3.25 Moist desquamation in most of irradiated area with slight moist Caucasians after receiving radiation therapy. Both these exudate studies (Ryan et al., 2007; Neben-Wittich et al., 2010) 3.5 Moist desquamation in most of irradiated area with moist demonstrate that patient-reported information is critical for exudates; necrosis effective symptom management. Overall, further research is required for the development of a standard and accurate scoring system for radiation skin injury. Table 2 continued on the following page

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Table 2. Continued development of effective radiation mitigators and protectors Score Observation (Ryan et al., 2011a). Because of the unpredictability and barriers to medical treatment following a radiological or Radiation dermatitis severity scale nuclear event, an effective remediation strategy must be a 0.0 Normal or none radiation mitigator (Williams and McBride, 2011; Ryan et al., 0.5 Patchy faint/slight follicular eyrthema; faint hyperpigmentation 2011a). However, for cancer radiotherapy, elucidation of the differences in the mechanisms involved in the response of 1.0 Faint and diffuse erythema; diffuse hyperpigmentation; mild epilation skin and other normal tissues to radiation in comparison with tumors is a critical component in this development (Ryan 1.5 Definite erythema; extreme darkening/hyperpigmentation et al., 2011a). Most importantly, interventions that ameliorate 2.0 Definite erythema/hyperpigmentation with fine dry radiation-induced toxicities in one scenario of radiation desquamation; mild edema exposure may also work in other scenarios of exposure 2.5 Definite erythema/hyperpigmentation with branny/scaly (i.e., ‘‘dirty bomb’’ vs. radiotherapy). desquamation Targeted gene therapy has emerged as a promising 3.0 Deep red erythema with diffuse dry desquamation; peeling in radiation mitigator and protector. Preclinical studies have sheets identified the following potential targets: TGFb1 pathway 3.5 Violaceous erythema with early moist desquamation; peeling in inhibitor (Anscher, 2010; Lee et al., 2010), synthetic super- sheets; patchy crusting oxide dismutase/catalase mimetics (Greenberger, 2008; 4.0 Violaceous erythema with diffuse moist desquamation; patchy Rosenthal et al., 2011), recombinant IL-12 (Cummings crusting; ulceration; necrosis et al., 2009), toll-like receptor-5 agonist (Burdelya et al., Abbreviation: NIH/CTCAE, National Institutes of Health Common 2008; Gudkov and Komarova, 2010), and inhibitors of Toxicity Criteria—Adverse Event. cyclin-dependent kinases (Gudkov and Komarova, 2010). Data compiled from Pommier et al., 2004; Elliott et al., 2006; Okunieff et al., 2006; Xiao et al., 2006; Holler et al., 2009; Jensen et al., 2011; and Furthermore, pravastatin reduced radiation skin injury by Ryan et al., 2011b. maintaining endothelial cell function after radiation exposure by increasing endothelial nitric oxide synthase (Holler et al., 2009). Curcumin, a component of turmeric, has also Evidence-based management of radiation skin injury demonstrated the ability to reduce radiation skin toxicity Over the years, ‘‘washing with mild soap’’ has been the only through its potent antioxidant and anti-inflammatory acti- intervention recommended for radiation-induced skin reac- vities (Okunieff et al., 2006; Ryan et al., 2011b). Recently, tions (Bolderston et al., 2006; McQuestion, 2006). In 2010, a Atiba et al. (2011) observed that acceleration of radiation systematic review revealed a lack of evidence to support delayed wound healing in mice upon stimulation of TGFb-1 ‘‘washing with mild soap’’ as an intervention for radiation- and basic fibroblast growth factor, suggesting that the growth induced skin reactions (Salvo et al., 2010). In this study (Salvo factor treatment may mitigate radiation skin injury. Although et al., 2010), although topical corticosteroid and nonsteroidal these agents still require formal and extensive clinical testing, creams appeared to reduce the severity of skin reactions, there the targeted approach appears specific and propitious. was no clear indication of a preferred topical agent. Amifostine Recently, stem cell therapy combined with surgical and oral enzymes emerged as somewhat effective preventative excision has demonstrated success in improving wound agents, whereas pentoxifylline reduced late, but not acute, repair of severe radiation burns. As previously discussed, effects of radiation on the skin (Benderitter et al., 2010; Muller surgical excision and grafting of radiation burns is compli- and Meineke, 2010; Salvo et al., 2010). Long treatment (X3 cated because of the ill-defined margins of radiation damage. years) of pentoxifylline and tocopherol (i.e., vitamin E) Lataillade et al. (2007) used dosimetry-guided excision and significantly reduced radiation-induced fibrosis. Unfortunately, mesenchymal stem cell injections to promote healing of a cessation of pentoxifylline–tocopherol treatment before 3 years severe radiation burn on a man’s buttocks from Iridium-192. resulted in a ‘‘rebound effect’’ and more severe radiation- After failure of the initial surgical excision and skin graft, a induced fibrosis (Delanian et al., 2005). In addition, intensity- secondary excision was performed followed by mesenchymal modulated radiation therapy was acknowledged as a stem cell injections around the lesion at the cutaneous and technological intervention that has significantly reduced skin muscular levels, as well as in the bed of the lesion under reactions from radiation (Pignol et al., 2008; Muller and the skin graft. No recurrence of radiation burn was observed Meineke, 2010; Salvo et al., 2010). In 2011, McQuestion 5.5 months after radiation (Lataillade et al., 2007). Similarly, (2011) published evidence-based guidelines for skin care Bey et al. (2010) used five local mesenchymal stem cell management in radiation therapy, which recommended the administrations combined with surgical excision and auto- following: (1) washing with lukewarm water and mild soap, (2) graft on the arm of a man exposed to Iridium-192. Although using unscented, lanolin-free, water-based moisturizing cream, the arm had functional and cosmetic limitations, there was and (3) intensity-modulated radiation therapy. Overall, an effec- no recurrence of the radiation burn. Ebrahimian et al. tive intervention for radiation-induced skin reactions remains to (2009) demonstrated that adipose tissue–derived stem cells be elucidated (Salvo et al., 2010; McQuestion, 2011). also promote wound healing in irradiated skin of mice. National Cancer Institute and the National Institute of Control of inflammatory waves, improved wound healing, Allergy and Infectious Disease both have interest in the and stabilization of skin barrier are imperative to minimizing

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radiation-induced skin injury from localized or total body unethical and radiological/nuclear events are unpredictable. radiation exposure. Much of our understanding of cutaneous radiation syndrome comes from our comprehension of localized skin irradiation. FUTURE CHALLENGES: CUTANEOUS RADIATION However, the National Institutes of Allergy and Infectious SYNDROME AND COMBINED INJURY Disease has established a network of Centers for Medical Recent events in Japan, the United Kingdom involving Countermeasures against Radiation, a collaborative network radioactive Polonium-210, as well as the nuclear weapons of academic institutions, whose primary goal is to identify, testing in North Korea, suggest increased potential for and develop, and deploy medical countermeasures for radiation reality of a nuclear and/or radiological event. It is recognized toxicity after an unfortunate event (Williams and McBride, that any skin injury in the setting of radiation poisoning greatly 2011). To plan effective remediation strategies, knowledge increases the risk of death. Skin injury due to radiation about mechanisms responsible for acute and chronic radia- exposure is a major component of the multi-organ toxicity, tion effects in skin, from localized and total body irradiation, which could occur because of an industrial or terrorist-related is needed. incident (Jungersted et al., 2008). A second injury, such as a burn, or wound after nonlethal or sublethal radiation exposure SUMMARY significantly increases mortality from B12 to 75% (Jiao et al., Over the past 10 years, the field of radiation skin injury 2009; Homeland Security Council, 2009). The combined has made substantial progress. This review summarizes the injury effect of trauma or burns with total body radiation strengths and weaknesses in published research. An expan- injury at Hiroshima lowered the LD95 and LD50 by sion in the knowledge on the mechanistic effects of radiation approximately 2 Gy (Flynn and Goans, 2006). These data in skin, as well as other normal tissues, has enabled confirm that a lower dose of radiation is required when innovative growth. Unfortunately, no gold standard exists combined with skin trauma or burns to cause death in 95 for the measurement or management of radiation skin injury. (LD95) or 50% (LD50) of individuals. Prolonged contact with Development of agents to prevent or mitigate radiation skin fallout on the skin can result in serious skin damage plus injury will benefit the general population, as well as patients increased total body dose (Flynn and Goans, 2006; Bridges receiving cancer treatment. et al., 2009). A 10 kiloton nuclear device has the potential to inflict second-degree burns on exposed skin up to 1.4 miles CONFLICT OF INTEREST from ground zero, whereas a 1 megaton device could inflict The author states no conflict of interest. second-degree burns within 15 miles from ground zero (DiCarlo et al., 2011). In the Chernobyl Nuclear Power Plant accident, skin involvement ranged from 4 to 50% of the total REFERENCES body surface from g-ray (Cs-137) and b-particle (Sr-90) Anscher MS (2010) Targeting the TGF-beta1 pathway to prevent normal tissue injury after cancer therapy. Oncologist 15:350–9 emissions (Gottlober et al., 2001), permitting detailed obser- Ashcroft GS, Yang X, Glick AB et al. (1999) Mice lacking Smad3 show vation of cutaneous radiation syndrome. Early radiation accelerated wound healing and an impaired local inflammatory changes in skin, such as erythema and blistering, were response. Nat Cell Biol 1:260–6 observed within a year after the accident. 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