Use of trolamine to prevent and treat acute radiation dermatitis: a systematic review and meta-analysis

ABSTRACT Objective: to evaluate the effects of trolamine in the prevention or treatment of radiation dermatitis. Method: systematic review and meta-analysis. Detailed individual search strategies for Cinahl, Cochrane Library Central, LILACS, PubMed, and Web of Science were developed in January 2016. A manual search was also performed to find additional references. A grey literature search was executed by using Google Scholar. Two researchers independently read the titles and abstracts from every cross-reference. The risk of bias of the included studies was analyzed by the Cochrane Collaboration Risk of Bias Tool. The quality of evidence and grading of strength of recommendations was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Results: seven controlled clinical trials were identified. The controls used were calendula, placebo, institutional preference / usual care, Aquaphor®, RadiaCare™, and Lipiderm™. The studies were pooled using frequency of events and risk ratio with 95% confidence intervals, in subgroups according to radiation dermatitis graduation. Conclusion: based on the studies included in this review, trolamine cannot be considered as a standardized product to prevent or treat radiation dermatitis in patients with breast and head and neck cancer.


Introduction
The most common effect of radiotherapy is radiation dermatitis, which has greater impact in patients with head and neck and breast cancer (1) . About 80 to 90% of these patients treated by radiotherapy experience radiation dermatitis during treatment (2)(3) .
The skin is an organ with high radiosensitivity and susceptible to damage by radiotherapy due to rapid cell proliferation and maturation. The epidermis loses a percentage of its basal cell exposure beginning at the first fractionated dose of radiotherapy, and the repeated exposure of the subsequent fractions leads to continuous cell destruction, which avoids tissue repair (4) .
Although the skin damage starts after the first exposure to radiation, the clinical signs are often present from the second week of radiotherapy. They are characterized by mild erythema, which can develop to dry or moist desquamation, and ulcerations in some cases (5)(6) .
Acute skin reactions generate local discomfort, itching and varied degrees of pain that impact the quality of life of patients and affect the therapeutic efficacy and the planning of radiotherapy, considering that severe intensity lesions can cause interruption of treatment (1,7) .
Trolamine has been indicated to prevent and treat radiation dermatitis but, to the best of our knowledge, there is no systematic review that evaluated trolamine as a potential topical product to manage skin reactions due to radiotherapy.

Background
Skin reactions may be intensified, according to the treatment plan received, a full high dose, fractional high dose, and the extension of the irradiated area.
Chemotherapy and patient related factors, such as age, skin color, smoking habits and obesity also aggravate the skin reactions (6,8) .
Topical products are commonly used as alternatives to manage skin reactions due to radiotherapy, although there is insufficient evidence regarding skin care products for the prevention or treatment of radiation dermatitis (6) .
Topical application of emulsions containing trolamine has bee used in clinical practice for more than three decades in Europe and in the United States for the management of radiation dermatitis. Trolamine has the capacity to heal through the recruitment of macrophages to the wound, promoting the growth of granulation tissue (9) . Trolamine emulsion is a compound with properties similar to nonsteroidal anti-inflammatory agents and has been considered as a safe and tolerable topical intervention, with low potential to develop contact dermatitis. Trolamine promotes skin hydration and reduces discomfort and pain, which contribute to Menêses AG, Reis PED, Guerra ENS, De Luca Canto G, Ferreira EB.
We used the following search terms to search PubMed and adapted the strategy for the other databases: ("biafine" OR "triethanolamine" OR "trolamine" OR "trolamine emulsion" OR "emulsion containing trolamine") AND ("radiodermatitis" OR "dermatitis" OR "radiation dermatitis" OR "radio-dermatitis" OR "skin damage" OR "skin toxicity" OR "skin reaction" OR "skin injuries" OR "radiation reaction" OR "radio-epithelitis" OR "acute skin toxicity" OR "acute skin reaction" OR "acute dermatitis" OR "acute radiodermatitis" OR "acute cutaneous toxicity" OR "acute radiation dermatitis" OR "acute radiation reactions" OR "acute radiation-induced skin reactions" OR "radiation-induced acute skin" OR "radiation induced skin injuries" OR "radiation-induced skin reaction" OR "radiation induced dermatitis" OR "radio-induced damage" OR "radiotherapy-induced skin reactions" OR "radiation skin reactions" OR "radiation-induced skin injuries").
After obtaining all references, duplicates were excluded by using appropriate software (EndNoteBasic ® , Thomson Reuters, USA). All the electronic database searches were undertaken on January 18 th , 2016.

Study selection
For the phase of screening and data extraction, ©Covidence (Web-based systematic review tool designed to facilitate the process) was used.
The study selection was conducted in two phases. In

Risk of bias in individual studies
To assess the risk of bias of the included randomized controlled trials (RCT), the Cochrane Collaboration Risk of Bias Tool (13)

Summary measures
The primary outcome was the development of different grades of radiation dermatitis or the reduction of the intensity/degree of reaction. Further measures considered in this review were risk ratio (RR) or risk differences for dichotomous outcomes.

Synthesis of results
The overall data combination of the included studies was performed by a descriptive synthesis.
Statistical pooling of data using meta-analysis was planned whenever trials were considered combinable and relatively homogeneous in relation to design, interventions and outcomes. Heterogeneity within studies was evaluated either by considering clinical (differences about participants, type of controls and results), methodological (design and risk of bias) and statistical (effect of studies) characteristics or by using the I 2 statistical test. A value from 0 to 40% was considered of not important consistency, between 30 and 60% moderate heterogeneity, whereas 50 to 90% was considered to represent substantial heterogeneity (13) .
The Cochrane Collaboration´s Review Manager ® 5 (RevMan 5) was used to summarize the results by means of the Mantel-Haenszel model. The results were presented with 95% confidence intervals (95% CI).

Risk of bias across studies
The quality of evidence and grading of the strength of recommendations was assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) (14)(15) . The criteria for this assessment were study design, risk of bias, inconsistency, indirectness, imprecision and other considerations. The quality of evidence must be characterized as high, moderate, low, or very low (15) .
No funnel plot was constructed to assess the possibility of publication bias because there were few trials per subgroups of meta-analysis.

Study Selection
In phase 1 of study selection, 195 citations were identified across five electronic databases. After the duplicated articles were removed, 138 citations remained. No references from grey literature were added. A thorough screening of the titles and abstracts was completed and 126 references were excluded. A manual search from the reference lists of the identified studies yielded no additional studies. Thus, 12 articles remained for a full-text screening (phase 2). This process led to the exclusion of five studies ( Figure 1). In total, seven articles (16)(17)(18)(19)(20)(21)(22) were selected for data extraction and qualitative synthesis ( Figure 2). Figure 1
Two studies included patients who also underwent concurrent chemotherapy (19,22) . Radical radiotherapy has been reported in five studies (16)(17)(18)(20)(21) . The use of tamoxifen has been described in only one study, among those including patients with breast cancer (17) .

Risk of bias within studies
The risk of bias was analyzed individually in all studies included. One randomized clinical trial was graded as having a low risk of bias in the six domains assessed (21) (Figure 2). Four studies (16,(19)(20)22)  Four studies were classified as high risk of bias because they contained one or more compromised domains (16)(17)(19)(20) . Two studies were classified as uncertain risk of bias (18,22)

Results of individual studies
The studies used trolamine to prevent or treat radiation dermatitis and reported different results for all 7 articles. Characteristics and results of the included studies are listed in Table 1.

Risk of bias across studies
The quality of the evidence from the outcomes evaluated by the GRADE system was assessed as very low

Discussion
In this review, seven studies evaluating trolamine to prevent or treat radiation dermatitis were included.
In four studies (17)(18)(19)21) , no benefits were shown for the use of trolamine to prevent radiation dermatitis and, in two studies (16,20) there was no difference to prevent radiation dermatitis between trolamine and evaluated controls. Only one study (22) showed satisfactory use of trolamine in the prevention of radiation dermatitis, but its results showed benefit only to prevent grade 3 radiation dermatitis.
The skin moisture and the skin reactions from the radiotherapy could be influenced by the number of intervention applications along the day. Some studies instructed the patients to apply the intervention three times a day (16,19,22) or twice daily (17,21) or five times a day (20) . Only one study (18) allowed patients to apply the intervention twice a day or more according to the frequence of radiation dermatitis and pain. None of this studies described a relation between the frequence of intervention and control applications and the skin moisture. One of the studies (17) asked patients to start the product application ten days before the onset of radiotherapy, but no contribution was added to prevent radiation dermatitis.
The product quantity in each application was not measured by the studies, except in one of the studies (18) in which the mean total number of tubes was 1.62 times more used in the trolamine group than in the calendula group.
Patients considered trolamine use more satisfactory than controls when compared to calendula (18) and Aquaphor R and RadiaCare R(21) .
Some studies have shown that chemotherapy and tamoxifen increased the intensity of skin reactions in patients undergoing radiotherapy (23)(24)(25)(26) . Two studies used chemoradiotherapy (19,22) and, in one study, tamoxifen was used concomitantly with radiotherapy in breast cancer patients (17) , but these studies did not report significant differences in the skin reactions between the groups using trolamine or controls.
Only one study evaluated the efficacy of trolamine to treat radiation dermatitis, and considered no efficacy of trolamine in head and neck cancer patients (19) . It is important that other studies evaluate trolamine to treat grade 1 and grade 2 radiation dermatitis, because these grades require products with moisturizing and antiinflammatory action. One of the studies (22) considered that trolamine prevents grade 3 of radiation dermatitis in head and neck cancer patients, but this conclusion is only based on those patients who did not develop grade 3 of radiation dermatitis. Moreover, the nondevelopment of maximum grades of radiation dermatitis depends on extrinsic (total dose, fractionation, radiation energy, volume of treated regions, treatment duration, boost aplication, and treatment site) and intrinsic factors (age, comorbid conditions, skin phototype, and genetic predisposition) (27) .

Conclusion
Based on the studies included in this review, trolamine cannot be considered as a standardized product to prevent or treat radiation dermatitis in patients with breast and head and neck cancer. Further well-structured blinded studies using trolamine as a treatment are required to evaluated the moisturizing and anti-inflammatory action.