Prophylaxis and management of acute radiation-induced skin reactions : a systematic review of the literature

Radiation therapy is a common treatment for cancer patients. One of the most common side effects of radiation is acute skin reaction (radiation dermatitis) that ranges from a mild rash to severe ulceration. Approximately 85% of patients treated with radiation therapy will experience a moderate-to-severe skin reaction. Acute radiation-induced skin reactions often lead to itching and pain, delays in treatment, and diminished aesthetic appearance—and subsequently to a decrease in quality of life. Surveys have demonstrated that a wide variety of topical, oral, and intravenous agents are used to prevent or to treat radiation-induced skin reactions. We conducted a literature review to identify trials that investigated products for the prophylaxis and management of acute radiation dermatitis. Thirty-nine studies met the pre-defined criteria, with thirty-three being categorized as prophylactic trials and six as management trials. For objective evaluation of skin reactions, the Radiation Therapy Oncology Group criteria and the U.S. National Cancer Institute Common Toxicity Criteria were the most commonly used tools (65% of the studies). Topical corticosteroid agents were found to significantly reduce the severity of skin reactions; however, the trials of corticosteroids evaluated various agents, and no clear indication about a preferred corticosteroid has emerged. Amifostine and oral enzymes were somewhat effective in preventing radiation-induced skin reactions in phase ii and phase iii trials respectively; further large randomized controlled trials should be undertaken to better investigate those products. Biafine cream (Ortho–McNeil Pharmaceuticals, Titusville, NJ, U.S.A.) was found not to be superior to standard regimes in the prevention of radiation-induced skin reactions (n = 6). In conclusion, the evidence is insufficient to support the use of a particular agent for the prevention and management of acute radiation-induced skin reactions. Future trials should focus on comparing agents and approaches that, in phase i and ii trials, suggest efficacy. These future phase iii randomized controlled trials must clearly distinguish between preventive and management strategies for radiation-induced dermatitis. Only then can evidence-based guidelines be developed, with the hope of standardizing the approach across centres and of improving the prevention and management of radiation-induced dermatitis.


INTRODUCTION
The goal of radiotherapy is to provide maximum benefit to the patient with minimal side effects 1 .However, even with the most modern radiotherapy techniques, up to 90% of patients will experience a dose-dependent skin reaction at the treated area [1][2][3][4] .Skin reactions related to radiation therapy usually manifest within 1-4 weeks of radiation start, persist for the duration of radiation therapy, and may require 2-4 weeks to heal after completion of therapy 5 .The severity of the skin reaction ranges from mild erythema (red rash) and dry desquamation (itchy, peeling skin) to more severe moist desquamation (open wound) and ulceration 6 .
After the initial dose of radiation, tissue damage occurs immediately, and every subsequent fraction of radiation generates inflammatory cell recruitment.Acute radiation dermatitis is the combined result of a decrease in functional stem cells, changes in the skin's endothelial cells, inflammation, and skin-cell necrosis and death 7 .Potential complications of radiation dermatitis in the acute setting include local infection.The severity of the reaction is related to the dose per fraction, total dose delivered, use of bolus or other SALVO et al.   beam-modifying devices, size of the treatment field, site treated, use of concurrent chemotherapy or other agents, and individual susceptibility 8 .Areas of the body that contain skin folds, such as the groin, are at higher risk of developing a reaction because of a phenomenon called the "bolus effect"; these areas are more likely to receive a higher dose of radiation and more prone to bacterial contamination 9 .Prescribed treatment at low doses (<2000 cGy) in conventional fractionation at depth usually does not elicit a skin reaction, and consequently, patients receiving palliative treatment are not usually at risk 6 .
Prevention and management of radiation-induced skin reactions are often confusing processes for patient and clinician alike.A study conducted in the United Kingdom noted substantial variation in the advice given to patients by different radiotherapy departments (n = 33) for preventing and managing skin reactions 10 .A survey of nursing practice in Belgium revealed that management of skin reactions varies, and traditional practices such as avoiding skin washing and using talcum powder are still advised by a significant number of nurses even though those practices are controversial in the literature 11 .The high incidence of radiation-induced skin reactions has generated interest in methods of preventing and effectively treating such reactions 1 .
It is generally agreed that the ideal method for preventing and minimizing skin reactions is moisturization of the irradiated area.The use of barrier or corticosteroid creams, Aloe vera, and other lanolinfree hydrophilic products is often recommended for this purpose 1 .A Cancer Care Ontario guideline for the prevention of skin reactions suggests skin washing with mild soap and water, but because of limited evidence, suggests no specific products for prevention or management 6 .The objective of treatment for dry desquamation is to lessen patient discomfort by providing moisture to the affected areas 12 .Treatment of moist desquamation usually involves the use of hydrocolloid dressings to reduce exposure to external pathogens and ultimately to prevent infection 1 .Although a general consensus among radiotherapy centres is lacking, the advice given to patients has a few commonalities: • During or after radiation treatment, avoid the use of metallic-based topical products (zinc oxide creams or deodorants with an aluminum base, for instance), because they may increase the surface dose to skin 12 .
• Wear loose-fitting clothing over the irradiated area to prevent friction injuries 1,12 .
• Maintain a clean and dry irradiated area 1 .
• Avoid the use of starch-based products because they increase the risk of infection 1 .
No general accord has been reached across radiotherapy centres about the treatment of radiation skin toxicities.An updated review summarizing comparative studies that have evaluated the use of agents for the prevention and management of radiation-induced skin reactions is therefore needed, because additional studies in the literature may lead to consensus.

MATERIALS AND METHODS
We used the earlier Cancer Care Ontario publication from the Program in Evidence-Based Care 6 as a template.Our goal was to update the literature search and to use the earlier reporting structure to facilitate comparisons.We searched the medline, PubMed, and Cochrane Library databases to uncover comparative studies published between January 1, 2000, and October 1, 2008, thus updating the previous systematic review of the literature 6 , which included studies up to April 2004.To find relevant articles, we used the search terms "dermis," "skin reactions," "radiation," "radiation adverse effects," "erythema," "desquamation," "radiodermatitis," "acute," and "radiotherapy adverse effects."Searches were limited to the English language, to studies conducted on human subjects, and to publications of randomized controlled trials (rcts), controlled clinical trials, and comparative studies.Relevant articles and abstracts were selected and reviewed by three reviewers, and the reference lists from those sources, and from review articles, were searched for additional trials.

Eligibility Criteria
Articles were included if they were fully published reports or published abstracts of clinical trials or studies that compared practices for the prevention or management of acute radiation-induced skin reactions and were published between January 1, 2000, and October 1, 2008.To be included, the trials must have reported a method of grading for the skin reaction and must have statistically evaluated the skin reaction as a primary or secondary outcome.Other primary or secondary outcomes that were assessed included pain, itchiness, burning, quality of life, toxicities, and patient perspective of the product, agent, or technique.Prospective and retrospective data were included.Trials that involved radiation-induced reactions in mucosal areas only were not included in the review.Letters, comments, editorials, practice guidelines, case reports, systematic reviews, and meta-analyses were excluded.
This update was planned as a qualitative review of the literature; no meta-analysis or pooling of results was performed.

RESULTS
Three of the identified trials were excluded because of ineligibility.Two trials did not report a statistical evaluation of the agent; instead, they provided subjective observation only 13,14 .The third trial had only an abstract in English translation, which did not allow for appropriate interpretation of results 15 .

Washing Practice
Two studies evaluated washing practice for preventing radiation dermatitis 16,17 .
Roy et al. compared no washing with gentle washing using water and mild soap (Dove: Unilever Canada, Saint John, NB; Ivory: Procter and Gamble, Toronto, ON) during radiation for breast cancer.Compared with patients in the non-washing group, those in the washing group had a significantly lower incidence of moist desquamation (p = 0.03); however, patients did not differ on other parameters such as maximum erythema score and mean time to maximal toxicity.The variety of soaps used in the washing group was large, and washing routines were not identical across all patients in the group 17 .
Westbury et al. looked at scalp care after cranial irradiation.Patients were randomized either to continue their normal hair-washing regime or to avoid washing the treatment area.The study did not find a significant difference in skin reactions between the two groups and did not report differences in pain or itchiness 16 .
Boström et al. 18 studied breast cancer patients receiving radiation after breast-conserving surgery.The patients received prophylaxis with either 0.1% mometasone furoate cream or an emollient cream in a blinded manner.Boström et al. found a significant benefit in favour of the mometasone furoate cream in maximum erythema scores (p = 0.011) and in grade 4 or greater (on a 7-point grading scale) skin reaction (25% vs. 60%).
In a randomized double-blind study, Schmuth et al. compared two topical corticosteroid agents: 0.5% dexpanthenol cream and 0.1% methylprednisolone aceponate cream 19 .These authors found that although neither cream reduced the incidence of radiation dermatitis, fewer patients in the methylprednisolone group developed a reaction with a score of 4 or more (p < 0.05) on a rating scale that summed the scores for erythema, desquamation, erosion, induration, or hyperpigmentation (each assessed on a 4-point Likert scale: 0, none; 1, mild; 2, moderate; 3, severemaximum possible score, 15).No other significant differences were found between the two treatment groups with respect to other measures of efficacy.
Shukla et al. 20 evaluated beclomethasone dipropionate spray, comparing treated patients with a control group that did not use a topical agent on the irradiated area.Those authors noted a significant difference in the incidence of moist desquamation in favour of the topical corticosteroid spray (13% vs. 37%, p = 0.0369).
Omidvari and colleagues 21 also assessed betamethasone in comparison with a group using petrolatumbased emollient and with a control group.Compared with the petrolatum and control groups, the betamethasone group showed a favourable significant difference at week 3 in the number of patients that reached a grade 1 (rtog) skin reaction (p = 0.027).Throughout   the study, no differences were found between the petrolatum group and the control group (p = 0.027).None of the studies evaluating the use of topical corticosteroid agents noted a significant difference in pain or itching attributable to radiation.

Nonsteroidal Topical Creams
Aloe vera: Two rcts assessed the efficiency of Aloe vera in preventing radiation-induced skin reactions 22,29 .In a single-blind trial, Olsen et al. 22 evaluated the use of mild soap plus Aloe vera against mild soap alone.At a cumulative dose of more than 2700 cGy, a protective effect of adding Aloe vera to mild soap was noted, although the difference was nonsignificant.In a large double-blind study by Heggie et al. 23 , Aloe vera was compared with an aqueous cream.The aqueous cream was found to be significantly better at reducing dry desquamation and pain secondary to treatment.
In a phase ii study, Szumacher et al. 26 assessed the ability of Biafine cream to prevent grade 2 or greater radiation dermatitis (National Cancer Institute of Canada acute toxicity criteria) in women with breast cancer receiving concomitant adjuvant chemotherapy and radiation to the affected breast.After the 5-week course of radiotherapy, the skin reaction occurring with highest frequency was grade 2 reaction in 83% of patients (grade < 2: 15%; grade 3: 2%).
Fisher et al. 24 evaluated the use of Biafine cream against best supportive care in a multicentre rct.Best supportive care was defined as "institutional preference" and included Aquaphor Healing Ointment (Beiersdorf Canada, St. Laurent, QC) and Aloe vera as the top two choices.In a similar large multicentre study, Elliot et al. 28 evaluated Biafine cream in the preventive and interventional settings against an institutional preference, which was different for each centre.Both trials reported no significant difference between Biafine cream and institutional preference for the prevention of radiation-induced skin reactions 24,28 .
Fenig et al. 25 compared the efficacy of Biafine cream with that of Lipiderm cream (G-Pharm, Salisbury, U.K.) for preventing radiation dermatitis by evaluating the maximal level of skin reaction and the number of gaps in treatment.Those authors found no significant differences between the two treatment groups and a control group.However, they did note that 86% of patients reported no difficulty when using the Biafine or Lipiderm creams.
In a rct, Ribet et al. compared the median time to emergence of the first objective signs of radiation dermatitis in patients using Biafine or Avène thermal spring water anti-burning gel (Pierre Fabre Dermo Cosmétique USA, Parsippany, NJ, U.S.A.) and found no significant differences between the groups 29 .
In the largest of the six trials involving Biafine, Pommier et al. 27 examined the preventive effects of Biafine cream with those of calendula ointment and found a significant difference in the number of grade 2 or greater reactions (rtog) in favour of calendula ointment (41% vs. 63%, p < 0.001).Those authors noted a difference in favour of the calendula-treated group for the mean maximal pain experienced (p = 0.03) and against the calendula ointment for the level of difficulty encountered in applying the cream (30% vs. 5%).The calendula ointment was recommended for use; however, the increased difficulty experienced by patients in the calendula group with application of the ointment meant that they were more likely to be noncompliant.

Hyaluronidase-Based Creams:
Hyaluronic acid is thought to accelerate the healing process by stimulating fibroblasts and fibrin formation.Leonardi et al. 30 assessed the efficacy of Xclair (Align Pharmaceuticals, Berkeley Heights, NJ, U.S.A.), a water-based cream with barrier-forming, hydrating, and antiinflammatory properties, against that of the vehicle alone in a double-blind randomized study of breast cancer patients receiving adjuvant radiation.Those authors found a highly significant difference between the two groups in the maximum grade of radiation dermatitis (p < 0.0001) after 3 weeks of radiation treatment.Their study also noted that patients in the Xclair group felt a decreased burning sensation (p = 0.039).There were no statistical differences noted for pain or itching.
Primavera et al. 2 used patients as their own controls in assessing the effectiveness of Xclair at managing radiation-induced skin reactions.Those authors found that the areas treated with Xclair showed a significantly lower nci grade of dermatitis than did areas treated with vehicle alone at week 4 of radiation (p = 0.031).The mean erythema scores were significantly lower in the Xclair treatment areas than in the vehicle areas at weeks 4, 5, and 6 of radiation (p = 0.01, 0.005, 0.03 respectively).No significant differences were found for pain and itch scores.Notably, 65% of patients preferred Xclair cream to the vehicle; only 10% favoured the vehicle.

Sucralfate or Sucralfate Derivatives:
Sucralfate is a persulfated disaccharide in complex with aluminum 31 .Two randomized trials evaluated the effects of sucralfate cream over control 31,32 .In an internal control setting, Evensen et al. 31 randomized areas of the treatment field to sucralfate or to vehicle.Those authors did not identify a significant difference in the incidence of erythema, desquamation, pain, or itching.In a factorial design, Wells et al. 32 compared sucralfate cream with aqueous cream and with no cream.They found no reliable differences in the severity of the reaction or in the level of discomfort between the groups.

Miscellaneous Creams:
In a randomized study of breast cancer patients, Enomoto et al. 36 compared RayGel, a gel formulated by a naturopathic physician, with a placebo.Both groups received instruction on the institution's standard skin care recommendation, which included the use of Aloe vera gel and vitamin E after radiation treatments in addition to RayGel or placebo.Enomoto et al. found a trend toward lower worst skin reaction scores for the RayGel group, but statistical significance was not achieved.
Using internal controls, Graham et al. compared Cavilon No Sting Barrier Film (3M, St. Paul, MN, U.S.A.) with sorbolene cream for the prevention of moist desquamation with breast radiation.Treatment areas were divided into medial and lateral components and each component was randomized to one of the topical agents.A significantly lower skin toxicity score was found on breast areas treated with the No Sting Barrier Film (p = 0.005).Pain was evaluated, but was not found to be significantly different between the groups 35 .
Matceyevsky et al. 38 evaluated the efficacy of Solaris lotion (Eugene-Perma, Paris, France) over a control in the prevention of dermatitis attributable to radiochemotherapy in head-and-neck cancer patients.That trial did not find any differences in the severity of skin reaction between the treatment arms; however, a difference in favour of the Solaris lotion was noted in the number of breaks from treatment (p = 0.034).
A comparison of moist skin care (0.3% urea lotion) versus dry skin care (powder) after radiotherapy was conducted by Momm et al. 33 in a multicentric study.Those authors found that significantly more patients treated with dry skin care (56% vs. 22% using lotion) experienced a grade 3 skin reaction (rtog, p = 0.0007).This study also noted that a greater number of patients in the dry skin care group were hospitalized because of the severity of their skin reaction (28% vs. 10% in the moist skin care group), but that finding was not statistically significant.
The last trial was performed by Ma et al. 37 , who studied a Chinese remedy, lian bai liquid in patients without a skin reaction (prevention group) and in those who presented with a grade 3 reaction (nci ctc, treatment group).Both groups were also compared with controls.Lian bai liquid was effective in reducing the incidence of skin reactions in the prevention group as compared with controls (p < 0.01).

Systemic Interventions
Amifostine: Amifostine is a thiol derivative that has demonstrated radioprotective effects in animal experiments 39 .One retrospective study 47 and one nonrandomized clinical trial 39 evaluated amifostine as a cytoprotective agent against acute radiationinduced skin reactions.
Kouvaris et al. 47 retrospectively compared patients treated with intravenous amifostine against historical controls.Those authors found that patients who received amifostine had dermatitis of significantly reduced severity (p < 0.001), a lower mean gross dermatitis score (p < 0.001), and a lesser mean treatment interruption time (p < 0.001).
Dunst et al. 39 assessed the efficacy of amifostine in patients receiving radiochemotherapy for rectal cancer.The maximum grade of erythema was higher in patients who did not receive amifostine (1.46 ± 0.64 vs. 0.87 ± 0.52, p = 0.009).However, maximum nausea scores were significantly higher in patients who received amifostine (0.27 ± 0.46 vs. 0.93 ± 0.53, p = 0.002).
Oral Enzymes: Two rcts examined the efficacy of oral hydrolytic enzymes 41,42 .Both trials compared Wobe-Mugos enzyme with no treatment; the study patients had either head-and-neck cancer 42 or cervical or uterine cancer 41 .Gurjal et al. 42 reported that the maximum extent of skin reaction was lower in the enzyme-treated group (p < 0.0001).Dale et al. 41 observed a lower average maximum extent of acute reaction in patients who were randomized to receive the enzyme (p < 0.001).Neither trial identified a difference in pain or itching between the two groups.
Pentoxifylline: One study by Aygenc et al. 43 assessed the effect of prophylactic pentoxifylline on radiation-induced toxicities.Pentoxifylline is a drug that is currently used to treat a variety of vasoocclusive disorders.It is known to improve microcirculation by increasing the flexibility of red blood cells.Aygenc and colleagues found no significant difference in the maximum acute skin reaction score between a pentoxifylline group and a control group; however, a significant difference in the maximum skin reaction score for late skin changes, 8 weeks post radiotherapy, was identified (average maximal score: 2.96 vs. 3.44, p < 0.05).
Supplements: One double-blind rct in head-andneck cancer patients compared a zinc supplement with placebo 44 .Grade 2 dermatitis (rtog) appeared earlier in the placebo group than in the group supplemented with zinc (p = 0.017).A similar finding was noted with grade 3 dermatitis (p = 0.0092).Two weeks post radiotherapy, both groups demonstrated similar improvements in relation to dermatitis 44 .

Dressings
One trial studied the effect of silver-leaf nylon dressing, which has been shown to have antimicrobial properties and to enhance healing in burn and skin grafts.Vuong et al. 45 examined 15 patients receiving radiation to the perineum who were instructed to wear the dressing from the initiation of radiation until 2 weeks post radiation.Results were compared with data from historical controls.The mean dermatitis grades (rtog) were significantly lower in the dressing group than in the control group, and the benefit was thought to be attributable to the antimicrobial properties of the dressings (mean rtog grade: 1.16 vs. 2.62, p < 0.0001).

Mode of Radiation Delivery
Two studies examined different methods of delivering radiation.One trial evaluated intensity-modulated radiation therapy (imrt) for adjuvant therapy of breast cancer in a multicentric double-blind rct.The goal was to observe whether this novel technique could deliver a more homogenous radiation dose throughout the breast.Theoretically, this approach would reduce the occurrence of higher spot doses of radiation, leading to a lower incidence of skin reaction.This trial, performed by Pignol et al. 46 , found that, as compared with a standard method of delivering radiotherapy, breast imrt significantly reduced the number of patients who experienced moist desquamation during or up to 6 weeks after treatment (31.2% vs. 47.8%,p = 0.002).
DeLand et al. 3 assessed the use of light-emitting diode (led) photomodulation after each series of imrt in breast cancer patients.The results were compared with data from historical controls who received similar doses of imrt without the led treatment.Those authors found that treatment with led immediately after imrt significantly lowered the grade of skin reaction (5.3% grade 2 reaction in led group vs. 85.7% grade 2-3 reaction in non-led group, p < 0.0001).

Topical Colony-Stimulating Factors
One nonrandomized open study by Kouvaris et al. 40 compared use of betamethasone alone with the use of gauze impregnated with a granulocyte-macrophage colony-stimulating factor (gm-csf) in addition to betamethasone.The authors found that the grades of skin reaction were significantly lower (p = 0.008) and the healing time significantly shorter (p = 0.02) in the gm-csf group.Grade 3 and 4 reactions, evaluated using the Subjective Objective Management Analytic (soma) grading system, were significantly fewer in the gm-csf group (p = 0.014).Kouvaris and colleagues also found that the time interval of treatment interruption was significantly shorter in patients who received the gm-csf (5.17 ± 1.76 days vs. 6.57± 2.30 days, p = 0.037) and that pain relief occurred significantly sooner after gm-csf application (3.12 ± 1.42 days vs. 5.48 ± 1.59 days, p = 0.0017) 40 .This study used a "sum of gross dermatitis score" that was evaluated by adding the dermatitis score (rtog criteria) to the pain score (soma grading system).Although the summed score was based on validated measurement tools, the summation method itself has not been validated for assessing radiation dermatitis.

Nonsteroidal Topical Cream
Garcia et al. 48conducted a phase i trial evaluating the efficacy of superoxide dismutase (sod) to treat grade 2 dermatitis (rtog) in varying cancer types.Those authors demonstrated a 77.1% response at the completion of radiation treatment (17.5% complete response; 59.6% partial response) and no worsening of the condition at the end of the 12-week study period.No acute toxicities related to sod were reported in the trial 48 .
MacMillan et al. 50studied a hydrogel (moist) dressing compared with a dry dressing in the management of moist desquamation.Patients were randomized to one of the two dressing types.All were instructed to wash the treatment area and were given a supply of unperfumed simple soap.Compared with patients who were allocated to the dry dressings, patients randomized to the gel dressings were significantly more likely to use their dressings (93.1% vs. 63.1%,p = 0.002).Patients assigned to the gel dressings also had a significantly longer healing time (defined by return to a grade 2 or lesser reaction, p = 0.03).No differences were observed in pain or itching scores between the two groups 50 .
Using internal controls, Vavassis et al. 51 compared silver-leaf nylon dressings with silver sulfadiazine cream in a small trial in patients receiving radiation for head-and-neck cancer.Those authors found no significant improvement in rtog skin toxicity grade; however, a reduction in the severity of the within-grade skin reaction was observed with the silver-leaf dressing (p = 0.035), and pain scores were subjectively superior for the silver-leaf dressing.
In a rct, Mak et al. 49 studied the effectiveness of hydrocolloid dressings over gentian violet in the management of moist desquamation.There was no difference between the groups in healing time, but wound size and wound pain were significantly less with gentian violet.However, gentian violet treatment received significantly lower ratings for dressing comfort and aesthetic acceptance 49 .

Other
One double-blind rct by Balzarini et al. 52 assessed the effects of Belladonna 7CH and X-Ray 15CH (homeopathic medicines), in the treatment of radiation dermatitis.Skin colour, warmth, swelling, and pigmentation were assessed and combined to give an "index of total severity."The differences in the index scores during the radiotherapy treatments were not statistically significant, but the differences in scores during the recovery period (time after radiation) showed a significant benefit for the Belladonna 7CH over the X-Ray 15CH 52 .
As mentioned earlier, the trial by Ma et al. 37 evaluated the effect of the Chinese remedy lian bai liquid on patients who presented with grade 3 skin reaction (nci ctc) and compared that group (and a prevention group) with controls.Lian bai liquid decreased the time to wound healing (11.07 ± 2.21 days vs. 18.08 ± 1.76 days, p < 0.01).

Prevention of Acute Radiation-Induced Skin Reactions
Overall, there is a general lack of support in literature for choosing Biafine over other agents in prevention of acute radiation-induced skin reactions.There is some evidence to suggest that topical corticosteroid agents may be beneficial in decreasing the incidence of radiation dermatitis, especially grade 3 and 4 reactions 19,21 .The evidence for the use of nonsteroidal topical agents is conflicting: some trials were positive for nonsteroidal agents 30,33,35,37 ; others showed no difference .The evidence did not support the use of Aloe vera 22,23 or sucralfate cream 31,32 .There was some evidence to suggest that led treatment, pentoxifylline, silver-leaf dressings, washing with soap and water, and zinc supplements help to prevent radiation-induced skin reactions 3,17,[43][44][45] .A large multicentric rct comparing breast imrt with standard breast radiation treatment showed a significant reduction in moist desquamation in the imrt group.Overall, the many trials evaluating a large variety of products and methods for the prevention of acute radiation-induced skin reactions do not support a general consensus on a superior product that should be used in this setting.Future trials should focus on comparing one or two of the agents for which some benefit is indicated, so as to better establish their efficacy.Such trials should take into account subjective patient evaluation of the product, compliance, and quality of life, because these factors are crucial when recommending the widespread use of one agent.

Management of Acute Radiation-Induced Skin Reactions
The treatments that were assessed for the management of radiation-induced skin reactions include topical steroid creams, nonsteroidal creams, dressings, and herbal remedies.No two trials evaluated the same agent or treatment, making it difficult to compare results.Only three of the trials showed a significant difference: one in favour of a corticosteroid cream, one favouring a nonsteroidal cream, and one for a dressing.However, all three of these trials were small and had limitations that prevent the generalizability of the results.The small number and large variety of trials make it difficult to draw any conclusions concerning the management of radiation skin reactions.A greater number of trials assessing treatments for radiation-induced skin reactions, especially moist desquamation and ulceration reactions (grades 3 and 4), must be performed.

CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH
To date, attempts to prevent or manage acute radiation dermatitis appear somewhat haphazard, trying various creams and lotions, systemic interventions, and radiation delivery methods without paying a great deal of attention to the underlying pathophysiology.Future efforts must be more systematic.They must incorporate new knowledge regarding radiationinduced dermatitis so that the pathophysiologic process set in motion by the radiation can either be prevented or attenuated, and in situations in which damage cannot be averted, the healing process accelerated.We make these suggestions: • The goal of the intervention-that is, prevention or treatment-must be clearly distinguished in advance.

•
Interventions must attempt to take into account the pathophysiologic process of radiationinduced dermatitis.
• Further work is required to develop and validate assessment tools that are sensitive to changes in skin damage resulting from radiation over time.Prevention and treatment interventions will likely require different tools.These tools must incorporate patient-reported outcome measures to better reflect the patient experience.
• Further study is required to determine differences in the risk of radiation-induced skin toxicity for various tumour types and anatomic areas.A variety of assessment tools may need to be developed, depending the level, or risk and severity, of the expected reaction.
• Consensus on the appropriate endpoints of interest both for prevention and for management trials must be developed.

CONFLICT OF INTEREST DISCLOSURES
This research was generously supported by Align Pharmaceuticals.All authors declare that no financial conflict of interest exists.
Pharmaceuticals, Titusville, NJ, U.S.A. b Physician-treated grade 2 or higher skin reaction.c Unknown because of lack of complete article.d Beiersdorf, St. Laurent, QC. e Patients stratified into those who received chemotherapy and external-beam radiotherapy, and those who received external-beam radiotherapy alone.nr = not reported; fr = fractions; xrt = external-beam radiotherapy; rt = radiotherapy; imrt = intensity-modulated radiotherapy.