INTRODUCTION
According to data from the American Cancer Society, breast cancer accounts for 30%
of all cancer cases in women, and an estimated 281,550 new cases were estimated in
2021. The incidence of this neoplasm increased by 0.5% between 2008 and 2017, probably
due to decreased fertility, increased overweight and obesity in the female population1.
Breast cancer treatment is multimodal and depends on factors such as staging at diagnosis,
tumor biological characteristics, and patient-related factors. The available treatment
modalities are radical or conservative surgery, radiotherapy, chemotherapy, hormone
therapy and biological therapy, which are often associated individually for each case2.
Radiotherapy plays an important role as an adjuvant to the surgical treatment of breast
cancer, decreasing local recurrence rates and increasing overall survival. It is estimated
that up to 95% of irradiated patients will develop some degree of radiodermatitis
(RDTE). In addition to interfering with the quality of life, skin toxicity induced
by radiotherapy, depending on the severity, can delay or interrupt adjuvant treatment3,4.
RDTE is an acute or chronic inflammatory condition caused by skin exposure to ionizing
radiation resulting in changes in the epidermis, dermis and local vascularization.
It is a dose and timedependent condition with a progressive spectrum of skin changes
such as erythema, hyperpigmentation, dry desquamation, wet desquamation, necrosis
and local ulceration3. Such changes are part of the most commonly used RDTE assessment and classification
scales: Radiation Therapy Oncology Group (RTOG) and National Cancer Institute’s Common
Terminology Criteria for Adverse Events (NCI-CTCAE)5.
The main risk factors for the development of RDTE are related to the characteristics
of the patient and the radiotherapy technique used, such as radiotherapy dose greater
than 50Gy; conventionaldose splitting regimen; use of bolus or boost techniques; among
others. It is known that a body mass index greater than 25kg/m2, smoking and the presence of large breasts are factors that predispose to moderate
and severe forms of RDTE6,7. On the other hand, the main protective factors concern the radiotherapy technique
used, and intensity-modulated radiotherapy (IMRT) and prone position have been proven
to reduce radioinduced skin toxicity5.
Unlike radiotherapy techniques, which have already standardized protocols to reduce
the risk of skin toxicity to the patient, the management of RDTE remains heterogeneous.
Numerous topical and curative drugs for the prophylaxis and treatment of RDTE have
been investigated in the medical literature, but a large number of proposed interventions,
the heterogeneity of reported results and the quality of studies make clinical decisions
challenging8. Thus, it is necessary to carry out extensive research in the medical literature
in search of available evidence on this topic.
OBJECTIVE
To carry out an integrative review of the literature on the use of topical therapy
for the prevention and treatment of RDTE in female patients with breast cancer undergoing
adjuvant radiotherapy.
METHODS
This is a descriptive, exploratory study that rigorously followed the six steps recommended
for the development of an integrative literature review9.
A search was carried out for articles published between 2010 and 2020 in the Latin
American and Caribbean Literature in Health Sciences (LILACS), Medical Literature
Analysis and Retrieval System Online (Medline) and Cochrane Library databases.
Four controlled descriptors were used: breast neoplasms, radiodermatitis, skin hygiene
and skin cream. Original articles from primary or secondary studies were included,
with female patients undergoing breast radiotherapy, published in full in Portuguese,
English or Spanish, and which could be accessed online. Secondary articles, such as
literature reviews and meta-analyses, were not included. However, the primary articles
that made up such studies did. Articles that evaluated different anatomical sites
of the breasts, publications of study protocols, studies with unavailable full text,
studies that evaluated non-topical therapies, such as oral medications or non-invasive
technologies, and duplicates were excluded.
After analyzing the articles’ abstracts, those that met the inclusion criteria were
read in full by a single reviewer and organized using a synthesis tool developed by
the main author. The data obtained were organized in an Excel spreadsheet, and the
respective references were stored in the bibliography manager software EndNote (Clarivate
Analytics).
RESULTS
The bibliographic research structured according to the previously established methodology
resulted in selecting this integrative review’s 48 original primary articles (Figure 1). As for the type of study, 35 (73%) randomized clinical trials (RCTs) were found;
three non-randomized clinical trials (6%), five pilot studies (11%), two case series
(4%), one case-control study (2%), one retrospective study (2%) and one prospective
cohort (2%).
Figure 1 - Flowchart of the steps for identification and selection of articles in this review.
Figure 1 - Flowchart of the steps for identification and selection of articles in this review.
In the 48 studies in this review, 40 different interventions for the prevention or
treatment of breast RDTE were identified, which were grouped into seven categories
to facilitate their analysis and interpretation (Table 1).
Table 1 - Topical therapies from this integrative review and their respective references.
| Herbal Medicines |
References |
| Aloe barbadensis extract 30mg/100ml |
10 |
| Curcumin Gel (PsoriaGold®) |
11 |
| Calendula officinalis cream
|
12-14 |
| Asian centella 7%, Cucumis sativus 20%, Thunbergia laurifolia 5%
|
15 |
| Boswellia serrata cream 2%
|
16 |
| Beta-sitosterol Ointment 0.25% (Mebo®) |
17 |
| Fatty Acids and Linoleic Acid (WO1932)/ Ultra Emu Oil® |
18.19 |
| Blend of essential oils |
20 |
| Omegas 3,6,9 (Quinovit®) |
21 |
| Jaungo Ointment (shikonin 0.07mg/g + decursin 3.6mg/g) |
22 |
| Sodium pentaborate pentahydrate 3% gel |
23 |
| Silymarin 0.25% (Leviaderm®) |
24 |
| Olive oil and calcium hydroxide emulsion |
25 |
| Emulsion of natural extracts (SkinSave®) |
26 |
| Hormones, vitamins and growth factors |
| Melatonin cream (Praevoskin®) |
27 |
| Recombinant epidermal growth factor (EGF) cream |
28 |
| Vitamin D (Daivonex®) |
29 |
| Vitamin E |
21 |
| Topical corticosteroids |
| Mometasone Furoate 0.1% |
14.30-32 |
| 1% hydrocortisone |
33 |
| 17-Betamethasone Valerate (Betnovat®) |
34.35 |
| Barrier |
| Silicone film (Mepitel®/Mepilex Lite®) |
36-40 |
| Hydrofilm® |
41 |
| Cavilon® (barrier cream) |
42.43 |
| Silicone gel (XtrataXRT®) |
44 |
| Hyaluronic acid |
| Hyaluronic acid gel, serum or cream |
14,21,45-46,47 |
| Silver |
| 48 silver impregnated film |
48 |
| 1% silver sulfadiazine |
49 |
| Others |
| HPR Plus® (free fatty acids, ceramides and hyaluronic acid) |
11 |
| Commercial formulations (Neoviderm®/Ixoderm®) |
21 |
| Aquafor® (panthenol and glycerin ointment) |
50 |
| Trolamine (Biafine RE®) |
50 |
| RadiaCare® |
50 |
| Hydrophilic gel with polyurethane polymers (Hydrosorb®) |
51 |
| Mucopolysaccharide Polysulfate 5mg/g (Hirudoid®) |
52 |
| Sucralfate |
53.54 |
| Flamigel® (hydroactive colloid gel) |
55.56 |
| 3% urea lotion |
57 |
Table 1 - Topical therapies from this integrative review and their respective references.
Herbal medicines
No benefits were found from the use of Aloe vera extract10, curcumin gel11; Calendula officinalis cream12,13,14, Centella Asiatica extracts 7%, Cucumis sativus 20%, Thunbergia laurifolia 5%15, Boswellia serrata cream 2%16, ointment of beta-sitosterol 0.25% (Mebo®)17, fatty acid emulsion18,19, blend of essential oils20, omega 3,6,9 (Quinovit®)21 and Jaungo ointment (shikonin 0.07mg/g + decursin 3.6mg/g)22 in the management of RDTE of the breasts.
A double-blind, randomized clinical trial with 47 patients showed that 3% sodium pentaborate
pentahydrate gel decreased the rate of RDTE grade RTOG > 2 in the subgroup of patients
undergoing radical or conservative surgery who did not receive radiotherapy boost
(34% vs. 67% p=0.03)23.
Studies that evaluated silymarin 0.25%24, emulsion of olive oil and calcium hydroxide25 and natural extracts (SkinSave®)26 showed a reduction in the proportion of patients with RDTE24,25, less pain24 and erythema26. Table 2 summarizes the data for this group.
Table 2 - Herbal medicines.
| Herbal |
Reference |
Result |
| Aloe barbadensis extract (30mg/100ml)
|
10 |
Negative |
| Curcumin Gel (PsoriaGold®) |
11 |
Negative |
| Calendula officinalis cream
|
12-14 |
Negative |
| Asian centella 7%, Cucumis sativus 20%, Thunbergia laurifolia 5% |
15 |
Negative |
| Boswellia serrata cream 2%
|
16 |
Negative |
| Beta-sitosterol Ointment 0.25% (Mebo®) |
17 |
Negative |
| Fatty Acids and Linoleic Acid (WO1932)/ Ultra Emu Oil® |
18.19 |
Negative |
| Blend of essential oils |
20 |
Negative |
| Omegas 3,6,9 (Quinovit®) |
21 |
Negative |
| Jaungo Ointment (shikonin 0.07mg/g + decursin 3.6mg/g) |
22 |
Negative |
| Sodium pentaborate pentahydrate 3% gel |
23 |
Positive |
| Silymarin 0.25% (Leviaderm®) |
24 |
Positive |
| Olive oil and calcium hydroxide emulsion |
25 |
Positive |
| Emulsion of natural extracts (SkinSave®) |
26 |
Positive |
Table 2 - Herbal medicines.
Hormones, vitamins and growth factors
Melatonin-based cream (Praevoskin®) reduced the incidence of grade 1 and 2 RDTE in
the intervention group (59% vs. 90%, p=0.03), with the benefit being greater in the subgroups of patients >50 years (p= 0.021) and smokers (p=0.007)27.
Recombinant epidermal growth factor (EGF) cream and vitamin D ointment could not prevent
the onset or progression of RDTE28,29. In the study that evaluated vitamin E, a 55% prevalence of grades 1-2 RDTE was observed
in the group of 20 patients who used this therapy (11/20)2.
Corticosteroids
Topical corticosteroids were studied in seven RCTs, six of which were double-blind,
and one was a pilot study, totaling 794 patients. Four of the seven studies evaluated
0.1% mometasone furoate; two, 17-betamethasone valerate; and one, 1% hydrocortisone
cream.
Mometasone furoate 0.1% reduced the severity of RDTE30, the incidence of wet scaling and skin toxicity31. These benefits were not observed in the pilot study14 and one of the double-blind RCTs32. In the latter, an improvement in the symptoms reported by the patient (secondary
outcomes) was observed, such as less local irritation, less persistence and recurrence
of symptoms and less discomfort with skin changes32.
1% hydrocortisone cream was not able to prevent the occurrence of wet desquamation33. The use of 17-betamethasone valerate (Betnovat®) twice a day, from the first day
of radiotherapy until 14 days after its completion, demonstrated a protective effect
against the onset and progression of RDTE, with the benefit being even greater in
the subgroup of mastectomy patients34,35.
Barrier (film or cream)
This intervention has the second largest RCT series, totaling 774 patients in studies
evaluating silicone film (Mepitel®/MepilexLite®), Cavilon® cream, silicone gel (XtrataXRT®)
and polyurethane film (Hydrofilm®).
Studies with silicone films showed beneficial results. Its application on the breast
surface to be irradiated resulted in a lower incidence of erythema36 and cutaneous toxicity37,38, a reduction in the rate of wet desquamation39, and better control of symptoms such as pain, tenderness, itching and local burning40. Patients who used Hydrofilm® (polyurethane film) had a lower RDTE score, indicating
protection against progression to more severe forms of RDTE, less erythema, itching
and pain in irradiated breasts after conservative surgical treatment41.
Cavilon® barrier cream prevented the appearance of wet desquamation at the end of
radiotherapy exclusively in the subgroup of mastectomized patients, and this benefit
was not observed in the 8 to 10 weeks post-radiotherapy follow-up42. In addition, its use does not reduce pain and pruritus or delay progression to RDTE
grade 243. Silicone gel (XtrataXRT®) was evaluated in a pilot study with 49 patients,
and no benefits were observed in the prevention of RDTE44.
Hyaluronic acid
Hyaluronic acid in different presentations as gel, serum or cream was evaluated in
five studies, totaling 422 patients. In none of the studies, there was any benefit
from the application of this intervention14,21,45,46,47. Topical hyaluronic acid did not prevent the onset or progression of RDTE, in addition
to potentially worsening skin toxicity in patients who used it46.
Silver-impregnated film
Silver-impregnated film was evaluated in RCT with 196 patients undergoing breast-conserving
surgery and adjuvant radiotherapy. The results obtained were negative for both preventions
of wet desquamation in the inframammary fold and relief of pain and burning48. On the other hand, the application of 1% silver sulfadiazine three times a day during
the radiotherapy period and up to 7 days after its completion resulted in lower scores
on the RTOG score, indicating a protective effect against the onset of moderate and
severe forms of RDTE in mastectomized patients49.
Others
This group comprises 11 studies: five RCTs, two non-randomized clinical trials, one
case series, two cohort studies and one case-control study. Doubleblind RCTs that
evaluated Aquafor® (panthenol and glycerin), Biafine RE® (trolamine), RadiaCare®50 and HPR Plus® (free fatty acids + ceramides + hyaluronic acid)11 did not observe benefits from the topical use of these substances. The unblinded
RCT with 278 patients with RDTE grades 1-2 randomized to topical treatment with Hydrosorb®
(hydrogel) was also negative51.
The application of Hirudoid® from 14 days after the beginning of radiotherapy until
3 months after its completion promoted less desquamation and greater skin hydration
in the period of 2 and 4 weeks after the beginning of adjuvant therapy, with no difference
at 3 months, as evidenced by the analysis of the corneometry of the breasts of patients
submitted to breast-conserving surgery, in an unblinded and nonplacebo- controlled
RCT52.
Studies with less evidence indicate some benefits in sucralfate gel 25% (Skincol®)53,54, hydroactive colloid gel (Flamigel®)55,56, urea lotion 3%57 and various commercial formulations21.
DISCUSSION
In this integrative review, 48 primary studies were identified evaluating topical
therapies for the prevention or treatment of RDTE, which were grouped into seven categories.
76% (13/17) of the articles that evaluated herbal medicines found no benefits from
this intervention, ten RCT10,11,12,13,14,15,16,17,18,19. Furthermore, studies with positive results have important methodological limitations,
as they are not blinded, controlled or randomized, which determines a high risk of
bias24,25,26. Similarly, the evidence favoring 3% sodium pentaborate pentahydrate gel is still
limited23.
It is concluded that there is sufficient scientific evidence to contraindicate the
use of most topical herbal formulations in the management of RDTE of the breasts.
Such findings agree with those reported in a study published in 2012 that critically
evaluated published systematic reviews on the management of RDTE and concluded that
topical agents based on Aloe vera and Calendula, among others, are ineffective58.
Positive results with the use of melatonin-based cream (Praevoskin®) and 1% silver
sulfadiazine need confirmation in studies with larger series, as scored by the authors27; or in studies with better methodological design regarding the use of placebo in
the control group and efficiency of blinding49.
Topical corticosteroids have been extensively investigated in RCTs over the last 10
years, building solid evidence from double-blind, placebo-controlled studies favoring
0.1% mometasone furoate and 17-betamethasone valerate30,31,34,35. These findings corroborate the results of a systematic review comprising six RCTs
published in 2013: a meta-analysis of five RCTs showed that the risk of wet desquamation
is 2.5 times lower with topical corticosteroids. A lower mean RDTE score was also
evidenced; however, the heterogeneity between the studies did not allow a metaanalysis
to be carried out for this outcome59.
In the review mentioned above, the authors emphasized that future studies should investigate
which topical corticosteroid would be most effective in managing RDTE. In the present
review, we observed that high (17-betamethasone valerate)34,35 and medium (0.1% mometasone furoate)30,31 steroids were beneficial, whereas no benefits were observed from topical hydrocortisone
1 %, a low-potency corticosteroid33.
The benefit of using silicone barrier films (Mepitel®/MepilexLite®) or polyurethane
(Hydrofilm®) is based on the results of RCTs with a restricted series (n<100)36,37,38,39,40,41. Furthermore, the risk of observational bias cannot be ruled out due to the absence
of blinding in most studies. On the other hand, Cavilon® barrier cream showed a limited
and transient benefit in preventing wet peeling42. In contrast, silicone gel reduced the incidence of erythema and hyperchromia (secondary
outcomes) without changing the severity of RDTE, which was the primary outcome of
the study by Ahn et al.44.
Formulations based on hyaluronic acid14,21,45,46,47, silver-impregnated films48, Aquafor®50, Biafine RE®50, RadiaCare®50, HPR Plus®11 and Hydrosorb®51 were evaluated in RCT and proved to be ineffective in the management of RDTE.
Hirudoid® promoted greater skin hydration, assessed by corneometry, up to 4 weeks
after the end of adjuvant RT in patients undergoing conservative surgery. It also
improved xerosis and skin scaling without changing the degree of erythema and local
pruritus52. Thus, the evidence for the indication of Hirudoid® in managing RDTE is still limited.
The positive results reported with the use of 1% silver sulfadiazine49, 25% sucralfate gel53,54, hydroactive colloid gel (Flamigel®)55,56, 3% urea lotion57 and commercial formulations such as Neoviderm® and Ixoderm® 21, do not come from
placebo-controlled RCTs. Thus, such benefits should be carefully evaluated, as the
limitations inherent to the methodology of these studies do not allow inferences about
the effectiveness of these substances in the management of RDTE.
This integrative review has limitations resulting from the evaluation period restricted
to the last 10 years and from exclusively contemplating articles published in journals
indexed in the three predetermined languages. However, previously published reviews
that considered the literature prior to 2010 concluded that the available evidence
regarding topical therapies for RDTE was insufficient, heterogeneous and, therefore,
a greater number of better quality studies were needed58,60,61.
The present study updated the literature related to the topic, clarified questions
raised by previous reviews, and critically evaluated the scientific evidence supporting
the indication or contraindication of topical therapies available for the management
of RDTE of the breasts.
CONCLUSION
For the prevention of breast RDTE, there is sufficient scientific evidence from good
quality randomized clinical trials to support the indication of topical corticosteroids,
mometasone furoate 0.1% and 17-betamethasone valerate. Barrier films such as Mepitel®,
Mepilex Lite® and Hydrofilm® have also been shown to be beneficial.
On the other hand, topical hyaluronic acid formulations, Aloe barbadensis extract, Centella Asiatica 7%, Cucumis sativus 20%, Thunbergia laurifolia, Boswellia serrata 2%, Calendula officinalis cream 5 or 10%, silver-based films, curcumin (PsoriaGold®), HPR plus® cream, 0.25%
beta-sitosterol ointment (Mebo®) and Biafine RE® (trolamine) were shown to be ineffective
in the management of RDTE of the breasts. Thus, the available evidence contraindicates
such substances’ use in managing RDTE.
Sodium pentaborate pentahydrate gel 3%, Praevoskin® (melatonin cream), Leviaderm®
(silymarin 0.25%), Cavilon®, silver sulfadiazine 1% and Hirudoid® (mucopolysaccharide
polysulfate 5mg/g) showed positive results in the management of breast RDTE in clinical
trials with limited series and/or of lower methodological quality. Although promising,
such substances need additional studies proving their effectiveness.
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1. Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo,
SP, Brazil.
2. Departamento de Dermatologia, Faculdade de Medicina do ABC, São Paulo, SP, Brazil.
Corresponding author: Mariana Alcantara Rodrigues de Moraes Alameda dos Maracatins, 426, Conj. 311, Moema, São Paulo, SP, Brazil Zip Code: 04089-000
E-mail: mari74.alcantara@gmail.com
Article received: July 01, 2021.
Article accepted: December 13, 2021.
Conflicts of interest: none.
Institution: Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São
Paulo, SP, Brazil.
