• The initial reaction to radiation is often erythema, although not always visible to the human eye, that can occur within a few hours and is caused by capillary dilatation and increased capillary permeability [5].

• Ten to fourteen days after the start of radiation, sustained erythema, likely mediated by cytokines, becomes apparent (Fig. 10.2) [6].

• With continued radiation, generally with doses of radiation above 40 Gy, one can see moist desquamation characterized by vascular dilatation, epidermal necrosis, fibrinous exudates, and pain (Fig. 10.3). Histologically, fibrin thrombi obstruct arterioles, extravasation of erythrocytes and leukocytes, as well as edema can be seen [5,6].

• The peak skin reaction occurs between 1 and 2 weeks after the completion of radiation therapy with regeneration occurring between weeks 3 and 5 [6]. The majority of patients will have completely recovered from their acute toxicities by 3 months after treatment, although often much sooner.

• Hair follicles, sebaceous glands, and sweat glands are also affected by radiation and can lead to dry skin and hair loss. Although hair loss often doesn’t occur for a few weeks, generally the damage was done early in the radiation course [5]. New hair can take up to 1 year to regrow and in some situations the hair loss can be permanent.

• The two most widely used scales for grading acute adverse events due to cancer therapy are the National Cancer Institute’s Common Toxicity Criteria for Adverse Events (CTCAE) version 4 [7] and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) grading system [8]. Both of these tools have specific criteria for acute radiation toxicity to the skin (Tables 10.1 and 10.2) and allow for consistent grading between practitioners.

• There is wide practice variation between institutions and even practitioners regarding the use of agents for prevention of radiation dermatitis. Most fall into one of two schools of thought regarding prophylaxis. Some believe in having patients use moisturizer up front, thinking that it can help prevent dry skin and delay the onset of acute toxicity. Others believe there is no benefit to initiation of moisturizer before the development of symptoms and cite concerns over confusion that could occur if the patient has a reaction to the lotion.

• Although there are many publications regarding the use of different products to prevent the development of radiation dermatitis, mostly within the breast and head and neck literature, the data can be contradictory and confusing. However on some topics, such as the use of routine washing and the use of antiperspirant, the literature is clear.

• Hygiene: Three trials evaluated and found no detriment to the use of routine washing with soap or shampoo and water during radiation therapy [9–11]. All three recommended continued normal hygiene practices during the course of radiation.

• Antiperspirant: Some practitioners believe the use of antiperspirant during radiotherapy could lead to a bolus effect on the skin, thereby worsening radiation toxicity. At least four randomized controlled trials have shown no difference in toxicity with the use of antiperspirant, even in preparations containing aluminum, compared to gentle washing alone [12–15].

• Topical Steroids: Multiple randomized controlled trials have been done examining the role of topical steroids to prevent or ameliorate acute radiation dermatitis. Although the trials are heterogeneous, the outcomes have consistently shown a benefit to use of topical steroids [16–20].

• Topical Trolamine: Trolamine, an oil-in-water emulsion with nonsteroidal antiinflammatory properties, has been relatively widely studied. The results of the published data is mixed with some trials showing a benefit to the use [21,22] and others showing no benefit [23–26].

• Topical Aloe vera: As Aloe vera is a commonly used treatment for a variety of skin conditions, from dry skin to sunburns, it is a natural extension to believe it may be helpful to prevent radiation dermatitis. Results from one trial suggested a benefit to the use of Aloe vera gel in delaying the onset [27], however, multiple trials as well as a systemic literature review did not find evidence to suggest a benefit [28–30].

• Topical Hyaluronic Acid: Similarly the results from studies evaluating hyaluronic acid also show mixed results with some studies showing a benefit [31] and others failing to do so [32].

• Topical Sucralfate: Three different trials evaluating the use of topical sucralfate have shown three different outcomes: a benefit [33], no difference [34], and possibly a detriment [35].

• Topical Petroleum Ointments: Aquaphor, a petroleum-based ointment, is a very commonly recommended topical treatment during radiation therapy. The published data on Aquaphor for prevention is mostly as a control arm and thus is difficult to determine effectiveness. However, there is some data that suggests there is no benefit to petroleum-based treatment compared to control [16,26]. Additionally, the study by Gosselin et al., also looked at RadiaCare gel and again did not find a benefit over control [26].

• Topical Calendula: One randomized control trial has evaluated the use of calendula (vs trolamine) and found an improvement in rate of acute dermatitis and patient satisfaction with calendula [23].

• Oral Agents: Minimal data has been published on the use of oral agents for prevention of radiation dermatitis. Two randomized, although not blinded, control trials comparing oral proteolytic enzymes (a combination of papain, trypsin, and chymotrypsin) to no treatment showed improvement in acute radiation side effects, including dermatitis [36,37]. Preclinical data and a single small double blind randomized control trial have suggested that oral zinc supplementation may decrease acute radiation dermatitis [38,39]. Studies on other oral agents, such as oral sucralfate and oral pentoxifylline, have not shown benefit to the development or severity of acute radiation dermatitis [40,41].

• The Multinational Association for Supportive Care in Cancer (MASCC) published guidelines in 2013 after a thorough review of the literature.

 A strong recommendation was made for washing of the skin and hair with water, either with or without a mild soap or shampoo, as well as allowing patients to use antiperspirants. Additionally, a strong recommendation for use of topical steroids to prevent radiation dermatitis was made [42].

 The MASCC recommended against the prophylactic use of Aloe vera or trolamine. For multiple other agents, sucralfate, hyaluronic acid, silver dressing, silver sulfadiazine cream, and others they did not make a recommendation for or against use due to insufficient evidence [42].

• Other Skin Care Tips: Other tips on skin care given to patients undergoing radiation therapy include staying out of the sun, wearing loose clothing, avoiding extreme heat or cold (i.e., heating pads or ice packs) directly onto the skin being treated, and avoiding products with alcohol or scents. Additionally, for those patients who are getting treated to the face or neck, it is advisable to use an electric razor rather than a manual one. For patients getting treated to the head, gentle brushing of hair and avoiding use of styling tools (i.e., curling irons, straightening irons) is recommended.

• Despite a thorough literature review there is a paucity of well designed, blinded, randomized trials evaluating treatment options. The intervention with the most data is on the use of dressings, however, the outcomes of these studies are mixed, with some showing longer healing times with use of moist dressings [43,44], while others showed faster healing times [45]. Additionally, there are a few publications on the use of topical steroids, none of which showed a benefit compared to their control group [46,47]. Sucralfate has also been studied and has found to have no benefit when mixed with sorbolene cream versus sorbolene cream alone [48].

• In lieu of randomized evidence, many institutions and practitioners have developed treatment recommendations for patients.

 Once a patient develops erythema, hypopigmentation, or dry desquamation, a common recommendation is for use of an emollient-based cream, such as Aquaphor, RadiaCare, or Biafine.

 If the patient has pain or burning, a mixture of Aquaphor mixed with lidocaine jelly (1:1 formulation) can be prescribed.

 Oral pain medication can also be used for severe skin reactions, although this is rarely, if ever, seen when treating a patient to palliative doses.

 If a patient notes itchiness, a topical steroid cream can be recommended. Steroid creams can be layered underneath or alternated with an emollient-based cream.

 If moist desquamation occurs, Domeboro soaks, Silvadene, or Xenaderm can be used. An example treatment regimen is offered in Fig. 10.4.

• Specific recommendations for patients undergoing treatment to the lower pelvis (i.e., gynecologic cancers):

 A recently published review [49] on complications of pelvic radiation gives some suggestions regarding treatment of skin toxicity in this unique population.

 Recommendations are made for prophylactic moisturizing, encouraging loose cotton clothing, and the use of a sitz bath with addition of sodium bicarbonate, Epsom salt, or Domeboro soaks.

 Early identification and treatment for Candida is also recommended.

 For patients who develop desquamation, nonadherent, silver clear nylon or hydrogel dressings can be applied [49].

 Additional recommendations may include the use of a peri bottle to assist with cleansing and instructions to pat rather than wipe after urination.

• Radiation-induced fibrosis is characterized by thickening and reduced compliance of the skin. Histologically, excessive collagen deposition, atrophy, and excess mesenchymal cells are present [50]. Severity of acute injury does not seem to play a role in development of fibrosis, although total dose, dose per fraction, and other patient-related factors, such as age, have been shown to have an association [51,52].

• Telangiectasias (Fig. 10.6) are small dilated blood vessels close to the skin’s surface. After radiation they appear as a result of damage to the microvascular endothelial cells and basement membrane [5]. Research into factors that influence the likelihood of developing telangiectasias have found an association with total dose of radiation, presence of severe acute injury (i.e., moist desquamation), as well as patient-related factors, such as age, long-term smoking, and certain comorbidities (allergies and hypertension) [52,53].

• Chronic dryness can be due to permanent damage to sebaceous and sweat glands.

• Similar to acute toxicity, commonly used grading tools include the RTOG/EORTC tool [8] as well as the Late Effect on Normal Tissue (LENT)/Symptom Objective Measures, Management, Assessment (SOMA) [54].

• The RTOG/EORTC grading tool has specific criteria for late skin toxicity (Table 10.3). The LENT/SOMA tool has a general grading system (Table 10.4) as well as a more complex grading system for late skin toxicity with multiple factors separately assessed within categories of subjective, objective, management, and analytic. Examples of criteria within each category include scaliness/roughness, objective fibrosis/scar (Table 10.5), management fibrosis/scar, and color photographs.

• Little data has been published on the prevention of late toxicity from radiation. Early data suggests lower fibrosis scores at 18 months in patients who started pentoxifylline and vitamin E after the completion of radiation and continued for 6 months [55].

• Similarly, minimal data is available regarding treatment of late toxicity from radiation.

• Pulse dye laser has been shown to improve the appearance of telangiectasias from radiation [56]. The MASCC skin toxicity study group gave a weak recommendation for the use of the pulsed dye laser to improve cosmetic appearance [42].

• The use of vitamin E and pentoxifylline in the treatment of radiation fibrosis has mixed results. A few studies have shown an improvement in fibrosis following use of pentoxifylline and vitamin E [57–59], however, other studies have not shown a benefit [60]. One study compared pentoxifylline combined with vitamin E, pentoxifylline alone, vitamin E alone, or placebo and found a benefit only in the combination of the two drugs [59].

• The MASCC Skin Toxicity Study Group notes insufficient evidence to make a recommendation either for or against the use of pentoxifylline for treatment of radiation-induced fibrosis [42].