Plant and Herbal Extracts as Ingredients of Topical Agents in the Prevention and Treatment Radiodermatitis: A Systematic Literature Review

: Background: The use of herbal extracts as the source of antioxidant substances capable of neutralizing free radicals and providing protection from ionizing radiation appears to be an alternative therapy for radiodermatitis. As concerns the prevention and treatment of side effects, a lot of recommendations are based on proper experience of radiotherapy centers. We summarize recent research aiming at reducing radiation-induced skin injuries by use of proper skin care, using topical preparations with herbal extracts including onco-cosmetics. Methods: This article is limited to a critical analysis of scientiﬁc and professional literature. It concerns preparations in different physicochemical forms, e.g., gels, emulsions, ointments. We stress the connection between the type of applied skin care (type of preparation, its composition, the dose), the properties of the herbal extract and the evaluation of its efﬁciency in preventing and treating radiation reaction on skin. Conclusions: Herbal extracts can be added to recipes because they are part of a category of cosmeceutical supplements and can be introduced into preparations without prescription. The effectiveness evaluation for herbal extracts in radiotherapy is not an easy task since there are no strict guidelines. Studies should be preceded by the analysis of herbal extracts and recipe in terms of physicochemical, dermatological and performance characteristics.


Introduction
Radiotherapy is a treatment method using ionizing radiation (most frequently X rays) applied in oncology for treatment of tumors and for relieving the pain related to the disseminated tumor process [1]. Its purpose is to stop the growth of the tumor tissue while at the same time preserving the healthy tissue surrounding the tumor. High frequency waves used during treatment cause the electron to be knocked out of the atom orbit which in turn leads to tissues' ionization. Moreover, free electrons lead to the creation of free radicals and peroxides causing negative changes in the DNA, proteins and cellular membranes [2,3]. As concerns free electrons, the damage occurs as a consequence of direct effect, whereas we talk about indirect effect when the damage to the DNA structure is caused by free radicals. Most of the damages occur as indirect effect. In any case, for 6-8 h after the radiation, the enzymes can repair part of the damages [4,5]. The necessity of repeating the radiation sessions leads to the damage of the defensive systems responsible for removing free radicals. In case of large damage, repair may not be successfully completed and cells die by apoptosis. Even if the normal cell function is restored, their incomplete reconstruction causes permanent changes or mutations leading to cells dysfunction [4,6,7].
Among general side effects of radiotherapy, the following examples can be mentioned: general weakness, lack of appetite, decline in activity, changes in bold parameters, postradiation skin reaction, hair loss, mucosal reactions in the mouth, throat, larynx and nasal It is estimated that even 95% of patients subjected to radiation treatment experience radiodermatitis [4,6,19]. Observed post-radiation skin reactions and their complications have a severe impact on a patient's organism, and may cause countless complications including treatment delay, lowering of the quality of life (physical and psychological pain) or esthetic effects [8,15,18].
Appropriate preventive actions can be applied to improve the quality of life of patients treated for cancer. These therapeutic strategies can be divided in four categories: physical therapy, external-use dressing/cream, biological therapy and surgical reconstruction [4,11]. Properly conducted preventive actions also protect patient's skin during radiotherapy from additional injuries, irritation or UV radiation [4,16,18,20,21].

Skin Care during Radiotherapy-Preventive Measures for Radiodermatitis
Skin care during radiotherapy should be properly adapted to patient's needs. The purpose of a normal care therapy is to ensure the skin is clean, which will facilitate its healing afterwards, but also bring comfort and relief to the irritated skin, reduce pain and protect the skin against injuries, and prevent and fight infections [11,15]. Therefore, the skin care plan should include gentle cleansing, moisturizing and regeneration [11,12,[22][23][24]. What is also important in skin care is the protection against UV radiation, appropriate clothing and appropriate diet [8,25]. There is a group of cosmetics available on the market which are dedicated to oncology patients, they are called cosmeceuticals and more precisely onco-cosmetics [11,12,[22][23][24].
Products used for skin care and treatment during radiotherapy can be classified according to their physicochemical form ( Table 2) and their purpose (Table 3). According to MASCC directives, preventive use of steroids to be applied topically prevents and heals radiation dermatitis -there is no standard for the type of topical steroid to be used in the radiation oncology population. The concentration, frequency, and duration of steroid applications vary by institution. Long use of steroids is not indicated because of side effects. Steroid preparations are used together with emollients Mometasone furoate, hydrocortisone [30] Washing (cleansing) Help remove contaminants such as dirt, perspiration, oil, dead skin cells form the skin within the treatment area, supports cleansing, reduces potential bacterial and biological burden at the treatment site Soaps, synthetic detergents Because of its high pH, soap disturbs the hydro-lipid balance of the skin which might lead to irritations and bacterial overgrowth Synthetic detergents do not contain soap, they are based on surfactants, they are neutral or slightly acidic. More strongly recommended for the therapy of oncology patients Some soaps contain additive antibacterial substances, they also contain humectants additional oils and/or lipids to prevent skin dryness Synthetic detergents also contain free fatty acids, lipids, proteins, preserving the natural epidermal barrier [30]

Sisnfectant and antiinfective
Cleansing aids in decreasing potential bacterial and bio burden on the treatment site (especially dry and exfoliating) Solutions, ointments, creams, powder forms Antibacterial and antifungal preparations for local application are active in the application zone with a minimal systemic absorption Chlorhexidine gluconate, clotrimazole, miconazole, nystatin, bacitracin, mupirocin, silver sulfadiazine cream [30,36,37] Dessicants and astringent agents  [30,38]

Barrier measures
Protect the skin against mechanical damage, abrasion by clothes or other parts of the skin. Reduces skin reaction severity Cremes, ointments, liquids, protective films Reduce injuries, keep moisture in intact skin and hence the limit potential friction and irradiated skin reactions, thereby reducing radiation injury. Reduction in frequency and duration of moist desquamation.

Active Substances in Skin Care Preparations after Radiotherapy
In case of a strong radiation reaction, skin care alone after radiotherapy may be insufficient. In such cases patients receive treatment by topical glucocorticosteroids for their anti-inflammatory action, special dressings and antibiotics [18,30]. Despite general use of steroids and some chemical-containing ointments, e.g., trolamine and biaffine, their prolonged use may cause serious side effects [2].
The main factors that damage skin are the free radicals originating from irradiated water molecules and from granulocytes in the inflammation area ( [49]. Hence, the use of antioxidant substances including herbal extracts containing antioxidants, capable of neutralizing free radicals and providing protection from ionizing radiation appears as an alternative therapy for radiodermatitis [18,50]. Studies of radioprotective action of herbal extracts components are of immense use because in addition to protecting the normal tissue, they will also permit the use of higher doses of radiation to obtain better cancer control and possible cure. Unfortunately, radioprotective action of many of the substances is limited. These substances possess inadequate clinical application principally due to their inherent systemic toxicity at their optimal protective concentrations [51].
Despite this, herbal extracts are applied in skin care and treatment during radiotherapy. The first research direction concerns their application as diet supplement and as drugs administered either orally or intraperitoneally where they demonstrate radioprotective systemic action. Not only do they act as antioxidants, but they also show a range of beneficial biologic properties such as anti-inflammatory, antiemetic or antibacterial effects which contribute to improvements of patients' quality of life [52][53][54][55][56]. Another research concerns their introduction into medicated preparations and cosmetics in form of creams, ointments and gels. Applied topically, they act as antioxidants, they reduce irritations and redness, they help heal and protect from UV radiations.
The source of plant materials used for this purpose include crops and harvest from natural stands. As the content of active substances in plants of a given species varies and depends on many factors, they are subject to the process of standardization from processing (collection, drying, stabilization, storage) to clinical study in the process of product development. Standardization is based on the pharmacopoeia standards of a given country or on the basis of quality standards for a given raw material or preparation. The standardized raw material contains a strictly defined amount of ingredients responsible for the therapeutic effect.
Some of the above-mentioned preparations are specifically intended for skin care after radiotherapy whereas others are well known for their therapeutic actions, namely anti-inflammatory, antioxidant, and healing. The research of safe and efficient preparations containing herbal extracts is subject to R&D research and clinical trials.

Scope
The first attempt to gather all the information concerning the application and the role of herbal extracts in prevention and treatment of radiodermatitis was carried out by Kalekhan et al. [57] and Heydariard et al. [58]. Heydariard and co-workers [58] focused on collecting data from randomized control trials, which compared herbal compounds against a standard medication or placebo treatment or prevention of radiodermatitis. Five dimensions were evaluated: bias related to the errors in the randomization process, bias due to not receiving the desired treatment, bias due to missing data related to the outcome, bias in evaluating and measuring the outcome variables and incomplete or selective reporting outcomes. Kalekhan et al. [57] summarizes clinical observations on the prevention of radiodermatitis by plant products such as: Adlay bran, Aloe vera, Calendula officinalis, Cucumis sativus, honey, Achillea millefolium, Matricaria chamomilla, olive oil and green tea (containing epigallocatechin-3-gallate) and some of polyherbal creams.
As concerns the prevention and treatment of side effects, a lot of recommendations are based on proper experience of radiotherapy centers [23]. That is why in our literature review we summarize recent research aiming at reducing radiation-induced skin injuries by use of proper skin care, using topical preparations with herbal extracts. Our literature review concerns preparations in different physicochemical forms, e.g., gels, emulsions (creams, lotions), ointments. We stress the connection between the type of applied skin care (type of preparation, its composition, the dose), the properties of the herbal extract and the evaluation of its efficiency in preventing and treating radiation reaction on skin.

Methods
This overview article is limited to a critical analysis of scientific and professional literature (included guidelines, clinical and preclinical studies and reports of clinical trials). Patents and articles in a language other than English were excluded. Animal research and basic laboratory-based research are included. In order to prepare a literature review, search engines such as PubMed, MEDLINE, Scopus, NCBI, Google Scholar, Google Books, and ResearchGate were used. Date of access: 15 December 2021 and revisited on 20 April 2022.
Main search terms chosen were: radiodermatitis treatment; topical agents in treatment radiodermatitis; herbal in radiotherapy; topical antioxidants in radiodermatitis; skin care of patients undergoing radiotherapy; herbal creams; plant extract in prevention of radiodermatitis; Aloe vera extract; Achillea millefolium extract; Azadirachta indica extract; Boswellia serrata extract; Calendula officinalis extract; Centella asiatica extract; Chamomilla recutita extract; Cucumis sativus extract; Glycyrrhiza glabra extract; Green Tea extract; Silymarin extract, Turmeric curcuma longa extract; Nigella sativa extract; Ocimum sanctum extract; Angelica gigas extract; Lithospermum radix extract; Annona muricata extract; Camellia sinensis extract; Hypercium perforatum extract; Thunbergia caurifolia. Relevant research was systematically categorized by name of plant and appraised according to study design. To exclude risk of bias, two authors independently collected and evaluated quality of all selected data and extracted data on recipe and form product, its applications, purpose of study, subjects, methodology, and key findings. Evaluation was based on reviewers' knowledge. Reference lists of relevant articles were reviewed to identify further studies. The review was performed in accordance with PRISMA guideline. The review was not registered. The protocol was not prepared. Automation tools were not used in the process.

Results
The study flowchart for the selection of the relevant research is presented in Figure 1. A total of 327 articles were evaluated, of which 34 are included in review. Summaries of analyzed research are provided in Table 4. Plant species from which the extract was obtained were sorted in alphabetical order.  At the end of the third week, the group receiving Achillea millefolium cream showed milder skin complications than other groups. At the end of treatment, rate of skin complications in groups receiving herbal drugs was lower than placebo group but it was not statistically significant. The results of this study did not present a significant difference between Glycyrrhiza glabra, Achillea millefolium L. and placebo on preventing RD.
According to Author, this is the first study that has evaluated the possible protective effect of these herbal drugs against radiotherapy induced skin dermatitis. Achillea millefolium L., especially at lower doses of radiation, might decrease radiation induced dermatitis. There were observed only two cases with grade 1 dermatitis at the end of third week in this group, so more research is required to verify this finding. [59]

gel ointment
To determine: whether a gel with acemannan extracted from aloe leaves affects the severity of ARSR if so, whether other commercially products (personal lubricating jelly and healing ointment) have similar effect and when the gel with extract should be applied for maximum effect. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. Groups of mice (gel treated, untreated, jelly-treated, ointment-treated) The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to the 35th day after irradiation. EDS o values, and 95% confidence limits were also obtained. The gel was applied daily to the irradiated area beginning immediately after irradiation. To determine timing of application for best effect, gel was applied beginning on day −7, 0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The average peak skin reactions of gel-treated mice were lower than those of the untreated mice at all radiation doses tested. The EDS o values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the EDSo values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received gel for at least 2 weeks beginning immediately after irradiation.
In this case, Aloe vera leaves were the raw material for extraction of Acemannan. Healing ointment contained the essence of chamomile. The authors of the study tried to define the time for starting the application of the preparation.

Aloe vera L. Burman gel
To determine effectiveness aloe vera gel for radiation-induced skin reactions. BC patients undergoing RT to breast and/or chest wall, minimum field 10 × 10 cm and minimum dose 50c Gy. RCT. Two groups: aloe vera gel or PL gel-first phase of trial, aloe vera gel or no treatment-second phase of trial. State of the skin was evaluated-patients self-graded skin reactions and clinical assessment by physician. Rated: severity, time of occurrence and duration of severe dermatitis. The evaluation was carried out once a week. Gel (aloe vera or placebo) was applied to the chest wall by the patient twice a day, starting 3 days within of radiation initiation. Usual skin-care (soap) advice were recommended.
No detailed information available concerning the products recipe and their quality control Aloe vera gel-98% aloe gel plus 2% inert gel for consistency.
Aloe vera gel was not effective. The dermatitis was less severe than expected. Allergic reactions were observed among patients both in groups using aloe vera gel and placebo gel.  Aloe vera L. Burman

gel cream
To determine if aloe vera gel is beneficial in reducing skin side-effects of RT when compared with aqueous cream. Women with BC undergoing RT post-lumpectomy or partial mastectomy. RCT. Two group: aloe vera gel and topical aqueous cream. Evaluation of the skin by nurse-limitation of side-effects such as erythema, pain, itching, dry desquamation, moist desquamation. Standard care was recommended on top of preparations application. Topical products were applied by patients three times a day after treatment and for 2 weeks after completing care. Weekly skin assessments were performed by nursing staff.
No information available concerning the products recipe and their quality control.
Aqueous cream was significantly better than aloe vera gel in reducing dry desquamation and treatment-related pain. Allergic reactions were observed in patients using both gel and cream.
No information available to objectively evaluate the efficiency of the study (including the dose of radiation administered to patients).   APP cream improves skin comfort variables such as: dry, soft, feels good, rough, smooth and dermatologic variables: dryness, erythema and peely as compared with aloe vera gel (statistically significant differences).
APP cream is more effective in prevention and treatment of RD. Grouped CTC scores were supportive of APP cream. In comparing the first and last assessments, two dermatologic variables, dryness and peely, favored APP cream.

cream powder
Test the efficacy of quality-tested Aloe vera extract in reducing the severity of radiation-induced skin injury. Examine the effect of a moist cream versus a dry powder skin care regimen. RCT. Patients with BC, previous mastectomy or segmental resection.
RT (45-50 Gy). Acute skin toxicity was scored weekly and after treatment at weeks 1, 2, and 4 using a modified 10-point Catterall scale. The patients scored their symptom severity using a 6-point Likert scale and kept an acute phase diary. Standard radiation skin care guidelines were complied. The patients apply nonmetallic baby powder or cornstarch to the irradiated intact skin during the treatment course followed by 1 month of Glaxal base cream twice daily. If they developed moist desquamation, they were advised to discontinue the powder. Patients apply approximately 2.5 cm 3 of cream to the irradiated skin, 3 times daily (avoid application within 3 h of radiation) throughout the course of radiation and for 1 month after radiation. Treatment of moist desquamation and other skin reactions, such as infection, was according to each physician's pattern of practice. Any prescribed treatment was to be applied 30 min before the use of the study creams.
Placebo cream contain: Aquatrix II, Lexamul 56, Methylparaben, Dimethicone, Isopropyl Myristate, Propylene Glycol, Cetyl Alcohol, Stearic acid, triethanolamine. The aloe cream formulation was 30 mg of the processed aloe (1000-5000 MW fraction) per 100 cm 3 of placebo cream. This represents the highest concentration possible without causing cream demulsification and is relatively equivalent to 50 mg of the 1000 to 5000 MW fraction of unprocessed fresh leaf gel extract.
The aloe formulation did not reduce acute skin toxicity or symptom severity. Study speaks in favor of dry care instead of introducing herbal extracts into creams or applying creams only.
Were excluded from the study people with confirmed allergy to Aloe vera. Placebo cream was chosen for its ability to penetrate the outermost skin layers and therefore to theoretically enable absorption of the aloe elemental components. The study included also the analysis of the extract itself introduced into the recipe of the cream. Such as: murine bioassay testing under the supervision of 1 of us (F.S.). The assay testing was conducted to determine whether the aloe oligosaccharides that prevent ultraviolet B (UVB)-induced immune suppression of T-cell-mediated immune responses were active in this study. The mechanism of aloe skin protection is unknown, and this element might be necessary for aloe extract to be effective in reducing RSR severity. [65]

Aloe vera L. Burman lotion
Evaluation of aloe vera lotion for prevention of RD. CT. Patients with a prescription of RT to a minimum dose of 40 Gy, were treatment area could be divided into two symmetrical halves. The grade of dermatitis in each half was recorded (according to RTOG) weekly until 4 weeks after the end of radiotherapy.
In the case of symptomatic dermatitis, topical corticosteroids were prescribed to the patients to use on the entire treatment area. Lotion were use twice daily from the beginning of treatment until 2 weeks after the end of RT, with no medication to be used on the other half.
Age and radiation field size had a significant effect on the grade of dermatitis. The prophylactic use of Aloe vera reduces the intensity of radiation induced dermatitis. The effect was more evident in patients undergoing radiotherapy with larger treatment field and higher doses of radiation.
The study verified the quantity (dose) of the lotion used. [66] Aloe vera L. Burman

gel soap
Determine whether the use of mild soap and aloe vera gel versus mild soap alone would decrease the incidence of skin reactions in patients undergoing RT. RCT. Oncological patients qualified for the RT. Group of patients applying mild soap and additional aloe vera gel and second group-control treatment used only soap. RTOG Acute Radiation Morbidity scale assessed weekly by physician or nurse. Unscented soap plus aloe vera gel or soap was applied liberally to the affected area daily after the RT in case of gel reapplied through day. Gel was washed off before RT. Standard care was recommended.
No information available concerning the composition, the quality assessment of the products. Gel without other active components Aloe vera gel seemed to offer a protective effect over soap alone when the cumulative dose increased over time. At low cumulative dose levels no difference existed in the effect of adding aloe to soap regimen.
Soap is not a typical product to compare. Besides, the differences in treatment depended on the radiation doses applied and those were different for the control group and for the group using gel with aloe and soap which leads to conflicting results.

gel cream
Compare a anionic phospholipid-based (APP) cream and an aloe vera-based gel in the prevention and treatment of radiation dermatitis RCT. Pediatric patients treated by radiotherapy (dose of 23.4 Gy). Control group use APP cream. Subject skin comfort and dermatologic assessments were conducted before and weekly during treatment. Photography was performed at each evaluation time point and patients were seen 4-6 weeks after the completion of RT. CTC was used. Aloe vera-based gel or APP cream were applied symmetrically, once a day by nurse daily next to the radiation area after RT.
No information available concerning the composition and the quality assessment of the products.
APP-based cream showed a statistically significant advantage over aloe vera gel for skin comfort and dermatological assessment variables.
Cream reduced dryness, redness, desquamation. No changes in CTC score before and after the treatment.
Complete data unavailable for objective evaluation of the study. [11,63] Aloe vera L. Burman

cream oil
To evaluate the efficacy of topical application of an aloe vera-based cream (AVC) for the prevention of ionizing RD.
Clinical study. Head and neck cancer patients requiring therapeutic radiation treatment (dose >62 Gy). Patients were treated with AVC or Johnson Baby Oil (JBO). Acute skin reaction was monitored and classified according to RTOG four-point rating scale on a weekly basis. The preparation was applied 5 times per day at defined timespans after RT. During the study it was recommended not to use other preparations. When moist desquamation occurred, the topical application of JBO or ACV was discontinued topically and continued on the remaining skin area.
AVC and JBO are is market products Composition unavailable. Application: 5 cm 3 JBO and 5 g AVC.
There was a statistically significant delay in the incidence of dermatitis at week three in the AVC application group. Application of AVC reduced the incidence of Grade 1, 2, and 3 dermatitis at subsequent time points, while Grade 4 dermatitis was not seen in either cohort. Continued application of AVC two weeks after the completion of RT was effective in reducing the average grade of dermatitis and was statistically significant.
This research and research with [67] indicate the usefulness of Aloe vera in delaying and mitigating dermatitis and promoting recovery. The action of this preparation is linked to the antioxidant properties of the Aloe vera.
[71] The extent of erythema developed differed between patients. Some of them developed more severe erythema; however, no one had to stop their radiation treatment because of severe skin reactions. No significant median differences were observed between the pairs no lotion-Essex, no lotion-Aloe vera and Essex-Aloe vera for any of the techniques tested.
As indicated in manuscript Essex lotion is a commonly used lotion that is not registered as a medical product and therefore there are no specific recommendations for its use. [72] Aloe vera L. Burman gel Whether the adjunctive use of aloe vera gel might reduce the prevalence and/or severity of radiotherapy induced dermatitis. Randomized study patients with newly diagnosed BC (total dose 50 Gy). One group received aloe vera gel. Second group no treatment during RT. The patients were examined weekly by 2 physicians and dermatitis grade was registered (according ARMSC). In case of patients with second or higher degree dermatitis, additional local or systemic treatment such as antibiotics, corticosteroid or analgesics were applied. Aloe vera gel was applied twice a day in at least six hour intervals with a thickness of 1-2 mm on the radiation therapy field.
Aloe vera gel contain 1% additive such as: pectin, vitamin C and Natamycin After 2 weeks first dermatitis was found among patients of both groups. Comparing the time of occurrence of dermatitis and their degree, no significant statistic difference were observed in both groups. Aloe vera gel did not show positive effect on prevalence or severity of radiation dermatitis in this study. First group-patients received Beclomethasone cream. Second group received herbal paste. To assess radiation-induced reaction RTOG score were applied and group I versus group II compered. EORTC QLC-C30 was used for QoL assessment. Preparations were topically applied from the day-1 of radiotherapy till 4-weeks after completion of RT.
Paste was properly mixed with 100 g of Aloe vera juice and fresh Ocimum sanctum leaves, Azadirachta indica leaves (50 g each) and Curcuma longa roots (5 g). Herbal plants have been grounded up before mixing.
During the timespans of the study, i.e., after the 4th, 5th, 7th week and also after 6 months, skin reactions were less severe within the group using herbal preparation. On evaluating EORTC QLC-C30, on functional scale, physical, emotional, cognitive and role functioning deteriorated in Group 1 patients (except social functioning), while in Group patients all these modalities showed improvement at 6 months post-treatment. Evaluation on symptom scale revealed that fatigue, pain, dyspnea, appetite loss and insomnia got worsened in Beclomethasone group, except for diarrhea, constipation and nausea or vomiting, while in herbal pasta group patients, all 9 symptoms showed improvement 6 months after of completion of treatment.
Aloe vera was the basis for the powdered plants. Patients known to be allergic to ingredients of herbal paste or with allergy to steroids were excluded from study. No information available on the Gy dose applied to patients. [74,75]  ointment Efficiency and security evaluation of adjuvant application of Jaungo (JUG) for RD in comparison with general supportive care (GSC). RTC. Women with unilateral BC, after breast conservation surgery, undergoing RT, (total dose >45 Gy). Both groups will be subjected to GSC, but only the JUG group participants will apply adjuvant JUG ointment on the irradiated skin, twice a day (not applied within 4 h of daily RT). Treatment started at onset of RT and continued until 4 weeks after RT was completed or until radiation dermatitis subsided. Assessment of incidence rate of RD using the RTOG for toxicity gradation of 2 or more. Onset and duration of RD, and maximum pain score were also evaluated.
GSC-skin clean and dry by gentle washing with neutral pH soap and patting with soft towel. No prophylactic creams or lotions for radiation dermatitis were allowed to either group.
JUG reduced the incidence of grade >2 and grade >3 RD in comparison with GSC. Delayed the onset of grade 2 dermatitis in terms of time onset of grade 3 and duration dermatitis and maximum pain score showed results comparable to those achieved with GSC, no adverse effect was observed.
Because of a low number of patients (29), the authors recommended further studies with a bigger sample of people.
Those studies are currently ongoing [76] and [77]. In this article market product (composition unavailable) was compared with emulsion w/o (X-derm)-composition unavailable. The efficiency was assessed by defining the improvement degree-excellent (more than 80%), good (more than 50%), fair (less than 50%), and no effect (less than 30%). In comparison people were treated by corticosteroid.
Ointment is effective in treatment of scalp dermatitis caused by radiation and dermal complications induced by molecular target drugs since favorable therapeutic effects were observed in all group of patients. Shiunko showed prominent analgesic effect in all cases which were not achieved in corticosteroid treatment but also promoted healing in areas eroded by radiations.
Ointment Shiunko is the JUG ointment JUG, the same as in the study [78].
In our document we only showed cases treated with this ointment and its positive effect. No information available on the group using placebo. [79]

Annona muricata L. cream
Investigate the protective effects of Annona muricata leaf polysaccharide (ALP) on radiation induced skin injuries by using in vitro and in vivo models. Normal human epidermal keratinocytes (NHEKs) irradiated cell using 137 Cs source in a Gammacell 40 Exactor. The dose rate used was 1 Gy/min. Performed cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nic-end labeling assay and annexin V/propidium iodide (PI) staining to detect apoptosis. Pro-inflammatory cytokines (level of TNF-IL-6, and IL-1ß in the cell culture supernatants) were measured using ELISA.
The mice were divided into five groups: (1) Normal group; (2) Irradiation + vehicle cream group; (3) Irradiation + 0.04% ALP (w/v) cream; (4) Irradiation + 0.2% ALP cream. The skin on the back was topically treated with 100 µL of vehicle or ALP cream for 7 days before and after irradiation. After treatment, mouse's skin was under histopathological observation.
In normal human epidermal keratinocytes (NHEKs), ALP treatments reduced irradiation-induced apoptosis by increasing antioxidant enzymes activities, including (SOD) and catalase. Furthermore, ALP treatments decreased levels of interleukin-1ß, nucleotide-binding domain and leucine-rich-repeat-containing family pyrin 3 (NLRP3), and cleavage of caspase-1 and caspase-3. The topical application of the ALP cream showed protective efficacy against irradiation exposure, including the reduction of epidermal thickening, as well as an increase in the number of apoptotic cells and antioxidant enzyme (SOD and catalase) activities in skin tissue. ALP can be potentially used to treat radiation-induced skin injuries.
To determine whether ALP protects gamma irradiationinduced cell death by regulating antioxidant enzymes and in flammasome complexes, Authors analyzed the intracellular antioxidant enzymes activity and levels of pro inflammator cytokines. Hence, they are ones of the first studies of antioxidant action. Defines the mechanism of action of polysaccharides isolated from the extract and, based on that, the action of the cream, not only clinical studies or skin observation. It is not clear if 2% is the concentration of the extract in the recipe or the concentration of boswellic acids extracted from Boswellia serrata-those acids have anti-inflammatory properties. B. serrata extract reduces skin reddening and irritation, they even out the color and sooth the skin.
According to the authors, further studies are necessary to compare with other topical preparations. [81]

Calendula officinalis L. ointment
Compare the effectiveness of calendula ointment with trolamine. Patients operated on for BC, received postoperative RT (2 Gy per session, five session per week). RTC. Two groups: 1st applied trolamine, 2nd calendula on the irradiated fields after each session. Occurrence of acute dermatitis of grade 2 or higher, occurrence of pain, the quantity of topical agent used, and patient satisfaction were investigated. Prognostic factors, including treatment modalities and patient characteristics, were also examined. Preparations were applied twice a day or more, depending on the occurrence of dermatitis and pain, until completion radiotherapy (not to use the agent 2 h or less before an irradiation session or before the treatment evaluation). Acute dermal toxicity was evaluated according to the RTOG scale at each irradiated volume. Pain was assessed each week on a 10-cm visual analog scale (VAS). No other prophylactic creams, lotions, or gels were allowed. Physicians can treat established dermatitis of grade 2 or higher and/or allergy as they considered appropriate.
Calendula ointment (market product) fabricated from a plant of the marigold family, Calendula officinalis. The digest is obtained by incubation at 75 • C in petroleum jelly to extract the liposoluble components of the plant.
The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% vs. 63%) with the use of calendula ointment than with trolamine. Patients receiving calendula has less frequent interruption of RT and significantly reduced radiation induced pain.
Trolamine is considered in many medical institutions as reference topical agent, Calendula ointment was more difficult to apply, but self-assessed satisfaction was greater.  Statistically significant evidence that the proportion of radiodermatitis grade 2 in EFA group is higher than Calendula group. Lower risk of developing radiodermatitis grade 1, form experimental group, it makes the usage of Calendula oil more effective.
Excluded patients with allergic reaction in the use of one of the research products (EFA or Calendula officinalis). Due to the physicochemical form of the products, they were applied to gauze.

Calendula officinalis L. ointment
Evaluation of anti-inflammatory action and of the impact on ionizing radiation induced skin toxicity of the extract from Calendula officinalis (CO) and Ching Wan Hung (CWH)-ointment. SKH-hr1 hairless mice (10 Gy/day for 4 days). Skin toxicity and inflammatory factors (Serum interleukin (IL)-1α monocyte, chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G-CSF)) were evaluated at multiple time points up to15 days post-radiation. Mice were evaluated every 2 days following IR with and without topical treatment of CO and CWH. IR-induced skin reactions, erythema, blood vessel dilation, and crust/scaling, were noted.
Gross assessment of early radiation dermatitis, erythema, edema, dyspigmentation, desquamation, exudation, and ulceration, was conducted using the dermatoscope. Skin toxicity was evaluated and scored as either 0 (no visible lesion), 1 (moderate lesion), or 2 (severe lesion), for both erythema and blood vessel dilation.
Both CO and CWH significantly inhibited IR-induced MCP1 KC and G-CSF. IR-induced erythema and blood vessel dilation were significantly reduced by CWH but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL-1α, MCP1 and vascular endothelial growth factor. There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema.
Looking at the composition, it is not surprising that the preparation with higher quantity of active substances showed better result. The same market product as in Pommier study [82]. [87]

Centella asiatica L. cream
Attempted to determine whether prophylactic treatment with herbal creams as well as a commercial moisturizing cream could reduce acute skin reaction RCT. BC patients undergoing RT (total physical dose 40-5-Gy). 5 different groups: 1-no treatment (standard care, no creams or substances). Other groups using creams containing respectively extracts from Centella asiatica L., Cucumis sativus L., Thunbergia laurifolia or using moisturizing market product (Johnson and Johnson). Participants' skin was evaluated by an oncologist-radiologist weekly up to one month after the irradiation in order to identify all kinds of dermatologic reaction (according to RTOG score). Satisfaction with the preparation was also evaluated (scale 1-5 with 5 being mostly satisfied and 1 being least). Creams were applied once a day after the first session of radiotherapy up to one month after the irradiation.
Centella asiatica 7% (w/w) Information on other components unavailable. They do not contain fragrance. Market creams available in Thailand.
Topical application of all herbal cream or the moisturizing cream could neither reduce the severity nor delay onset of dermatitis compared with no treatment group. Cucumis sativus cream was shown to help with skin recovery post-irradiation. Study authors advise to prophylactically use moisturizing preparations on the irradiated area of skin.
One clinical study which evaluated three plants Centella asiatica L., Cucumis sativus L., Thunbergia laurifolia. Before the study allergic tests were made for unwanted reaction to the extracts and the moisturizing cream. No statistical differences over time were seen between the groups on adverse events. Itching, burning and hyperpigmentation were more frequently reported in the urea group.
According to the Brazilian Health Surveillance Agency (Agęncia de Vigilância Sanitária-ANVISA), products made of Chamomile recutita do not require proof of safety because chamomile is already registered at the Brazilian Simplified Registry of Traditional Phytotherapic Products. The study in which the concentration of the active substance was defined before starting the comparative study. [89,90]  Topical application of all herbal cream or the moisturizing cream could neither reduce the severity nor delay onset of dermatitis compared with no treatment group. Cucumis sativus cream was shown to help with skin recovery post-irradiation. It is related to the high content of water and soothing properties reducing irritations and skin oedema in cucumber. Cucumber cream proved efficient in regeneration of irradiated skin which most probably is also linked to the presence of tannins and flavonoids.
One clinical study analyzing three plants: Centella asiatica L., Cucumis sativus L., Thunbergia laurifolia. Before the study there were allergic tests made to check on side effects of the extracts and moisturizing creams.
Cucumber has protective effects against both reactive oxygen species and reactive carbonyl species by free radical scavenging activity. [88] Glycyrrhiza glabra Torr.

(Licorice root)
cream The same as in Achillea milefolium L. research [59] The same as in Achillea milefolium L. research [59] The same as in Achillea milefolium L. research [59] The same as in Achillea milefolium L. research [59]  To explore the effect of topically-applied tea extracts on the duration of radiation-induced skin toxicity. Patients with head, neck or pelvis area cancer undergoing RT (daily fractions of 1.8-2.0 Gy). During the study, patients used standard skin care program which consisted of once-daily treatment with moisturizing creme. In case of erythema, the cream was applied 2-3 times and stopped with occurrence of moist desquamation. Green or black tea extracts were applied to the irradiated skin area with lesions of 2nd degree and higher (RTOG score) 3 times per day for 10 min from the occurrence of moist desquamation. Dermal toxicity was evaluated daily by the qualified medical personnel before each extract application. The disappearance of moist desquamation was considered as the end of the study. Tea extracts were compared for their ability to modulate IL-1ß, IL-6, IL-8, TNFα and PGE2 release from human monocytes. Effects of tea extracts on 26S proteasome function were also assessed and NF-κβ activity was monitored by EMSAs. Viability and radiation response of macrophages after exposure to tea extracts was measured by MTT assays.
Moisturizing cream-market preparation containing 3% of urea.
Tea extracts are effective for treatment of patients suffering from acute dermal toxicity caused by irradiation. Tea extracts supported the restitution of skin integrity, inhibited proteasome function and suppressed cytokine release. NF-κβ activity was altered by tea extracts in a complex, caspase dependent manner, which differed from the effects of epigallocatechin gallate. Analyzed tea extracts, as well as epigallocatechin-gallate, slightly protected macrophages from ionizing radiation. The molecular mechanisms underlying the beneficial effects are complex, and most likely not exclusively dependent on effects of tea polyphenols such as epigallocatechin-gallate. No difference between green and black tea in duration of grade 2+ skin reactions in patients treated for cancer of the head and neck region.
There is no information, if without the application of moisturizing cream the extracts effect on skin would be the same.
[91] 40 Gy/15 fractions). Data from these study were compared with 100 retrospectively collected matched data sets derived from hospital records. These routine medical care patients were treated according to the hospital treatment guidelines and recommendations of the SASRO. The assessments of ARSR Grades 1, 2, 3, and 4 were performed according to CTCAE. Lotion (0.4% CSNF) was applied 2x per day 7 days before RT-during RT on irradiated zones (but not directly before the RT), 4-8 weeks after RT if necessary. CSNF prophylactic gel (2.5%) was applied 1-2 h before each RT session on the day of irradiation. Irradiated zones were: thoracic and supraclavicular zones, front and back.
Composition unavailable. The only information available concerns the % of extract in the given form of preparation and that the extract is proprietary. Comparative preparations were various market preparations such as Excipial ® hydrolotion (oil-in-water emulsion containing urea), Bepanthol ® body lotion or Bepanthen ® cream (preparations contained dexpanthenol and sodium hyaluronate or sodium hyaluronate and silver sulfadiazine. The study showed that combined use of gel and CSNF balsam retarded the occurrence of ARSR ≥ G2 and can reduce the risk of moist desquamation of irradiated skin by 50%. The proportion of patients requiring rescue treatment during RT and follow-up was markedly higher in the control compared to the CSNF group (1% to 51% vs. 0% to 15%). CSNF gel and lotion were well tolerated both during and after RT.

Camellia Sinensis Nonfermentatum
Extract is potentially effective in healing skin irritation in women with breast cancer.
Comparative studies with the data from hospital files. The first study in which two types of skin care preparations were used, they contained the extract from a given plant but there was no comparison with the placebo group. According to Authors, preparations containing oils cannot be used directly before the RT because they can increase the risk of skin irritation following radiation concentration in tissues. The CSNF extract reduces oxidative stress and DNA damage, downregulates numerous factors related to apoptosis, inflammation, and carcinogenesis in experimental studies, and showed a similar protective effect for skin of healthy volunteers exposed to UV-light.
Patients undergoing RTor chemo radiotherapy for head and neck cancer (70 Gy/35 fractions (2 Gy daily). Medical evaluation consisted of a weekly clinical evaluation with a visual examination of the neck region skin performed by the physician in charge of the patient and a consequent physician-rated score of acute skin toxicity up to 90 day after end of treatment (according to RTOG/EORTC toxicity scale). Holoil ® product series treatment were started whenever bright erythema, moderate oedema or patchy moist desquamation were observed. For erythema and/or oedema gel preparation was employed. For patchy moist desquamation the oil preparation was administered. Holoil ® was used during all RT course and during follow up time, until acute skin toxicity recovery. Before the lesions appeared, patients received moisturizing cream. Holoil ® was applied on the bilateral neck 2-3 times a day, at least 3 h before treatment session. Other creams or cosmetic products in the irradiated area were prohibited.
No information available on the product composition (market products The maximum detected acute skin toxicity was Grade 1 in 7% of patients, Grade 2 in 68%, Grade 3 in 25%, while at the end of RT was Grade 0 in 3.5%, Grade 1 in 32%, Grade 2 in 61%, Grade 3 in 3.5%. G2 acute skin toxicity mainly started at weeks 4-5; G3 begun during weeks 5-6. Median times spent with G2 or G3 toxicity were 17.5 and 11 days. Time between maximum acute skin toxicity and complete skin recovery after RT was 27 days. Various physicochemical forms were used in the studies, depending on the radiodermatitis type: Holoil ® as gel (erythema and oedema) or oil formulation (moist desquamation). Patient's compliance was consistent, with no particular complaints or difficulties. Carrier neem oil itself has anti-inflammatory, antioxidant and regenerating properties. No information available on the concentration of Hypercium perforatum L. in products. According to Authors Holoil ® proved to be a safe and active option in the management of acute skin toxicity. A prophylactic effect in the prevention of moist desquamation may be hypothesized for hypericum and neem oil and need to be tested within a prospective controlled study. [94]

Nigela sativa L. gel
Evaluate the effectiveness of Nigella sativa L. extract on preventing the incidence of ARD. RCT. BC patients undergoing RT after breast surgery (minimum total prescribed dose, 50 Gy).
2 group: placebo and N. sativa 5% gel. The severity of ARD, the incidence of moist desquamation, worst experienced pain, and skin-related quality of life (SRQOL) scores were assessed weekly during RT. Preparations application: twice daily during RT period at least two hours before and after RT. After applying the gel, patients were asked to wait for at least 10 min before dressing and not to wash the affected area for at least 2 h.
Group of patients treated with the N. sativa gel developed ARD significantly less frequently compared to those who used the placebo. The incidence time of grade 2 and 3 dermatitis was prolonged significantly with N. sativa gel as compared to placebo (35 vs. 29 days and 42 vs. 40 days, respectively). Also occurrence of moist desquamation was delayed 37 vs. 33 days for N. sativa gel vs. placebo respectively. At week 3 the mean score of the worst pain that patients experienced in N. sativa gel was significantly lower than in placebo group. No significant effect on the SRQOL after application of N. sativa gel was observed.
Both extract and gels were obtained by the authors. Active substance in the isolated extract was Thymoquinone the concentration of which in gel was 0.01% Gels were also studied with respect to their microbiological purity and stability. Participants with known allergy or hypersensitivity to N. sativa or any ingredients of the gel were excluded from the study. [95] Silybum marianum (L.) Gaertner gel Investigate the efficacy of silymarin gel in prevention of RD. RCT. Patients with BC received placebo or silymarin gel on chest walk skin following modified radical mastectomy (total radiation dose of 50 Gy). RD severity was assessed weekly based on RTOG and NCI-CTCAE criteria radiodermatitis grading scale for 5 weeks. Preparations (half fingertip unit) applied daily starting at the first day of RT for 5 weeks.
1% silymarin gel Used in the recipe dry extract contain 80% active ingredient based on silymarin flavonolignans (including silybin, silychristin, silydianin, 2,3-dehydrosilybin, and 2,3-dihydrosilychristin). No information available on the remaining components for both placebo gel and silymarin gel The median NCI-CTCAE and RTOG scores were significantly lower in silymarin group at the end of the third to fifth weeks. The scores increased significantly in both placebo and silymarin groups during RT but there was a delay in RD development and progression in silymarin group. Prophylactic administration of silymarin gel could significantly reduce the severity of RD and delay its occurrence after 5 weeks of application (80% patients in this group remained asymptomatic). None of patients in silymarin group experienced grades higher than 1 during RT in contrast to placebo group were was patients with grade 2 and grade 3.
Were excluded from the study people with history of allergy to silymarin, history of autoimmune and connective tissue diseases, concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, and other immunosuppressive or antioxidant medications. Because Silymarin could reduce the severity of radiodermatitis the silymarin gel should be prescribe before the beginning of the RT. The authors of the study suggest that the silymarin 1% gel, and increasing the silymarin content of the gel may increase its efficacy in RD prevention.

Silybum marianum (L.) Gaertner
cream Silymarin-based cream (Leviaderm ® ) was tested in efficacy in prevention of RD comparison to standard of care (SOC). Patients with histologically documented diagnosis of BC were evaluated after breast-conserving surgery followed by RT with 50.4 Gy plus boost 9-16 Gy. Participants were documented consecutively before, during, and 4 weeks after the scheduled end of RT. The occurrence of side effects and adverse drug reactions were recorded unblinded by the medical staff of the department during the weekly clinical examinations. One group of patients were treated with the silymarin based cream, second group were documented receiving a panthenol-containing cream interventionally, if local skin lesions occurred. The acute skin reactions were classified according to the RTOG and VASscores.
SOC treatment consisting out of 5% dexpanthenol containing cream, which was applied as an interventional treatment to the affected breast skin after occurrence of the first signs of skin alterations (e.g., erythema) every day during RT and, thereafter, until skin recovered to normal. Silymarin-based cream was applied to the skin three times a day, 2 weeks before beginning RT, during RT, and 2 weeks afterwards. During RT, silymarin-based cream was applied daily at least 2 h before radiation. Silymarin-based cream was not applied to open wounds.
Leviaderm ® market product, patented. It is mainly based on silymarin (Silybum marianum, content 0.25%), Adelmidrol ® , vitamin E, bisabolol, and extracts from Vitis vinifera, Epilobium angustifolium, and Hordeum vulgare. The reference cream was the cream used in standard care. No detailed recipe for the product (contains 5% dexpanthenol) The median time to toxicity was prolonged significantly with silymarin-based cream (45 vs. 29 days (SOC)). Only 9.8% of patients using silymarin-based cream showed grade 2 toxicity in week 5 of RT in comparison to 52% with SOC. At the end of RT, 23.5% of patients in the silymarin-based study group developed no skin reactions vs. 2% with SOC, while grade 3 toxicity occurred only in 2% in the silymarin-based arm compared to 28% (SOC).These results reaching statistical significance for RTOG are in line with those determined for subjective toxicity (VAS). Silymarin-based cream was well tolerated and can, thus, be used over several weeks.
Patients with allergies to the product were excluded from study. According to Authors Leviaderm ® represents a new concept of cream by combining prevention and therapy of RD. It may induce antioxidative actions when skin is exposed to irradiation because silymarin, protect against free radical-induced inflammation. Additonaly Adelmidrol ® , or N,N-bis (hydroxyethyl)-nonandiamide, here used in a subclinical concentration of 0.5%, belongs to a family of lipidic molecules collectively defined as ALIAmides, which in preclinical and clinical testing using therapeutical concentrations (at least 2%) have been reported to restore skin reactivity by down regulating mast cell hyperactivity. To confirm the results of this nonrandomized, observational trial, this product should be tested in larger multicenter studies in this setting.
[97] Topical application of all herbal cream or the moisturizing cream could neither reduce the severity nor delay onset of dermatitis compared with no treatment group. Cucumis sativus cream wash shown to help with skin recovery post-irradiation. Authors recommend prophylactic application of moisturizing preparations on irradiated area of skin.
One clinical study in which three plants were analyzed: Centella asiatica L., Cucumis sativus L., Thunbergia laurifolia. Before the study, allergy tests were carried out to prevent side effects of extracts and moisturizing cream. [88] Turmeric curcuma longa L.

cream oil
Assess effectiveness of Vicco turmeric cream (VTC) on radiodermatitis. RCT. Patients with head and neck cancer scheduled to receive chemoradiotherapy or RT (dose 60 Gy). Two groups of patients first received topical Johnson's baby oil (JBO), second group received VTC. Acute skin reactions were assessed twice weekly (according to RTOG scores) by an investigator who was unaware of the details. Time of application: 2 weeks after the end of the RT, starting on day 1, preparations were applied 5 times per day on the irradiated area.
VTC contain: extracts of Turmeric curcuma longa (16% w/w), Sandalwood Oil in a non-greasy base Oil-petroleum oil Oil and VTC cream both are market preparations.
Cream based on Curcuma longa and Sandalwood oil was effective against post-radiation dermatitis. Significant reduction in grades of dermatitis was seen at all time points, including 2 weeks post RT. The occurrence of grade 3 dermatitis was lower in the cohorts using VTC and was statistically significant. No adverse effects (allergic reactions) were found in the groups, indicating that Curcuma cream is safe for patients with head and neck cancer.
VTC was shown to be effective in preventing radiodermatitis and needs to be validated in larger double-blind trials. [98] Turmeric Curcuma longa L.

cream oil
To ascertain the benefit of Vicco turmeric Ayurvedic cream (VTC) in preventing radiodermatitis. Investigator-blinded randomized trial (double blind). Women receiving breast radiation therapy (50 Gy in 2 Gy fractions daily for 5 weeks).
Two groups of patients first received topical Johnson's baby oil (JBO) second group received VTC. To assess the delay in the appearance and the degree of severity (RTG score) of dermatitis throughout the study period. Application of products 5 times a day.

Market preparations.
No information on composition available. VTC contain: extracts of Turmeric Curcuma longa (16% w/w), Sandalwood Oil in a non-greasy base.
Topical application of VTC delayed and mitigated the radiodermatitis. Compared to the JBO significant decrease in the incidence of 1 grade was seen at two week, and also in grade 2 and 3 at week 3 and 4 respectively in the VCT cohort. VCT cream significantly reduced radiation dermatitis.
Studies extended with regards to Pallaty [98]. Studies carried out with Johnson&Johnson company. Cream dose 5 g at each application and 5 cm 3 for the oil. The authors tend to attribute the effectiveness to the curcuma and oil properties such as: anti-inflammatory, antioxidant, modulating cytokines and enhancing wound healing process. All of it contributes to the mechanism giving protective effects. Decreased the epithelial desquamation after radiation group treated with curcumin-showed reduced expression of cyclooxygenase-2 and nuclear factor-kappaB. Curcumin treatment stimulated wound healing.
The authors obtained the gel with the extract themselves. They also refer to the results of study [101] which demonstrated that the gel showed the highest permeability of curcumin without skin irritation or anti-inflammatory effects. Physicochemical study of the preparation was not presented. Besides, in the study the authors use the terminology vehicle cream whereas it is a gel (hydrogel) with no active substance (curcumin) added. [102]

Discussion
In this literature review we quoted the results of 34 studies (between 1996 and 2021), three of which concern preparations containing more than one herbal extract (paste with a mixture of Aloe vera L., Turmeric curcuma longa, Azadirachta indica and Ocimum sanctum [74,75], ointment Jaungo containing Angelica gigas, Lithospermum radix [78,79]). In addition, in two presented studies, two or more preparations were analyzed in parallel: specifically, preparations containing Achillea millefolium or Glycyrrhiza glabra [59], or the preparations containing respectively Centella asiatica, Cucumis sativus or Thunbergia laurifolia [88]. In the study by Franco et al. [94] the carrier of Hypericum perforatum extract was neem oil with curative properties.
In total, 36.4%, which is the highest fraction of the quoted studies, used Aloe vera L. (12 studies). This is due to the fact that Aloe vera L. is the most used plant with soothing properties. The most important therapeutic effects described after applying Aloe vera L. are: the reduction of dermatitis, reduction of skin colonization by bacteria and healing acceleration. Second place is occupied by studies concerning Calendula officinalis (15.2%, 5 studies). In total, 4 studies (12.1%) concern the application of Turmeric curcuma longa, and 2 (6%) Silybum marianum.
Plant materials are one the best remedies for the treatment of wide variety of persistent diseases due to the presence of large number of bioactive natural products with potential biological properties. The plants used to carry out the study were characterized by various actions and indications in skin care after radiotherapy following due to presence of compounds such as flavonoids, saponin, polyphenols, polysaccharides, phytosterols, tannins, etc. (Table 5).
The dominant actions among the plants presented in the table are: anti-inflammatory, antioxidant and antimicrobial. This is linked to the mechanism of formation and healing of radiodermatitis but also to the physician's actions aiming at preventing and treating inflammation, pain or skin damage and bleeding which are prone to bacterial superinfection. Some of the plants used in the study prove efficient in skin smoothing and moisturizing because dry skin with a pathological basis caused by dermatosis requires the same care as dry non-pathological skin [23]. Works of Hoopfer et al. [65], Byun et al. [2], Pajonk et al. [91] were the only ones including the analysis of the herbal extract as such. The main purpose of these studies was to discover skin protection mechanisms for the given extract and to link it to the effectiveness in reducing radiation skin reaction severity.
For a cosmeceutical to be effective, its recipe is essential. Recipe assumptions concern not only the esthetic aspect such as application, scent, sensation on the skin (which are certainly important for oncological patients), but they also allow for the maximum action during regular application [103]. Therefore, the recipe is an integral part of the system for providing active substance aiming at maximum action and visible effect for the consumer, meaning the cosmetic is effective. The effectiveness concerns immediate effects, short term effects and effects occurring after 30-60 days. Besides, the process of healing for the skin takes 4-5 weeks. Hence, the studies evaluated the skin condition weekly, after various time lapses until, on average, 2-6 and even 8 weeks after the end of the radiotherapy. They allowed us to demonstrate the preparation's long-term effectiveness. The longest study of preparation impact on the skin was analyzed in [74,75] and lasted 6 months. To determine the timing of application resulting in the best effect, in studies [60,97], cosmeceutical was applied beginning on day −7, 0, +7 relative to the day of irradiation (day 0) and continued for 5 weeks and applied beginning on day −14, 0 +14 respectively.
For a full assessment of the cosmetic's impact on skin after radiotherapy, a threefold approach should be considered: instrumental measurement of skin condition, expert's evaluation, and self-evaluation by the participants to the study group. A double-blind testing with control group using placebo or positive control of the prescribed product carried out by independent experts using a statistically significant number of participants are also acceptable sources of information. In total, 83.5% of the studies presented by us were randomized clinical studies and clinical studies. Studies on animals included 11.76% of the quoted studies. In most discussed clinical studies, the assessment was done by a team of experts or the members of the study group. To do this, the assessment tools were: the scale (guidelines) RTOG/EORTC [59,66,67,71,74,75,78,[81][82][83][84][85][86][88][89][90]94,[96][97][98][99], Acute Radiation Morbidity Scoring Criteria [73], Common Toxicity Criteria [63,64], modified 10-point Catterall scale [65], Common Terminology Criteria for Adverse Events [92] or National Cancer Institute Common Terminology for Adverse Events [96]. Photographs of skin were taken in studies [11,63,72,81,89,90]. To measure erythema Near Infrared Spectroscopy, Laser Doppler Imaging and Digital Colour Photography were applied [72]. A subject's skin comfort [64] and skin-related quality of life (SRQOL) [95] was also evaluated, mostly using QLQ-C30 questionnaire [74,75]. The effectiveness was also evaluated by defining the degree of improvement of skin lesions [69].  The availability and the effectiveness of the given component can be modified depending on the phase in which it was added to the preparation during production. The type of the solvent used for extraction is hence essential. The effectiveness can be increased by using a proper substrate and carrier system. Known ways of delivery of herbal extract in topical therapy are: creams and water-based liquids, ointments based on oils and waxes, powders and pastes, masks from freshly cut herbs, warming compresses or compresses from warm soaked herbs [104]. Among the analyzed physicochemical forms including extracts, 42.9% were gels (15 studies), 28.6% were creams (10 studies), 11.4% ointments (4 studies). Rarely used substances were (5.8%): lotions and oils (2 studies each), but also pastes and solutions (single studies, 2.8%). One work among presented studies analyzed more than one physicochemical form of the preparation [94]. A gel preparation gives a refreshing sensation, and it is oil-free, which is a more appropriate formulation to apply in skin exposed to radiation therapy, avoiding a bolus-like effect and making it easier to remove before the next radiation therapy session.
In terms of products' effectiveness assessment, it should be emphasized that in case of radiation reaction, its characteristics should be analyzed, and appropriate treatment and care should be adopted for the given degree. In the case of dry desquamation, treatments aim mainly at moisturizing the skin and reducing the skin discomfort linked to burning and itching. Hence, hydrophilic preparation (mostly gels) with neutral pH are most appropriate. They are often combined with the topical application of corticosteroids. Corticosteroids however have a lot of side effects. In works [74,75] the effectiveness of the paste with herbal extracts was compared to Beclomethasone cream. The evaluation of paste effectiveness as compared to corticosteroids was analyzed in [79]. In case of moist desquamation, the principle of treating the moist with the moist is applied; hence, the best option seems to be hydrocolloid dressings.
Most of the quoted studies aimed at preventing dermatitis. Hence, the studied preparation was applied throughout the whole treatment. Possible changes in treatment were linked to allergy or to development of dermatitis of second degree or higher, which required the introduction of corticosteroids, antibiotics or analgesics. In the case of moist desquamation, individual works [71,88] stopped the application of the preparation in the area of occurrence. Only the studies carried out by the team Franco et al. [94] included the application of two forms of preparations depending on the type of radiodermatitis observed. Thus, for erythema and/or oedema, gel preparation was employed. For patchy moist desquamation, the oil preparation was administered.
In the works quoted, multiple forms of preparations were compared simultaneously during the study; for example, cream and oil or powder [65,71,98,99], creams with water infusion [88], gels with creams [11,[62][63][64]72,89,90,100], gels with soap [67], gels with ointments [60], gels with oils [94]. We know currently that the skin barrier layer should not only be moisturized but also rebuilt, which cannot be done with preparations such as soap. Besides, in studies [11,61,67,78,83,84,100] standard care was recommended or moisturizing preparations were applied together with the analyzed one [88,92]. The study results presented in [65] speak in favor of dry skin care instead of applying moisturizing creams enriched with herbal extracts.
From a scientific but also from practical point of view, the time of application of cosmeceuticals and the dosage are important. As shown in [60], there was no effect if the gel was applied only before irradiation or beginning 1 week after irradiation. According to [97], the minimal application time is two weeks before the beginning of radiotherapy, while a significant part of the works concerned studies in which the preparation application started at the same time as the irradiation. Studies [73,79,102] mentioned the doses of applied products.

Conclusions
In the current review paper, the literature data have been systematically reviewed and we discussed the connection between the type of applied skin care (type of preparation, its composition, the dose), the properties of the herbal extract, and the evaluation of its efficiency in preventing and treating radiation reaction on skin.
From this research, the following conclusions can be drawn: 1.
The application of herbal extracts in preparations preventing radiodermatitis is important and still up-to-date (most recent publications about ongoing clinical studies are from 2021). Moreover, many herbal extracts such as Dilenia idica, and the Lamicale Family show potential in treating dermatitis but have not been introduced in the recipes of ointments, creams or gels.

2.
Herbal extracts obtained from plants can be added to recipes because they are part of a category of cosmeceutical supplements which are not subject to regulations and can be introduced into preparations without prescription. Herbal extracts can be a raw material from which active substances are isolated. For example, tea is a source of epigallocate-hin-3-gallatechin. Polysaccharides can be obtained from Annona muricata L. Both have potential in the treatment of dermatitis.

3.
The dominant actions among the plants are: anti-inflammatory, antioxidant and antimicrobial. This is linked to the mechanism of formation and healing of radiodermatitis but also to the physician's actions aiming at preventing and treating inflammation, pain or skin damage and bleeding which are prone to bacterial superinfection. Some of the plants used in the study prove efficient in skin smoothing and moisturizing because dry skin with a pathological basis caused by dermatosis requires the same care as dry non-pathological skin. 4.
In the available study results there is conflicting information concerning the effectiveness in treatment and prevention of radiodermatitis by the products containing herbal extracts in their recipe (e.g., Aloe vera). There are also works mentioning that preparations such as ointments are poorly tolerated and appreciated by patients, and that some preparations cause allergies. Hence there are premises indicating that there is a need to widen the preparations offer for radiotherapy patients, the recipe of which is projected already at the evaluation stage of herbal extracts.

5.
The effectiveness evaluation for herbal extracts in radiotherapy is not an easy task since there are no strict guidelines. Studies should include both apparatus analyses of the skin condition and clinical studies including patients. They should also be preceded by the analysis of herbal extracts and recipe in terms of physicochemical, dermatological, and performance characteristics.