Version May 2024
INTRODUCTION — Radiation dermatitis is one of the most common side effects of radiotherapy for cancer, affecting over 90 percent of patients receiving radiotherapy [1-6]. Cutaneous adverse effects of radiation therapy can be divided into early/acute reactions, occurring within 90 days of initiating treatment, and late effects, which often become apparent months to years after radiation treatment has been completed (table 1).
This topic will discuss the pathogenesis, clinical manifestations, and treatment of radiation dermatitis. The complications of breast and chest wall irradiation and radiation-induced fibrosis are discussed separately.
●(See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)
PATHOPHYSIOLOGY
Acute effects — Basal keratinocytes, stem cells in the hair follicles, and melanocytes are highly radiosensitive [7-9]. During radiation therapy, the first fractionated dose of radiation causes immediate structural tissue damage, ionization of cellular water and generation of short-lived free radicals, irreversible double-stranded breaks in nuclear and mitochondrial deoxyribonucleic acid (DNA), and inflammation [2,10-13]. The destruction of a large proportion of basal keratinocytes results in the disruption of the self-renewing property of the epidermis. Repeated exposures do not allow time for basal skin cells to replenish and maintain optimal renewal of the epidermis.
Possible mechanisms leading to radiation-induced inflammation are summarized below:
●Ionizing radiation incites signaling between the epidermis and dermis through resident skin cells. The hallmark of radiation-induced skin injury is the transendothelial migration of leukocytes and other immune cells from circulation to irradiated skin [14,15].
●Keratinocytes, Langerhans cells, fibroblasts, and endothelial cells in the skin stimulate resident and circulating immune cells [15,16]. Numerous cytokines and chemokines are produced in response to these activation signals, which act on the endothelial cells of local vessels, causing the upregulation of adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin) [14,15,17]. Acute radiation skin toxicity has been correlated with increased formation of various cytokines and chemokines, in particular interleukin (IL) 1-alpha, IL-1-beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-8, chemokine ligand 4 (CCL4), cysteine-X-cysteine motif chemokine ligand 10 (CXCL10), and chemokine ligand 2 (CCL2) [14,18,19].
●In addition, ionizing radiation induces degranulation of mast cells in the dermis [16]. Research suggests that fibroblasts are a key cell type responsible for the late/delayed effect of radiation (ie, fibrosis) [3,15,16].
●Radiation skin injury also involves imbalances in antioxidant status and redox control of wound healing [12,14-16,20]. Specific enzymes that have been implicated in oxidative stress following radiation exposures include superoxide dismutases, glutathione peroxidases, thioredoxins, heme oxygenases, heat shock protein 27 (HSP27), and nitric oxide synthase [12,20]. A T helper type 2 (Th2)-mediated immune response may also be responsible for nonresolution of inflammatory response and delayed wound healing following irradiation [20].
Late effects — Transforming growth factor (TGF)-beta levels are increased within hours of radiation exposure, and this is thought to be implicated in the late, radiation-induced, fibrotic changes [21]. TGF-beta is a regulatory protein that controls cell proliferation and differentiation, wound healing, and synthesis of extracellular matrix components in normal tissue inflammatory response [22]. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)
EPIDEMIOLOGY — Radiation dermatitis occurs in over 90 percent of patients receiving radiotherapy, especially in patients with breast cancer, head and neck cancer, skin cancer, lung cancer, or sarcoma [1,7,23-25]. The reason for the higher incidence in these cancer patient populations is the higher radiation dose to the skin. In most cases, the skin reaction is mild or moderate, but approximately 20 to 45 percent of patients experience higher grade dermatitis with moist desquamation and ulceration (table 4B) [26,27].
Signs and symptoms of radiation therapy adverse effects, including radiation dermatitis, may be underrecognized and underreported. In a United States study that included nearly 10,000 patients with breast cancer undergoing radiation therapy, 72 percent completed a patient-reported outcome questionnaire. Of these, 99 percent were matched to physician Common Terminology Criteria for Adverse Events (CTCAE) assessments performed within three days of the questionnaire completion [28]. Among 5510 patients reporting at least one symptom (ie, pain, pruritus, edema, fatigue), underrecognition of at least one symptom occurred in 53 percent of cases. Factors independently associated with underrecognition included age younger than 50 years, being of Black or other than White ethnicity, receiving conventional fractionation, and male physician sex.
RISK FACTORS — Risk factors for radiation dermatitis include patient-related factors, radiation dosing and schedule, and use of concurrent chemotherapy (table 2).
Patient related
●Body areas – Different areas of the body have different sensitivities to radiation (table 2). The most sensitive regions of the body are the anterior of the neck, extremities, chest, abdomen, and face [3]. Hair follicles on the scalp as well as the breast tissue are also radiosensitive. In patients with breast cancer, larger breast size is associated with increased risk of grade 2 or higher radiation dermatitis [29,30]. In addition, breast reconstructions and implants are associated with increased risk of severe radiation dermatitis due to the skin's inability to dissipate heat following reconstruction procedures. These reactions are usually confined to surfaces of transposed flaps or to mastectomy flaps [31,32].
●Comorbidities and lifestyle factors – Obesity, poor nutritional status, chronic sun exposure, and smoking appear to increase the risk of radiation dermatitis [2-4,33,34]. In a French study of 200 patients with breast cancer, a body mass index (BMI) >30 was associated with increased risk of grade ≥2 radiodermatitis [35].
Based upon limited evidence from case reports and small case series, patients with connective tissue diseases (and, in particular, those with scleroderma) were considered in the past to be at increased risk of severe, acute and chronic radiation dermatitis [36]. In one study, skin thickening localized to the field of irradiation was reported in approximately 50 percent of patients with scleroderma [37]. However, data from large case series and a few case-control studies do not show an increased frequency of acute or late complications in patients with connective tissue diseases undergoing radiation therapy [38-40]. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Issues with specific therapies' and "Malignancy and rheumatic disorders", section on 'Safety of radiation therapy for malignancy in patients with rheumatologic disease'.)
●Staphylococcus aureus colonization – It has been hypothesized that colonization with S. aureus may play a role in the development of severe radiation dermatitis [41,42]. In a prospective study of 76 patients with breast or head and neck cancer undergoing radiation therapy, patients who developed grade 2 or higher dermatitis had a higher baseline prevalence of nasal S. aureus colonization compared with those with grade 1 dermatitis (35 versus 13 percent, respectively) [41].
●Genetic susceptibility – Patients with inherited diseases associated with impaired DNA repair capacity, such as ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, Gorlin syndrome, or xeroderma pigmentosum, are at risk of developing severe radiation dermatitis [2]. (See "Ataxia-telangiectasia" and "Bloom syndrome" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)" and "Xeroderma pigmentosum".)
However, even in the absence of a known genetic disease, some individuals may have an increased susceptibility to radiation dermatitis. DNA sequencing studies have identified a number of single nucleotide polymorphisms (SNPs) associated with the development of radiation dermatitis [43-46]:
•One study of 114 patients with locally advanced nasopharyngeal carcinoma found an association between the codon 399 Arg/Arg SNP in the X-ray repair cross-complementing gene 1 (XRCC1) and risk of acute radiation dermatitis [45].
•Another study of 446 female patients receiving radiation therapy after lumpectomy for breast cancer found that females with polymorphisms encoding reduced or absent activity in the glutathione S-transferases function had a greater than twofold increase in risk for acute radiation dermatitis [43].
•In another study of 156 patients with breast cancer, SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with a nearly threefold increased risk of radiation-induced dermatitis [46].
Radiation dosing and schedule — The total dose, dose per fraction, and volume and surface area exposed to radiation influence the risk of radiation dermatitis. In addition, the use of bolus material to ensure full skin dose in certain clinical scenarios (eg, skin cancer, scar recurrence) enhances the development of radiation dermatitis.
Among patients with early breast cancer undergoing adjuvant radiation therapy, evidence from observational studies and randomized trials indicates that hypofractionated radiotherapy (40 to 42.5 Gy given in three to four weeks) is associated with a lower risk of acute, toxic effects compared with conventionally fractionated radiotherapy (50 Gy in 25 fractions) [47,48] (see "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer"):
●In a multicenter cohort study including 2309 patients with breast cancer treated with adjuvant radiotherapy, the frequency of moist desquamation, dry desquamation, and grade ≥2 dermatitis was significantly lower among patients treated with hypofractionated radiation therapy compared with those treated with conventional radiation therapy (6.6 versus 28.5 percent, 18.7 versus 58.8 percent, and 27.4 versus 62.6 percent, respectively) [48].
●Similar results were obtained in a randomized trial including 287 patients with breast cancer treated with hypofractionated or conventional radiation therapy [47]. In this study, the rate of grade ≥2 dermatitis was 47 percent among patients treated with hypofractionated radiation therapy and 78 percent among those treated with conventional radiotherapy.
●In a 2016 Cochrane review, acute skin toxicity was reduced with hypofractionated radiation therapy (relative risk [RR] 0.32, 95% CI 0.22-0.45; two studies, 357 females) [49]. Late subcutaneous fibrosis was similar with either hypofractionated or conventional schedule (RR 0.93, 95% CI 0.83-1.05; four studies, 5130 females).
Concurrent anticancer therapies — Patients receiving conventional chemotherapy agents (eg, anthracyclines, taxanes) or targeted anticancer therapy with epidermal growth factor receptor (EGFR) inhibitors plus radiation therapy are at increased risk of developing severe radiation dermatitis [50,51] (see "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy"):
●In a meta-analysis of 15 randomized trials comparing chemoradiotherapy versus radiation therapy alone for the treatment of nasopharyngeal carcinoma, chemoradiotherapy was associated with a nearly doubled risk of severe (grade 3 or 4) radiation dermatitis (RR 1.80, 95% CI 1.13-2.88) [51].
●In a systematic review of 48 studies including 2152 patients with locally advanced head and neck squamous cell carcinoma treated with concurrent radiotherapy and cetuximab, grade 3 or 4 radiation dermatitis developed in 32.5 percent of patients (95% CI 28.5-36.5 percent) [52]. In a subsequent report of 51 patients treated with radiotherapy and cetuximab, grade 3 or 4 radiation dermatitis occurred in 43 percent of patients [53].
●Treatment with immune checkpoint inhibitors preceding or following radiation therapy does not seem to increase the risk of radiation dermatitis. In a meta-analysis of 23 clinical trials of immune checkpoint inhibitors plus radiation therapy for the treatment of various cancers, the overall rates of all-grade and severe dermatitis were 22 percent (95% CI 16-29) and 3 percent (95% CI 2-5), respectively, similar to the rates of skin toxicities reported for immune checkpoint inhibitor therapy alone [54].
PREVENTION
Modern radiation therapy techniques
●Intensity-modulated radiation therapy – Intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT), advanced forms of radiation therapy that deliver radiation to the planned treatment volume while minimizing radiation to normal tissue outside the target, have been reported to reduce the occurrence of skin reactions. In a multicenter, randomized trial, 331 patients with breast cancer were treated postoperatively with adjuvant radiotherapy using either a standard wedge missing-tissue compensation technique or breast IMRT [55]. Fewer patients experienced moist desquamation in the IMRT group than in the conventional radiotherapy group (31 versus 48 percent). In a multivariate analysis, breast IMRT decreased the risk of moist desquamation by nearly 60 percent (odds ratio [OR] 0.42, 95% CI 0.23-0.75). (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)
●Hypofractionated radiation therapy – Hypofractionated irradiation has become increasingly popular for breast radiation therapy [56]. Hypofractionation delivers a higher fractionated radiation dose daily for an equivalent total dose over a shorter period of time (ie, fewer number of sessions). A prospective evaluation of hypofractionated versus standard fractionated therapy suggests that rates of dermatitis, pruritus, hyperpigmentation, and pain are decreased with hypofractionated therapy [47]. (See 'Radiation dosing and schedule' above.)
●Partial breast irradiation – Accelerated partial-breast irradiation (APBI) is an alternative to whole-breast irradiation in select low-risk patients with breast cancer after breast conservation surgery [57]. APBI has been associated with a lower rate of acute toxicity without an increased risk of relapse compared with whole-breast radiotherapy [58,59]. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Accelerated partial-breast irradiation'.)
General skin care — The skin in the treatment area needs to be protected from irritation and friction during radiotherapy treatment and for two to four weeks after radiotherapy treatment has finished. General skin care measures for patients undergoing radiation therapy include [7,24,33,60,61]:
●Keeping the irradiated area clean and dry.
●Washing with lukewarm water and mild soap (liquid, synthetic, "soap-free" and fragrance-free body washes with a near-physiologic pH of 4 to 6 are preferable).
●Using unscented, lanolin-free, water-based moisturizers two to three times per day, including a nontreatment day on the weekend.
●Avoiding skin irritants, such as perfumes and alcohol-based lotions.
●Wearing loose-fitting clothes to avoid friction injuries.
●Avoiding corn starch or baby powder in skin folds.
●Avoiding sun exposure.
●Avoiding wet shaving within the treatment area; an electric razor is a safe alternative.
It is important to instruct patients to gently clean and dry the skin in the radiation field before each irradiation session:
●Washing – The benefit of a washing routine during treatment for the prevention of severe radiation dermatitis has been evaluated in a few randomized trials involving patients with breast cancer and head and neck cancer and in one meta-analysis [61-64]. Although washing practices do not seem to reduce the overall risk of developing radiation dermatitis, washing with soap and water or water alone is associated with a significant reduction in itching, erythema, and desquamation compared with no washing [61,62]. Moreover, allowing patients to continue their normal hygiene routine may prevent unnecessary distress and social isolation.
●Moisturizing – Although patients are typically advised to avoid applying topical moisturizers, gels, emulsions, or dressings shortly before radiation treatment, as they can cause a bolus effect (ie, increase in the radiation dose delivered to the epidermis) [26], the application of moisturizers in small amounts is generally safe. A study that evaluated the dosimetric effect of topical agents commonly used for radiation dermatitis (ie, petrolatum-based ointment, silver sulfadiazine cream) by using optically stimulated luminescent dosimeters found that the surface radiation dose increased when a very thick layer (≥3 mm) of the topical agent was applied but did not increase if only a moderately thick layer (1 to 2 mm) was applied [65].
●Use of deodorants – The use of deodorants (and, in particular, metallic deodorants) during radiation therapy has been debated due to concerns that the deposition of aluminum salts may influence the superficial radiation dose or cause a bolus effect [66]. However, a randomized trial including 333 patients with breast cancer using aluminum-containing deodorants, non-aluminum-containing deodorants, or no deodorants during conventionally fractionated postoperative radiation therapy did not find any significant difference among the three groups in the incidence or severity of radiation dermatitis [67]. Patients in the aluminum-containing deodorant group experienced significantly less sweating than the control group. The odds of their sweating being barely tolerable and frequently or always interfering with their daily activities was decreased by 85 percent (OR 0.15, 95% CI, 0.03-0.91).
Topical corticosteroids — We recommend topical corticosteroids for the prevention of severe radiation dermatitis and for the reduction of discomfort and itching [60]. Low- to medium-potency topical corticosteroids (groups 4 and 6 (table 3)), such as mometasone furoate 0.1% or hydrocortisone butyrate 0.1% cream, are applied to the treatment field once or twice daily, starting on the day of the first radiotherapy session and continued through the entire treatment cycle.
Evidence from several randomized trials and one meta-analysis indicates that the regular use of topical corticosteroids during radiation therapy treatment and for a few additional weeks after the completion of treatment may reduce the incidence of severe dermatitis (moist desquamation) [62,68-72]:
●A 2017 meta-analysis including 10 randomized trials (919 participants with breast cancer) found that topical corticosteroids applied once or twice daily to the breast or chest wall from the first day of radiotherapy to up to three weeks after completion of radiotherapy reduced the risk of wet desquamation compared with placebo creams (OR 0.29, 95% CI 0.19-0.45) [73]. All studies showed that the mean radiation dermatitis score assessed by the Radiation Therapy Oncology Group (RTOG) or Common Terminology Criteria for Adverse Events (CTCAE) version 3 was lower in the corticosteroid group than in the control group. Moreover, in six studies, patients' subjective reports of pruritus and burning were fewer in the topical corticosteroid group than in the control group.
●In a 2018, randomized trial, 124 patients with breast cancer undergoing postmastectomy radiation therapy were treated with mometasone furoate 0.1% cream or an emollient cream twice daily, starting on the first day of radiation therapy and continuing until either the development of moist desquamation or two weeks after the completion of radiation therapy. Moist desquamation occurred in fewer women in the mometasone furoate group than in the emollient group (44 versus 67 percent, respectively) [72].
●In a 2021, phase 3, randomized trial that included 211 patients with head and neck cancer undergoing bilateral neck irradiation in combination with cisplatin therapy, topical corticosteroids applied at least once daily and continued for two weeks post-treatment reduced the frequency of grade ≥3 radiation dermatitis compared with placebo (13.9 versus 25.5 percent, respectively) [25]. The frequency of grade ≥2 radiation dermatitis was similar in the topical corticosteroid and placebo groups (73.3 percent [95% CI 64.6-81.9] and 80.4 percent [95% CI 72.7-88.1], respectively).
Other topical agents/dressings — A variety of other agents and dressings have also been evaluated in single randomized trials and in systematic reviews, including aloe vera, trolamine (triethanolamine), sucralfate, hyaluronic acid, silver sulfadiazine, petroleum-based ointments, ascorbic acid, allantoin, almond oil, olive oil, dexpanthenol, chamomile, calendula, barrier film, silver nylon dressings, and a silicone-based, film-forming gel dressing [60,74-79]. However, there is limited or no evidence for efficacy of these topical agents in preventing or reducing the severity of radiation dermatitis:
●Silicone-based gel dressings – In a single-blind, randomized trial, 197 patients with head and neck cancer were treated with a silicone-based, film-forming gel dressing (StrataXRT) or a moisturizer (sorbolene) at the start of radiotherapy (twice a day until the skin reaction subsided, up to four weeks post-treatment) [80]. The rates of grade 2 and grade 3 radiation dermatitis were lower in the active treatment group than in the control group (80 and 28 percent versus 91 and 45 percent, respectively). The risk of developing grade 2 or grade 3 radiation dermatitis was reduced by 40 and 50 percent, respectively, in the active treatment group compared with the control group, after adjusting for cetuximab treatment (hazard ratio [HR] 0.59, 95% CI 0.44-0.80, and HR 0.51, 95% CI 0.32-0.80, respectively).
Another phase 3, intrapatient, randomized trial (n = 78) used a soft silicone dressing film (Mepitel), which was applied before the start of radiotherapy and for several weeks afterwards [81]. The rate of moist desquamation was significantly reduced compared with control (0 percent with Mepitel film versus 26 percent with aqueous cream).
●Silver nylon dressings – Silver nylon dressings, which have traditionally been used as burn wound dressings, have demonstrated some efficacy in reducing radiation-induced skin toxicity. In a small, randomized trial including 42 patients with anal or rectal cancer treated with radiation therapy, the use of silver nylon dressings was associated with a lower radiation dermatitis severity score compared with standard skin care [82]. In contrast, in a randomized trial including 196 patients with breast cancer, silver nylon dressings did not reduce the incidence or severity of radiation dermatitis compared with standard skin care [83]. However, patients in the silver nylon dressing group experienced less itching, pain, and burning compared with those in the standard care group.
●Silver sulfadiazine – Silver sulfadiazine is known to have anti-inflammatory and barrier-enhancing properties, which may protect radiation-damaged skin from other infectious agents [84]. In a randomized trial including 102 patients with breast cancer, silver sulfadiazine 1% cream applied three times a day for three days a week for five weeks during radiotherapy and one week thereafter was compared with general skin care in the prevention of radiation dermatitis [75]. Patients in the silver sulfadiazine group experienced a less severe dermatitis than patients in the control group (mean dermatitis score 5.49 versus 7.21, respectively).
Evidence from a limited number of randomized trials does not support the use of aloe vera, trolamine (triethanolamine), sucralfate, or hyaluronic acid for the prevention of radiation dermatitis [85-92]:
●Aloe vera – In a randomized trial including 225 patients with breast cancer, more patients in the aloe vera gel group than in the aqueous cream group developed dry desquamation, dermatitis of grade 2 or higher, and greater pain [87]. A subsequent systematic review did not find evidence for efficacy of aloe vera in preventing or minimizing radiation dermatitis in patients with cancer [89]. A subsequent randomized trial found that the use of either an aloe cream or placebo cream during radiation therapy increased the incidence and severity of radiation dermatitis compared with a dry powder regimen (nonmetallic baby powder or cornstarch) [91].
●Trolamine – In a randomized trial, 166 patients with advanced squamous cell carcinoma of the head and neck were assigned to prophylactic trolamine, 175 patients were assigned to interventional trolamine, and 165 patients were assigned to institutional preference product [85]. Grade ≥2 dermatitis was reported in 79, 77, and 79 percent of the three groups, respectively. In another trial including 254 patients with breast cancer, trolamine cream or calendula cream was applied after each session [86]. The occurrence of acute radiation dermatitis of grade 2 or higher was significantly lower with the use of calendula cream than with trolamine cream (41 versus 63 percent, respectively). However, in a subsequent study including 420 patients with breast cancer, the incidence of grade ≥2 dermatitis was similar in patients using a calendula cream and in those using a water-based emollient cream [88].
●Sucralfate – Sucralfate cream for the prevention of radiation dermatitis was compared with aqueous cream or no treatment in a randomized trial including 357 patients undergoing radiotherapy to the head and neck, breast, or anorectal area. After five weeks, the severity of erythema, desquamation, itch, pain, and discomfort, as reported by patients, was similar in the three groups [90].
●Hyaluronic acid – In a meta-analysis of eight, randomized trials that included 500 patients with breast cancer, hyaluronic acid was associated with a lower-grade radiation dermatitis compared with phytosterol; vitamin E; and omega-3, -6, and -9 [93]. No difference was found between hyaluronic acid and emollients, vitamin C, and alginate.
Bacterial decolonization — In a small, randomized trial, 77 patients with breast or head and neck cancer undergoing radiation therapy were assigned to S. aureus decolonization (intranasal mupirocin 2% ointment twice daily and chlorhexidine gluconate 4% body cleanser once daily for five consecutive days prior to radiation therapy and then for five days every two weeks throughout radiation therapy) or standard care (normal skin hygiene and emollients) [94]. After completion of radiation therapy, the rates of colonization with S. aureus were significantly lower in the bacterial decolonization group compared with the standard of care group (5.4 versus 24.3 percent, respectively). None of the 39 patients treated with bacterial decolonization developed grade 2 or higher radiation dermatitis compared with 9 of 38 patients (24 percent) treated with standard of care. Of note, the use of topical corticosteroids was not included in standard of care during the conduct of the trial.
Systemic agents — Several oral agents have been evaluated in single small, randomized trials, including proteolytic enzymes (a combination of papain, trypsin, and chymotrypsin) [95], pentoxifylline [96], antioxidant supplements, zinc supplementation [97], sucralfate [98], and curcumin [99]. However, there is little or no evidence for efficacy of any of these systemic treatments.
Examples of studies that examined the role of systemic agents in the prevention of radiation dermatitis include:
●In a small, randomized study including 78 patients treated with postoperative radiation therapy for squamous cell carcinoma of the head and neck, oral pentoxifylline (400 mg three times daily) was not more effective than placebo in the prevention of acute radiation dermatitis [96]. However, the authors noted a beneficial effect of pentoxifylline in reducing late skin changes, fibrosis, and skin necrosis.
●In a multicenter, randomized trial including 686 patients with breast cancer undergoing radiation therapy, curcumin 1.5 g per day taken throughout the prescribed course of radiotherapy and then for an additional week was not more effective than placebo in reducing the severity of radiation dermatitis [100].
CLINICAL MANIFESTATIONS
Skin findings — Acute radiation dermatitis, defined as dermatitis occurring within 90 days of starting treatment, typically occurs gradually during a fractionated course of radiation therapy. The time of onset varies from days to weeks after starting radiotherapy. The skin changes (picture 1A-C) depend upon the radiation dose and individual skin sensitivity and include (table 1) [101,102]:
●Erythema
●Edema
●Pigment changes
●Hair loss
●Dry desquamation
●Moist desquamation
During a fractionated course of 2 Gy per fraction of radiation therapy, erythema occurs at doses of 12 to 20 Gy, dry desquamation occurs at doses ≥20 Gy, and moist desquamation occurs at doses >50 Gy or higher [8].
Patient-reported symptoms may include skin pain, pruritus, and fatigue [103].
Clinical course — The acute dermatitis typically continues to progress up to 10 to 14 days after completion of radiation therapy (picture 1A). Re-epithelialization usually begins within 10 days after radiation exposure in the absence of infection [7]. Severe dermatitis (grade 4) with necrosis of the epidermis or underlying dermis is associated with prolonged inflammation and healing time, resulting in fibrosis and loss of adnexal elements.
Histopathology — Acute radiation dermatitis is characterized by apoptotic keratinocytes, vacuolization of the basal layer, and epidermal edema. Depending upon the radiation dose, epidermal necrosis with blister formation and sloughing of the epidermis may be seen [104]. These changes manifest clinically as "moist desquamation." Hyperkeratosis is seen with dry desquamation. Dermal changes include dermal and endothelial cell edema, vasodilation, erythrocyte extravasation, and fibrin thrombi in vessels. An inflammatory infiltrate is noted throughout the dermis.
Patients receiving EGFR inhibitors — In patients treated with epidermal growth factor receptor (EGFR) inhibitors and radiotherapy, the clinical presentation of radiation dermatitis may be different and more severe than that seen in patients treated with radiotherapy alone [50,52,105]. The skin reaction develops earlier (in the first two weeks of starting radiation therapy) and is more often severe (grade 3 or 4), with marked xerosis, intense inflammation, and epidermal necrosis, resulting in superficial ulceration, spontaneous bleeding, and crusting (picture 2) [106-108]. Moreover, these patients may concurrently develop a papulopustular eruption typically induced by EGFR inhibitors [108]. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
Grading — The severity of radiation dermatitis can be assessed by several grading systems (table 4B and picture 1A) [2,7,24]. The most commonly used are the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), under injury, poisoning, and procedural complications (table 4A), and the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) toxicity criteria [56,109]. The RTOG/EORTC follows the same grading criteria as the NCI CTCAE, which are described below:
●NCI CTCAE grade 1 – Faint erythema with dry desquamation. Mild dermatitis is characterized by mild, blanchable erythema or dry desquamation. The onset is typically within days to weeks of initiating therapy, and symptoms may fade within a month. Pruritus, hair loss, and decreased sweating are common, associated symptoms.
●NCI CTCAE grade 2 – Moderate dermatitis is characterized by moderate to brisk erythema and patchy, moist desquamation mostly confined to skin folds and creases. It may be associated with moderate edema. Moist desquamation is characterized by epidermal necrosis, fibrinous exudates, and often considerable pain [2].
●NCI CTCAE grade 3 – There is confluent, moist desquamation in locations other than skin folds. There may be bleeding when associated with trauma.
●NCI CTCAE grade 4 – This is characterized by skin necrosis or ulceration of full-thickness dermis. Spontaneous bleeding from the involved site can occur. Skin graft may be indicated, and it can have life-threatening consequences.
●NCI CTCAE grade 5 – Death due to dermatitis alone is a very rare event.
Although commonly used in clinical and research settings, these grading systems are highly subjective. Real-time laser Doppler flowmetry has been proposed as a quantitative method to detect changes in cutaneous microcirculation that relate to increased radiation-induced skin injury [110]. A grading atlas has also been developed, based upon a selection of representative digital photographs of radiation dermatitis graded according to the CTCAE by an expert panel [111]. Additionally, the NCI has established a Patient-Reported Outcomes version of the CTCAE, which can aid in assessment of symptomatic adverse reactions from radiation therapy [112-114].
Complications — Radiation exposure reduces the skin's antimicrobial defenses, leading to an increased risk of bacterial infections in irradiated skin, most often from S. aureus [62]. Bacterial cultures are indicated if there are clinical signs of infection.
Radiation dermatitis has a negative impact on patients' quality of life, with larger effects in higher-grade dermatitis [115]. The worsening of quality of life is especially marked for the physical domain (due to itching, burning, and irritation), followed by the emotional and functional domains.
DIAGNOSIS — The diagnosis of acute radiation dermatitis is clinical, based upon the finding of skin changes (picture 1A) in a patient with a history of radiation therapy in the previous three months. The sharp demarcation of the skin changes and their limitation to the irradiated areas are important clues to the diagnosis. Subjective symptoms, including skin pain and pruritus, should also be assessed. Key elements of history are the duration of treatment and the cumulative dose of radiation.
A skin biopsy is usually not necessary for the diagnosis of radiation dermatitis. However, histopathologic examination of a skin biopsy may be helpful if the diagnosis is uncertain. (See 'Histopathology' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of radiation dermatitis includes other skin conditions that can develop during or after completing the treatment:
●Allergic contact dermatitis – Allergic contact dermatitis to cosmetics, skin care products, topical antibiotics, adhesive bandages, or simulation markings may mimic radiation dermatitis. Allergic contact dermatitis is usually associated with intense pruritus and responds to treatment with topical corticosteroids. (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Intertrigo – Intertrigo is a common, inflammatory condition of skin folds characterized by moist erythema, malodor, weeping, pruritus, and tenderness and is often associated with candidal or bacterial secondary infection (picture 3). (See "Intertrigo".)
●Radiation port dermatophytosis – Dermatophyte infection rarely can occur at the site of irradiation [116,117]. It presents as single or multiple, annular, erythematous plaques with a well-defined, scaling border (picture 4). A potassium hydroxide (KOH) preparation can confirm the diagnosis.
●Herpes zoster – Herpes zoster (shingles) presents with grouped, erythematous papules, vesicles, and pustules typically located in a single dermatome, most often thoracic or lumbar (picture 5). Pain, described as burning, throbbing, or stabbing, is the most common symptom. In cases with atypical presentation, polymerase chain reaction (PCR) testing can confirm the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
●Graft-versus-host disease – Acute graft-versus-host disease is a complication of hematopoietic cell transplantation. It presents with a maculopapular rash that initially involves the nape of the neck, ears, shoulders, and the palms of the hands. The rash may become generalized, with bullae and extensive skin sloughing (picture 6). The histopathologic features are similar to those of radiation dermatitis and include vacuolization of the basal layer; apoptotic keratinocytes; satellite cell necrosis; and a superficial, perivascular, lymphocytic infiltrate (picture 7). (See "Cutaneous manifestations of graft-versus-host disease (GVHD)" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)
●Stevens-Johnson syndrome/toxic epidermal necrolysis – Severe radiation dermatitis shares clinical and histopathologic features with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a rare, severe skin reaction typically induced by medication (picture 8A-B). The differentiation of SJS/TEN from high-grade radiation dermatitis can be difficult in patients treated with both radiation therapy and conventional or targeted anticancer agents, although SJS/TEN usually also occurs in sites distant from radiation exposure (table 5). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
MANAGEMENT — The management of radiation dermatitis is guided by the severity of skin damage and involves general skin care measures, prevention and treatment of secondary skin infection, and the use of dressings [60,84,118]. It is important to educate the patient and family/caregivers about the care of the patient's skin during treatment to reduce irritation and trauma, relieve discomfort, and promote healing.
Patients with grade 1 dermatitis — Patients with mild dermatitis (Radiation Therapy Oncology Group [RTOG] and National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 1 dermatitis (table 4B)) have faint erythema and dry desquamation. In addition to general skin care measures, including cleansing and moisturizing with hydrophilic (oil-in-water) moisturizers, we suggest that patients continue (if already using for prevention) or initiate topical corticosteroids (groups 4 and 5 (table 3)) to control itch and irritation. Topical corticosteroids are applied once or twice daily and continued for two weeks postradiation therapy. (See 'General skin care' above and 'Topical corticosteroids' above.)
Antihistamines are generally not effective in reducing pruritus related to radiation dermatitis.
In patients with grade 1 radiation dermatitis, the use of special dressings does not seem to be effective in halting the progression of dermatitis. In a four-week, randomized trial, 278 patients with breast cancer and grade 1 radiation dermatitis were treated with a hydrocolloid dressing or placebo (a water-based spray) [119]. At four weeks, the rates of local treatment failure, defined as skin deterioration or interruption of radiation therapy due to radiation dermatitis, were similar in the active treatment and placebo groups (49 versus 51 percent, respectively). The intensity of erythema and pain and quality-of-life scores were also similar in the two groups.
Patients with grade 2 to 3 dermatitis — Patients with grade 2 and 3 dermatitis (table 4B) present with moist desquamation involving the skin folds (grade 2) or other skin areas (grade 3). Treatment involves measures aimed at preventing secondary skin infection and the use of dressings over the areas of skin sloughing [26,60]. If infection occurs, standard therapy for bacterial infections should be initiated with topical and/or systemic antibiotics.
For moist desquamation, we typically use soft, absorbent, silicone foam bandages (eg, Mepilex Lite, Biatain). This type of dressing is atraumatic to the wound and surrounding skin when removed. The bandage can be applied with or without topical agents (eg, silver sulfadiazine, amorphous hydrogels). The dressing should be changed daily or more frequently, depending upon the severity of weeping.
The use of dressings in the management of moist desquamation is based upon the observation that a moist environment promotes the rate of re-epithelization and increases the speed of wound healing [120]. (See "Basic principles of wound management", section on 'Wound dressings'.)
In clinical practice, a variety of wound dressings are used, including nonadherent, hydrogel, or hydrocolloid dressings (eg, StrataXRT, Mepitel, Mepilex) [7]. However, there is little evidence to aid in the choice among the various types of dressings. A few randomized trials have compared different dressings or dressings versus other topical agents with inconclusive results [121-123]:
●In one study, 100 patients with moist desquamation received dry, nonadherent dressing or hydrogel dressing [121]. The time to healing was longer in the hydrogel group than in the dry dressing group.
●Two small trials compared hydrogel or hydrocolloid dressing with gentian violet 0.5% aqueous solution [122,123]. In one study, patients in the hydrogel group were more likely to heal than patients in the gentian violet group [122]. The median time to healing was 12 days for hydrogel dressing and more than 30 days for gentian violet. In another study, the healing time was similar for patients receiving hydrocolloid dressing and those receiving gentian violet (11.4 versus 11.7 days, respectively) [123]. However, dressing comfort and acceptability were higher for hydrocolloid dressing than gentian violet. Grade 3 radiodermatitis with moist desquamation may require interruption of radiation therapy, depending upon the body location and the patient's discomfort.
Patients with grade 4 dermatitis — Grade 4 dermatitis (table 4B) is rare. Patients presenting with full-thickness skin necrosis and ulceration should be treated on a case-by-case basis. They may require discontinuation of radiation therapy and a multidisciplinary approach, involving a wound specialist, radiation oncologist, dermatologist, and nurse [26]. Treatment may include surgical debridement, full-thickness skin graft, or myocutaneous or pedicle flaps. For infected or at-risk wounds, systemic or topical antibacterial agents should be considered. (See "Basic principles of wound management".)
Patients receiving concurrent EGFR inhibitor therapy — In patients receiving concurrent epidermal growth factor receptor (EGFR) inhibitor therapy who develop grade 1, 2, or 3 radiation dermatitis, interruption or dose reduction of the drug is not generally necessary [26,108,124-126]. However, some experts suggest a dose reduction of cetuximab in patients with severe grade 3 reaction [126]. Interruption of both radiation therapy and cetuximab is advised in patients with grade 4 reaction. Cetuximab should be interrupted until the skin reaction has resolved to at least grade 2 [108,124].
Patients treated with cetuximab may need additional treatment or prophylaxis for the papulopustular, acneiform eruption commonly associated with EGFR inhibitors. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors", section on 'Management' and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors", section on 'Prevention'.)
OTHER ACUTE REACTIONS TO RADIATION THERAPY
Radiation recall reaction — Radiation recall is an acute, inflammatory reaction confined to an area of previous radiation exposure that is triggered by chemotherapeutic agents or other drugs [127]. The reaction occurs in approximately 6 to 9 percent of patients receiving chemotherapy after radiation therapy; is drug specific for each individual; and can occur weeks, months, or years after radiation therapy [127,128]. The diagnosis is based on the appearance within the previous radiation therapy field (picture 9). (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Radiation recall dermatitis and radiation enhancement'.)
Radiation recall occurs most frequently with conventional chemotherapy agents, in particular anthracyclines (doxorubicin), taxanes (docetaxel, paclitaxel), and antimetabolites (gemcitabine, capecitabine, pemetrexed) [127]. However, it has also been reported in association with targeted anticancer agents, such as epidermal growth factor receptor (EGFR) inhibitors, B-Raf proto-oncogene (BRAF) inhibitors, and immune checkpoint inhibitors [129-135].
The clinical manifestations of radiation recall include mild rash, dry desquamation, pruritus, swelling, maculopapular eruptions, and ulceration [127]. In approximately one-third of cases, recall reactions occur in other sites, such as the lungs, oral mucosa, and gastrointestinal system. After withdrawal of the drug, the reaction usually resolves within one to two weeks. The management is similar to that of acute radiation dermatitis.
Radiation burns — Radiation burns may occur rarely as a result from high exposure to radiation during repeated diagnostic medical imaging, interventional radiology procedures, or radiation therapy [136]. The most distinctive feature of radiation burns compared with thermal burns is the difficulty in delineating radiation-injured tissue from uninjured tissue [137,138]. This difficulty stems from the unpredictable progression of tissue injury, which can occur weeks to years after irradiation and often results in necrosis of skin grafts [137,138]. Additional unique characteristics of radiation burns include a dose-dependent clinical pattern and opiate-resistant pain [2,3,8,33,137,139].
Eosinophilic, polymorphic, and pruritic eruption — Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) is an uncommon reaction to radiation therapy that most commonly develops in patients with cervical cancer and breast cancer [140-142]. EPPER presents with erythematous papules, pustules, excoriations, and occasionally wheals, vesicles, and bullae, accompanied by localized or generalized pruritus (picture 10). The eruption is not confined to the irradiated area but may involve the adjacent areas and the upper and lower extremities. Biopsy shows a superficial and deep, perivascular, lymphohistiocytic infiltrate with eosinophils. Treatment includes topical and systemic corticosteroids and antihistamines. EPPER usually resolves in a few weeks after completing radiation therapy.
Fluoroscopy-induced subacute radiation dermatitis — Subacute radiation dermatitis is an uncommon form of radiation dermatitis that typically presents weeks to a few months after the initial exposure to ionizing radiation during a diagnostic or interventional radiologic procedure [143]. The clinical appearance is that of an erythematous patch or plaque over the irradiated area that may become indurated, hyperpigmented, and ulcerate [144-146]. The diagnosis may be delayed given the delayed presentation and rarity.
Histologically, fluoroscopy-induced subacute radiation dermatitis is indistinguishable from acute graft-versus-host disease or fixed drug reaction [145]. Histologic findings include atypical keratinocytes, hypergranulosis, and compact hyperkeratosis. An interface dermatitis with keratinocyte necrosis is usually present. In addition, clefting along the dermal-epidermal junction, fibroblast proliferation, and telangiectatic vessels may be seen. The papillary dermis may show a variable, lymphocytic infiltrate with histiocytes around the papillary dermal plexus but no eosinophils, in contrast to fixed drug reactions.
LATE-EFFECT CUTANEOUS REACTIONS OF RADIATION THERAPY
Chronic radiation dermatitis
Clinical manifestations — Late-effect or chronic radiation dermatitis typically presents months to years after radiation exposure [24]. It is characterized by dermal fibrosis and poikilodermatous skin changes, including hyper- and hypopigmentation, atrophy, and telangiectasias (table 1) [3,8,147].
Histopathology — Histologically, late-stage radiation dermatitis is characterized by eosinophilic, homogenized sclerosis of dermal collagen; scattered, large, atypical fibroblasts; absence of pilosebaceous units; and vascular changes. The deep vessels show fibrous thickening, sometimes with luminal obliteration and recanalization, whereas telangiectases are prominent in the upper dermis.
Management — Several small, randomized trials suggest that prolonged treatment with pentoxifylline in combination with vitamin E for up to more than three years may be helpful for the treatment of subcutaneous radiation-induced fibrosis [148-150]. However, the optimal dose and duration of therapy and the role of tocopherol have not been determined. It is also unclear whether this therapy should be continued indefinitely to maintain benefit.
Physical therapy may include active and passive range of motion exercises, which may help to improve range of motion and reduce contractures. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis", section on 'Pentoxifylline plus tocopherol'.)
Hyperbaric oxygen has been evaluated as a treatment for radiation-induced fibrosis; however, there is currently insufficient evidence to show efficacy [151].
There are a few reports of successful treatment of radiation therapy-induced telangiectasias and hyperpigmentation with laser therapy [152,153]. (See "Laser and light therapy for cutaneous vascular lesions" and "Laser and light therapy for cutaneous hyperpigmentation".)
Postirradiation morphea — Postirradiation morphea is a rare, late complication of radiotherapy occurring months to years after treatment and is characterized by the development of sclerotic plaques that resemble idiopathic morphea in the irradiated area. In some patients, sclerotic changes may also involve the adjacent, nonirradiated skin [154,155]. Postirradiation morphea occurs in females undergoing radiation therapy for breast cancer in most cases, is associated with considerable morbidity and pain, and is cosmetically disfiguring (picture 11) [156]. In a retrospective study of 25 patients (23 females) with postirradiation morphea, 11 had a coexistent autoimmune disorder [155].
Treatment of postirradiation morphea is similar to that of idiopathic morphea and includes topical and intralesional corticosteroids, phototherapy, and systemic immunosuppressive agents in various combinations [154]. (See "Morphea (localized scleroderma) in adults: Management".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Radiation dermatitis".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and risk factors – Radiation dermatitis is one of the most common side effects of radiotherapy for cancer, affecting approximately 90 percent of patients receiving radiotherapy, especially patients with breast cancer, head and neck cancer, lung cancer, or sarcoma. Risk factors for radiation dermatitis include body site, older age, female sex, and obesity (table 2). (See 'Introduction' above and 'Epidemiology' above.)
●Clinical presentation and grading – Acute, radiation-induced skin changes (table 1) depend upon the radiation dose and include erythema, edema, pigment changes, epilation, and dry or moist desquamation (picture 1A). The severity of radiation dermatitis is commonly assessed by using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) or the Radiation Therapy Oncology Group (RTOG) toxicity scoring system and ranges from mild (grade 1) to severe (grade 3 and 4) (table 4A-B).
●Diagnosis – The diagnosis of acute radiation dermatitis is clinical, based upon the finding of erythema, dry desquamation, or moist desquamation in a patient with a recent history of radiation therapy. (See 'Diagnosis' above.)
●Prevention:
•Radiation therapy techniques – Modern radiation therapy techniques, such as intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT), which deliver radiation to the planned treatment volume while minimizing radiation to normal tissue outside the target, may reduce the occurrence of radiation dermatitis. (See 'Modern radiation therapy techniques' above.)
•Topical corticosteroids – For patients undergoing radiation therapy, we recommend prophylactic topical corticosteroids in addition to general skin care measures for the prevention of severe radiation dermatitis (Grade 1B). Low- to medium-potency topical corticosteroids (groups 4 to 6 (table 3)) are applied to the treatment field once or twice daily after each radiotherapy session. Agents of unproven efficacy include aloe vera, trolamine, sucralfate, hyaluronic acid, silver sulfadiazine, and silver nylon dressings. (See 'Topical corticosteroids' above and 'General skin care' above.)
●Management – The management of radiation dermatitis is guided by the severity of skin damage (table 4B):
•Patients with grade 1 radiation dermatitis usually do not require any specific treatment in addition to general skin care measures. (See 'Patients with grade 1 dermatitis' above.)
•For patients with grade 2 to 3 radiation dermatitis and moist desquamation, we typically use soft, absorbent, silicone foam bandages. Bacterial superinfection is treated with topical and/or systemic antibiotics. (See 'Patients with grade 2 to 3 dermatitis' above.)
•Patients with grade 4 radiation dermatitis who present with full-thickness skin necrosis may require surgical debridement and full-thickness skin graft or myocutaneous or pedicle flaps. (See 'Management' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Marilyn Ling, MD, who contributed to an earlier version of this topic review.
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