0
1
2
3
4
Skin
No change from baseline
Follicular, faint, or dull erythema/epilation/dry desquamation/decreased sweating
Tender or bright erythema, patchy moist desquamation/moderate edema
Confluent, moist desquamation other than in skin folds/pitting edema
Ulceration, hemorrhage, necrosis
Table 2
NCI: common terminology criteria for adverse events v3.0
Adverse event | 1 | 2 | 3 | 4 |
|---|---|---|---|---|
Radiation dermatitis | Faint erythema or dry desquamation | Moderate to brisk erythema/patchy moist desquamation, mostly confined to skin folds and creases/moderate edema | Moist desquamation other than skin folds and creases/bleeding induced by minor trauma or abrasion | Skin necrosis or ulceration of full thickness dermis/spontaneous bleeding from involved site |
Table 3
RTOG late radiation morbidity scoring criteria
0 | 1 | 2 | 3 | 4 | |
|---|---|---|---|---|---|
Skin | No change from baseline | Slight atrophy/pigmentation change/some hair loss | Patchy atrophy/moderate telangiectasia/total hair loss | Marked atrophy/gross telangiectasia | Ulceration |
For acute radiodermatitis, the RTOG grade zero is equivalent to no skin change from baseline [26]. The lowest grade on the NCI Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) is a grade one [28]. The RTOG and NCI CTCAE both equate a grade one with skin that has mild erythema or follicular erythema and/or dry desquamation [26, 28]. Grade two is associated with significant erythema, patchy moist desquamation within the skin folds, and/or edema [26, 28]. Grade three denotes confluent moist desquamation not isolated to intertriginous zones and bleeding with minor trauma. Grade four on the NCI CTCAE and RTOG scales is characterized by ulceration, spontaneous bleeding, and/or necrosis [3]. Grade five is given when radiodermatitis is associated with death [26, 28].
Chronic radiodermatitis is defined as any adverse skin effects of radiation exposure that occur more than 90 days after treatment. Chronic radiodermatitis is classified according to the RTOG Late Radiation Morbidity Scoring Schema (Table 3). According to the RTOG, a score of zero is consistent with no change from baseline. A score of one is consistent with loss of some hair, slight atrophic changes, and change in pigmentation (together known as poikilodermatous changes) [3, 28]. A score of two is associated with patchy atrophy, moderate telangiectasia, and complete alopecia. A score of three is consistent with significant atrophy and gross telangiectasias [28]. A score of four is associated with ulceration of the formerly irradiated skin [3, 28]. According to the RTOG, a score of five is assigned for radiodermatitis-associated death [28]. The symptoms of chronic radiodermatitis can change and progress for up to ten years [29].
Radiation-recall dermatitis is defined as radiodermatitis that occurs days to years after radiation exposure secondary to concomitant drug administration (usually chemotherapeutic medications) which affects the epithelia and mucosa of many organs including the heart, lungs, gastrointestinal tract, and bladder [30]. Symptoms typically progress from erythema to a dry desquamation. In more severe cases, radiation-recall dermatitis may result in vesicular lesions, ulceration, and necrosis.
Management of Radiodermatitis
The overarching goals for the management of radiodermatitis include preventing or minimizing symptoms, preventing or identifying and treating infection, reducing healing time, and maximizing quality of life. The prevention and management of radiodermatitis is challenging as there is no universally accepted set of guidelines.
There is a general consensus regarding hygiene of the irradiated skin. The skin should be routinely washed with a gentle soap that has a low pH, like Dove or Aveeno, and warm water [3, 31, 32]. Studies by Roy et al. and Campbell and Illingworth, showed that the severity of radiodermatitis did not significantly vary with or without washing the affected area [33, 34]. Although not statistically significant, Roy et al. concluded that washing should not be discouraged as there was a lower incidence of moist desquamation and less pain, burning, and itching reported in the group that washed [35]. In addition, patients should also be encouraged to wash their hair as this does not affect the severity of radiodermatitis, even in patients undergoing cranial radiotherapy [36]. In the past, patients were cautioned to avoid deodorant with a metallic base due to concern for a radiation “bolus” effect. Many patients who refrained from deodorant use during radiation treatment have expressed concerns about body odor [36]. According to studies by Burch et al. and Theberge et al., deodorant does not affect the severity of radiodermatitis [37, 38]. Thus, normal hygiene including washing with mild soaps and using topical deodorants and lotions should be encouraged.
Management of Acute Radiodermatitis
There are many research trials that test and compare agents to prevent and treat acute radiodermatitis [31]. Unfortunately, none have been proven by double-blind, randomized clinical trials with high statistical power to be the best management strategy.
Topical Agents
Natural Products
Natural products are used by many different cultures to treat a variety of disease states. Unfortunately, research has shown that many natural products are not effective in the management of radiodermatitis. A study that compared chamomile cream with almond ointment found no significant difference in the severity of radiodermatitis between these two treatment modalities [39]. Another natural agent, calendula ointment which is an extract of the marigold plant, has been found to significantly reduce pain and frequency of grade two or higher acute radiodermatitis compared to Biafine (see next section) [20]. The effect of drinking wine has also been studied. A retrospective study found that women who drink one glass of wine per day, but no more or less, have a reduced incidence of grade two or higher radiodermatitis [40].
Aloe vera extract has long been used to treat cuts and burns. Aloe vera has been touted to have anti-inflammatory and antibacterial effects that, in theory, would benefit irradiated epidermis [29]. The available data, however, suggests that aloe vera is not effective for the prevention or treatment of radiodermatitis [23, 29, 41, 42]. One study suggested that aloe vera may delay the onset of skin symptoms in patients with fewer risk factors for radiodermatitis and in those with skin that is more resistant to radiodermatitis [43]. The preponderance of evidence suggests that aloe vera does not reduce dermatologic adverse effects caused by radiation exposure.
Biafine
Biafine, a trolamine containing compound commonly used in France for radiodermatitis prophylaxis, also lacks support for its use in the management of acute radiodermatitis. According to Fisher et al., in a comparison of Biafine to four other standards of care (aloe vera, Aquaphor, no treatment, other) for prophylaxis of radiodermatitis, there was no statistically significant difference in average of RTOG grade criteria between these groups [2]. The RTOG Trial 99-13 showed that the use of a trolamine emulsion versus standard of care did not reduce grade two or higher radiodermatitis [44]. Yet another study comparing Biafine, Lipiderm, and no treatment showed no significant difference among the groups with regard to ratings by the patients, nurses, and radiotherapists [45].
Topical Corticosteroids
Topical corticosteroids have been trialed for the prevention and management acute radiodermatitis, but results have varied. Mometasone furoate, a medium potency corticosteroid, has shown promising results in reducing radiodermatitis severity [46]. Furthermore, it is dosed once daily and causes less cutaneous atrophy than other topical steroids [46]. Another medium potency corticosteroid, betamethasone, as compared to petrolatum, has demonstrated a reduced severity of acute radiodermatitis [47]. Beclomethasone spray has also been shown to reduce the incidence of wet desquamation [48]. Conversely, the use of very high potency corticosteroids, like clobetasone, is associated with significantly higher rates of severe skin reactions as compared to a low potency steroid-like hydrocortisone [49]. Low dose corticosteroids do not appear to effect the presentation and symptoms of radiodermatitis [50, 51]. These results suggest that there may be a role for medium potency corticosteroids in the management of acute dermatitis. More research is required before steroids may be accepted as a standard of care [3].
Sucralfate
Sucralfate cream is another product that has evidence to both support and negate its use in clinical practice for the treatment of radiodermatitis. Sucralfate has been shown to be better than placebo in reducing radiodermatitis severity, yet results are comparable to that of aqueous creams and sorbolene creams [52–55]. Oral Sucralfate tablets have also been tested and have not been found to be superior to placebo in reducing radiodermatitis [56].
Hyaluronic Acids
Hyaluronic acids stimulate the process of healing. In a comparison of a cream containing sodium hyaluronate and silver sulfadiazine to placebo, the hyaluronic acid cream was found to reduce the incidence of high-grade radiation dermatitis and was favored by both patients and physicians [57]. To date, this is the only human study using hyaluronic acids for the management of acute radiation dermatitis, thus, further research is required [31].
Other Topical Products
Various other products including a dexpanthenol containing cream, a gel product containing reduced glutathione, a vitamin C solution, and a cream containing CM-glucan, methylsilanol hydroxyproline aspartate and matrikines, have been trialed in the management of radiodermatitis, but none of these significantly affected the incidence or severity of radiation dermatitis [58–61]. Hydrolytic enzymes have been shown to significantly reduce the severity and duration of radiodermatitis when compared to no treatment [62]. MAS065D, a water-in-oil cream with hydrating and anti-inflammatory characteristics, has also been shown to reduce skin toxicity, burning, and desquamation associated with radiodermatitis when compared to placebo [63].
Dressings
A moist environment is believed to be beneficial to wound healing [31]. However, in the case of moist desquamation, too much moisture may result in maceration. Dry dressings are preferred to hydrogel dressings for moist desquamation as hydrogel dressings prolong healing time and do not provide symptom relief [64]. Gentian violet, an antifungal agent, is associated with significantly less pain and smaller wounds compared to a moist hydrocolloid dressing for the management of moist desquamation [65]. The old adage “if it’s dry, wet it, and if it’s wet, dry it” appears to hold true for radiodermatitis.
Silver-leaf nylon dressings, a silver-coated nanocrystalline material, are used to treat burns and/or skin grafts. A study that tested the efficacy of this dressing versus no dressing, showed significantly reduced severity of radiodermatitis [66]. In a study of 12 patients comparing silver sulfadiazine and silver-leaf dressings, the silver-leaf dressings did not improve healing in patients with RTOG grade two or higher radiodermatitis, although patient reported pain was reduced [67]. Silver sulfadiazine cream has been shown to reduce radiodermatitis severity when compared to no topical treatment [68]. These agents need to be avoided in patients with known sulfa sensitivity.
Management of Chronic Radiodermatitis
Chronic radiodermatitis is a serious sequela of radiation exposure. The signs include tissue fibrosis, atrophy, ulceration, and pain. Chronic radiodermatitis is the dose-limiting side effect of radiotherapy [69–71]. Thus, prevention of chronic radiodermatitis is crucial to avoiding treatment delays that may compromise the effectiveness of radiotherapy. Unfortunately, there are no proven methods to prevent chronic radiodermatitis. There are, however, some promising potential treatment options for chronic skin changes related to radiation.
Pentoxifylline
Pentoxifylline is a hemorheologic agent that is commonly used to treat intermittent claudication and other vaso-occlusive disease processes. Pentoxifylline increases red blood cell membrane flexibility, stimulating fibrinolysis, inhibiting platelet aggregation, and altering both fibroblast physiology and immune modulation [72]. It has been shown to increase healing of soft tissue necrosis and formerly nonhealing, radiation-induced necrotic ulcers [73]. Pentoxifylline is associated with reduced radiation-induced fibrosis and fibrosis-associated pain [69, 71]. Other studies have demonstrated significant regression in fibrotic scarring with the use of pentoxifylline plus α-tocopherol [70, 74].
Hyperbaric Oxygen
Hyperbaric oxygen therapy promotes revascularization within irradiated tissues to heal radiation injury to soft tissues. A study from M. D. Anderson Cancer Center showed improved soft tissue texture, increased sensation, and increased mucosal secretions in patients who underwent hyperbaric oxygen treatments [75]. Hyperbaric oxygen therapy is also associated with significant reduction in erythema, pain, and edema, but no reduction in fibrosis or telangiectasia [76]. Unfortunately, compliance is a potential issue with hyperbaric oxygen therapy as these treatments are often over an hour long and must be completed multiple times per week.
Superoxide Dismutase
Superoxide dismutase (SOD) is a group of enzymes that are known for their antioxidant effects in neutralizing free radicals. SOD has also been shown to reduce radiation-induced fibrosis. SOD is associated with fibrotic tissue softening, a significant reduction in the length, width, and depth of fibrosis, and histologically, demonstrates replacement of fibrotic tissue with normal tissues [77, 78].
Conclusion
Radiodermatitis is a common side effect of radiotherapy that is associated with pain, decreased quality of life, and treatment delays that may compromise the delivery and effectiveness of radiation treatment [1–3]. Radiodermatitis ranges from mild to severe and may be acute or chronic. Symptom severity is influenced by the degree of exposure to irradiation as well as several treatment-related and individual-related risk factors. Familiarity with these risk factors will allow dermatologists and radiation oncologists to anticipate the potential for skin toxicity and to plan treatment accordingly.
A multitude of interventions have been studied for the prevention and management of radiodermatitis with varied results. The use of many natural products, including aloe vera and calendula for the management of acute radiodermatitis is not supported by research. Washing the skin with a mild soap and the use of deodorant is recommended as these interventions do not increase toxicity but do improve patient comfort. Medium potency topical corticosteroids have been shown to reduce symptoms and severity of acute radiodermatitis. Interestingly, low potency corticosteroids are less effective and high potency steroids may be associated with increased incidence of severe radiodermatitis. Hydrogel dressings may be appropriate for the management of dry desquamation but result in maceration and prolonged healing in moist desquamation. Instead, dry dressings or gentian violet dressings should be used for the management of moist desquamation. Pentoxifylline and hyperbaric oxygen therapy promote healing of chronic wounds related to radiodermatitis. Preliminary data for the use of several newer agents, including hyaluronic acids and SOD, is favorable. Additional randomized controlled trials with large sample size and standardized assessment tools are needed to develop practice guidelines for the prevention and management of radiodermatitis.
References
