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Open Access

Peer-reviewed

Research Article

Clinical efficacy and applicability of natural products in the treatment and prevention of radiotherapy-induced oral mucositis: A systematic review

  • Wen Zhang,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft, Writing – review & editing

    Affiliation Phase I Clinical Research Unit, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    ⨯
  • Lu Fan,

    Roles Formal analysis, Investigation, Software, Writing – review & editing

    Affiliation Phase I Clinical Research Unit, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    ⨯
  • Yifang Xie,

    Roles Data curation, Formal analysis, Writing – review & editing

    Affiliation Phase I Clinical Research Unit, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    ⨯
  • Tenghui Gao,

    Roles Formal analysis, Investigation, Resources, Software, Writing – review & editing

    Affiliation Phase I Clinical Research Unit, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    ⨯
  • Jieping Zeng

    Roles Supervision, Visualization, Writing – review & editing

    zengjieping2000@126.com

    Affiliation Phase I Clinical Research Unit, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    ⨯

Abstract

The aim of this systematic review was to describe the efficacy and acceptability of natural products in the management of oral mucositis caused by radiation. From the day it started to August 7, 2023, a thorough search for randomized controlled trials (RCTs) was carried out among seven databases: the Web of Science, PubMed, Embase, OVID, Scopus, the Cochrane Library and the CINAHL database. Only English-language articles were identified during the search. Using the revised Cochrane risk-of-bias tool, version 2, two researchers screened the articles, collected information on study characteristics, and appraised risks of bias. The data were analyzed and descriptively presented with a narrative synthesis methodology involving the Synthesis Without Meta-Analysis (SWiM) reporting element applied in detail. The PROSPERO registration number of this study is CRD42023476932. Thirty-six clinical trials were included in the study; the included studies included a variety of 20 types of natural products. Honey and Curcuma longa were the most commonly assessed natural products. A total of 2,400 participants reported taking part in therapy with natural products for oral mucositis. Natural products demonstrated substantial efficacy in terms of influencing intensity, incidence, pain score, quality of life, and symptoms such as xerostomia and dysphagia. Except for manuka honey, most natural products were well accepted. Regarding the clinical trials’ risk of bias, 2 clinical trials (5.56%) had a high risk of bias, 17 studies (47.2%) had a low risk of bias, and 17 studies (47.2%) were rated with “some concern.” Natural remedies work well as alternate treatments for managing oral mucositis caused by radiation therapy. However, additional clinical trials are still needed. The safety of these conventional medications as well as their effectiveness and safety when used in combination with other conventional or naturopathic therapies should be fully examined.

Citation: Zhang W, Fan L, Xie Y, Gao T, Zeng J (2024) Clinical efficacy and applicability of natural products in the treatment and prevention of radiotherapy-induced oral mucositis: A systematic review. PLoS ONE 19(5): e0303988. https://doi.org/10.1371/journal.pone.0303988

Editor: Yuri N. Clement, The University of the West Indies, TRINIDAD AND TOBAGO

Received: February 15, 2024; Accepted: May 5, 2024; Published: May 23, 2024

Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The probability of developing mucositis is highly dependent on the sites irradiated. Patients who undergo routine radiotherapy (RT) fractionation for head and neck cancer have a greater probability of developing oral mucositis [1]. Radiation-induced mucositis can occur in up to 91% of patients with head and neck cancer who undergo radiotherapy [2]. In patients with head and neck cancer, oral mucositis is a common restricted cytotoxic lesion, and there may be incapacitating reactions caused by radiation exposure [3]. Radiation-induced mucositis manifests as dry mouth, dysphagia, severe erythematous ulcers, and many secondary infections [4]. Patients with severe oral mucositis may not be able to tolerate treatment, which could result in unwarranted hospital stays and treatment interruptions, impairing tumor control and patient survival and increasing the financial burden on society [5, 6].

Many strategies, such as oral hygiene, sodium bicarbonate, benzydamine hydrochloride rinses, glutamine, growth factor, cytokines, anti-inflammatory drugs, analgesics, low-level laser therapy, and cryotherapy [4, 7] have been suggested for treating oral mucositis, but none of these strategies are fully effective; moreover, some agents are associated with drug side effects and ancillary costs [8, 9]. In addition to being less expensive, more widely available [10], and having fewer side effects [11] than synthetic drugs, natural products also show potential in pharmacological laboratory studies and clinical trials for their antioxidant, anti-inflammatory, antimicrobial, immunomodulatory, and wound-healing properties [12], all of which may have varying degrees of impact on the pathophysiology of mucositis.

Based on the body of existing scientific research, the purpose of this systematic review was to evaluate the effectiveness, acceptability, and safety of natural products in the management of radiotherapy-induced oral mucositis.

Methods

This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 statement [13]. This review was submitted to the National Institute for Health Research (PROSPERO) (CRD42023476932). We developed a population, intervention, comparison, and outcome (PICO) model.

Search strategy

We systematically searched seven electronic databases, the Cochrane Library, Web of Science, PubMed, Embase, OVID, Scopus and CINAHL databases, from inception to August 7, 2023. The search terms included “oral mucositis”, “radiotherapy”, “natural products” and related synonyms. The detailed search strategies for each database were listed in S1 File. Two investigators independently searched for literature in seven databases. The third investigator verified the study selection process.

Eligibility criteria

The inclusion criteria were as follows: (a) population—adults with a diagnosis of oral mucositis after radiotherapy or combination of radiotherapy and chemotherapy; (b) intervention—patients in treatment groups received a single natural product or the natural product in combination with another therapeutic strategy; and (c) control—patients in control groups received placebo, other standard agents, nothing or a combination of the above; interventions could be administered by any route, formulation or dose; (d) outcome—the primary outcome was the severity of oral mucositis (including, e.g., the incidence, score, even time of onset, duration), and acceptability of medicines; the secondary outcome was access to other symptom complications (e.g., pain level, quality of life assessment and others; e.g., xerostomia, dysphagia and cytokines).

The exclusion criteria were as follows: duplicates, no access to the full text, literature reviews, trial protocols, clinical studies without a control group, research conducted in vitro or animal, studies using a drug solution containing ethanol, and studies that could not verify the composition of specific constituents.

Study selection and data extraction

Two authors eliminated irrelevant articles by reviewing the full title and abstract of each study based on the inclusion criteria. The eligibility of the articles was assessed by scanning the full texts of the articles that met the inclusion criteria, and detailed information on the study characteristics was independently extracted to data extraction forms. The extracted information was collected, including details about the author, study year, study design, participants, natural product of interventions, agent of comparators, agent administration route and outcome results. Disagreements were resolved by consensus or by consulting another researcher.

Evaluation of the risk of bias

Two reviewers separately evaluated the risk of bias. Randomized controlled trials were assessed using the revised Cochrane Risk-of-bias Tool for Randomized Studies (RoB 2) [14]. Bias risk was divided into three categories: low, some concerns, and high.

Methods for synthesis

Given the variation in interventions across study designs and lack of standardized data about the Consolidated Standards of Reporting Trials (CONSORT) statement on standards for herbal and Chinese medicine interventions, it was not feasible to perform a meta-analysis. The synthesis of findings was directed by narrative synthesis methods and the Synthesis Without Meta-Analysis (SWiM) reporting guidelines [15]. Synthesis descriptions were grouped according to outcome indicators.

Results

Study characteristics

Fig 1 shows the process of database searching. A total of 817 studies were found. After completing the elimination of duplicate studies and assessing the titles and abstracts, we chose 69 studies for full-text evaluation. Finally, 36 studies that met the inclusion criteria were included in the qualitative analysis. Table 1 generalizes the features of the studies included in this review, including information on study location, study design, funding, intervention duration and participant sample size. The included studies spanned 21 years (2003 [16] to 2023 [17, 18]). Table 2 shows the fundamental characteristics of the clinical trials using natural agents. Table 3 shows the main results of the primary and secondary outcomes of clinical trials included in the systematic review.

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Fig 1. The flow diagram on the searching and screening.

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Table 1. Summary of clinical trials included.

https://doi.org/10.1371/journal.pone.0303988.t001

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Table 2. Fundamental characteristics of included trials.

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Table 3. Description of the primary and secondary outcomes of clinical trials included.

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Of the included studies, 7 studies reported Curcuma longa [18–24], 6 studies reported honey [16, 25–29] (including pure honey from tea plant Camellia sinensis [16], pure honey from Thymus and Astragale [25], pure honey (Dabur honey) [26], pure honey from the clover plant Trifoliumalexandrenum [27], manuka honey [28], and thyme honey [29]), 3 studies reported aloe vera [30–32], 2 studies reported black mulberry molasses [33, 34], and 2 studies reported FITOPROT [18, 24] (an adhesive herbal remedy that contains glycerinated extract of Bidens pilosa L. and curcuminoids from Curcuma longa L. [18]), 2 studies reported Silymarin [35, 36], and 1 study reported essential oils of manuka and kanuka [37]. Seven studies reported on propolis [38], Zataria [39], green tea [17], Cystus® tea [40], Indigowood root [41], Plantago major L [42], and Kangfuxin solution [43]. The remaining studies reported herbal medicines in treating oral mucositis: Mucotrol™ [44] (a herbal remedy made up of centella asiatica, sorbitol, magnesium stearate, acesulfame K, aloe vera sp., and glycyrrhizin extract [44]), SAMITAL® [45, 46] (a blend of three botanical medicine extracts from the roots of Echinacea angustifolia and V accinium myrtillus (bilberry, and the fruits of Macleaya cordata [46]), Faringelb (comprising propolis, Aloe vera, calendula, chamomile, and honey) [47], Shuanghuabaihe tablets (extracts from a range of Chinese herbs, such as Isatidis radix, Asari radix etrhizoma, serpentine bile, Rehmanniae radix, Liliibulbus, Arnebiae radix, Rhizoma Coptidis, and Lonicerae Japonicae Flos) [48], CHIN (Chining decoction modified from Liangge San consisting of Radix Liriopes, Radix Scrophulariae, Lumbricus, Scutellaria, Rhubarb, Licorice, Mint, and Forsythia, Red peony root) [49], Qingre Liyan decoction (which includes the Astragalus, Crocus sativus, Ophiopogon flexuosus, Panax ginseng, Draba hebecarpa, Ligustrum, Radix et Rhizoma Glycyrrhizae, Radix Angelicae Sinensis and Glycyrrhizae) [50].

Oral mucositis measurement

Assessment of oral mucositis was performed using scales for assessing the degree of mucositis. The scales used for assessment included the World Health Organization (WHO) scale [17, 21, 23, 26–28, 32, 35, 42, 44, 45, 50, 51], the Common Terminology Criteria scale (NCI-CTC) [16, 21–23, 33–36, 38, 41, 43, 47–49], the Radiation Therapy Oncology Group (RTOG) [16, 28, 29, 31, 33, 37, 40, 44, 50, 52] scale (used for the Cooperative Group Common Toxicity Criteria), the Oral Mucositis Assessment Scale (OMAS) [34, 45, 48] and the Oral Assessment Guide (OAG) [25, 28, 39, 45].

All trials reported the efficacy of natural products for treating oral mucositis caused by radiation therapy. Twenty-six trials reported a reduction in mucositis grade and scale score and a decrease in the degree of mucositis. Sixteen studies (including Aloe Vera [31], Curcuma longa [19, 22, 23], FITOPROT [18], Honey [27], Yashtimadhu [52], black mulberry [34], SAMITAL® [45], Indigowood Root [41], Faringel [47], Zataria [39], Shuaghuabaihe Tablets [48], Cycus tea [40], QingReliyanb decoction [50], and Kangfuxin solution [43]) revealed a possible reduction in the incidence of mucositis during radiotherapy. Thirteen studies, including those involving Aloe vera (30,32), Curcuma longa [19–21], Honey (Dabur honey) [26], Glycyrrhiza glabra (Yashtimadhu) [52], SAMITAL® [45], essential oils [37], silymarin [35], Shuaghuabaihe tablets [48], Cycus tea [40], and Kangfuxin [43], reported that using the natural products postponed the beginning of oral mucositis, regarding which the Cycus tea and SMITAL studies found no discernible differences. Three trials reported that turmeric [20], zataria [39], and silymarin [36] reduced the risk of mucositis onset, and there was one report of aloe vera shortening the duration of mucositis with no discernible significant difference.

Pain reduction

Regarding the outcome of pain (mainly assessed by the visual analog scale (VAS)), eighteen trials reported results. Thirteen of these studies showed a significant reduction, including curcumin [22], FITOPROT [24], thyme honey [29], black mulberry molasses [34], SAMITAL® [45, 46], essential oils [37], Payayor [32], Zataria [39], Shuanghuabaihe tablets [48], Plantago major L. [42], CHIN [49] and Kangfuxin solution [43]. Five studies [17, 28, 31, 33, 47] showed no significant effect.

Quality of life assessment

A total of seven trials assessed patients’ quality of life, mainly using the UW-QOL, EORTC QLC-C30 and EORTC QLC-H&N35 scales. Two [28, 31] of the trials of aloe vera and manuka honey showed no significant results in terms of pain reduction, while the other six [18, 24, 29, 34, 45, 46] trials of aloe vera, honey, black mulberry molasses, FITOPROT and SAMITAL® showed a significant reduction in pain symptoms.

Other symptoms

When assessing the effects on other symptoms, nine trials revealed that curcumin (19, 22), honey [16, 25, 29], black mulberry molasses [33], Payayor [32], propolis [38] and zataria [39] were able to reduce weight loss, although these effects were not significant in studies on payayor [32] or propolis [38]. Four studies revealed that SAMITAL® [45], payayor [32], propolis [38], and the herbal compound CHIN [49] were effective at reducing xerostomia. Four studies revealed that curcumin [22], Indigowood root [41], SAMITAL® [45], and black mulberry molasses [33] reduced the symptoms of dysphagia. FITOPROT [18], honey [16, 27], and SAMITAL® [45] were useful for decreasing the interruptions of radiotherapy. In addition, patients using Indigowood root were found to have significantly lower levels of leukocytes in the blood and IL-6 in the serum [41], and FITOPROT reduced salivary nitrite and IL-8 levels [24]. Honey significantly reduced the number of aerobic pathogenic bacteria as well as the extent of Candida colonization [27].

Acceptability

Twenty-five trials reported acceptability. In the studies by Su [31], Soni [22], Fasanaro [45] et al., good compliance was reported for patients treated with aloe vera, curcumin, and SAMITAL®. In the studies by Elyasi [35], Soltani [42] et al., patients showed good tolerance to silymarin and Plantago major L. In a study of Manuka honey, some subjects withdrew from the study due to the strong taste and moderate to severe nausea [28].

Adverse events

Among the trials that reported adverse events, nausea and vomiting were reported in the trials of aloe vera and Manuka honey [28, 30–32], and nausea, burning sensation in the mouth and gastrointestinal reactions were reported in the trials of SAMITAL®, silymarin, Plantago major L. and Shuanghuabaihe tablets [35, 36, 42, 45, 46, 48]. For Plantago major L., the adverse effects reported were gastrointestinal reactions and burning sensations in the mouth [42]. The gastrointestinal reactions were mainly diarrhea with mild abdominal pain and cramps. Importantly, it is difficult to distinguish whether these side effects are caused by natural medicines or cancer radiotherapy, and it is necessary to report side effects consistently in each trial so that researchers can accurately assess treatment-related toxicity to minimize bias.

Risk of bias

The methodological quality of the 36 included studies is illustrated in Fig 2 and assessment of the risk of bias in each trial is showed in Fig 3. The revised risk-of-bias tool ROB 2 was used to evaluate the risk of bias in each included trial. In domain 5, every study received a rating of "some concern." It is unknown whether articles of clinical trials or even records were analyzed in accordance with a predetermined plan that was finished before information on nonhidden outcomes was available for examination.

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Fig 2. Summary of the risk of bias.

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Fig 3. Assessment of the risk of bias in clinical trials.

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Discussion

The present study investigated the role of natural products in radiotherapy-induced oral mucositis. Natural products can simultaneously target different primary pathways that support pathobiology and affect the pathogenesis of mucositis at different levels without compromising the efficacy of antitumor regimens [53, 54]. In this respect, natural products are very good alternative therapies compared to synthetic drugs.

In this article, we categorized and reported the results of the effects of natural products on relieving oral mucositis, reducing pain, improving quality of life and ameliorating comorbidities such as xerostomia and dysphagia. Studies have shown that turmeric, honey, Zataria, Indigowood root, black mulberry molasses, SAMITAL®, Kangfuxin solution, and the Chinese herbal compounds Shuanghuabaije tablets, CHIN, and Qingreliyan decoction have favorable ameliorative therapeutic effects on radiotherapy-induced oral mucositis. However, most studies’ outcomes were frequently constrained by the small number of participants involved and/or lack of standardized intervention methodology. Even comparisons between the same drugs are difficult because of the limitations of the different concentrations used, dosages used, and extraction methods, such as essential oils (from manuka and kanuka), propolis, aloe vera, bluebell root and silymarin. The essential oils appeared to be effective in preventing OM due to their wound-healing, anti-inflammatory, antimitotic, analgesic, and antibacterial qualities, but an important limitation of the study was the small sample size [37]. Although the use of very small doses of Manuka and Kanuka in a gargle may have a favorable effect on the development of radiation-induced mucositis, additional trials are needed to corroborate these findings, according to the findings of feasibility studies. Propolis is rich in flavonoids, which have healing, antiulcer, anti-inflammatory and antioxidant effects, and the findings of this study support this hypothesis regarding the management of oral mucositis; however, the small sample size was also the primary drawback of this study, and further research is needed to clarify the potential radioprotective mechanisms involved [38, 55, 56]. Aloe vera has been shown to have anti-inflammatory, antimicrobial, antioxidant, antitumor, skin-protective and wound-healing pharmacological effects in several in vitro studies [57]; however, of the two studies included in this review, the study by Su et al. revealed no discernible impact of oral aloe vera solution in the treatment of mucositis [31]. A study by Sahebjamee et al. revealed that aloe vera delayed the onset of mucositis and severe mucositis [30]. There is still a need for extensive mechanistic studies on aloe vera extracts and further determination of the therapeutic effect of aloe vera by increasing the sample size, subdividing the type of primary site and conducting clinical trials with different routes of administration. Indigowood root has anti-inflammatory properties, and the component it contains, Indigofera, is thought to lessen the degree of dysphagia, anorexia, and oral mucositis caused by radiation therapy; however, the specific mechanism and pathway by which Indigowood root reduces radiotherapy-induced mucositis requires further analysis [41]. Silymarin is extracted from Milk thistle (Silybum marianum L.). The extract contains several flavonolignans, the major component being silymarin, which is associated with many pharmacological properties, including antioxidant, anti-inflammatory, immunomodulatory and hepatoprotective properties [58, 59]. The efficacy of these agents in preventing radiotherapy-induced mucositis was increased in the included studies, but clinical trials with larger sample sizes, especially with different doses, durations and nanoformulations of silymarin, are advised to verify this possible effect [35].

This study has certain limitations, and there is room for methodological improvement in RCTs investigating natural products. First, because not all protocols or registration information from the included trials were available, the articles may have publication bias due to unpublished unfavorable or negative results. Some of the trials did not describe how allocation was concealed, and the presence of some drugs, such as honey, which could not be blinded, made the literature less reliable. Second, the WHO, RTOG, OMAS, NCI-CTCAE and OAG oral mucositis grading scales were used, the grading criteria were not standardized, and only a few trials reported that grading was performed by a person with a professional background in mucositis, making it difficult to compare the staging and grading of the disease. In addition, safety was described in general terms and not specifically documented using the relevant scales. Only one of the trials included in the review described the effect of therapy in combination with other conventional therapies for the treatment of radiation-related oral mucositis, and safety studies of natural products combined with other conventional and/or naturopathic therapies are incomplete. The safety and efficacy of these treatments need to be investigated further.

In conclusion, according to our review of trials, the application of natural remedies in the treatment of radiotherapy-induced oral mucositis exhibited good efficacy and safety. The vast majority of these natural products were well accepted, but in the manuka honey trial, patients withdrew from the study due to nausea and unpleasant taste. Nonetheless, there is a need to extend investigations by increasing the sample size, improving the dosing regimen, and assessing compliance with the CONSORT guidelines for the herbs and Chinese herbal medicines included, thereby enhancing the quality of the clinical trials.

Conclusion

The results of the present systematic review reveal that curcumin, honey, zataria, Indigowood root, black mulberry molasses, aloe vera, silymarin, Kangfuxin solution and the herb compounds Mucotrol™ FITOPROT, SAMITAL®, Shuanghuabaihe tablets, Qingreliyan decoction, and CHIN have favorable effects on the treatment of radiotherapy-induced oral mucositis. Additionally, we support the use of natural products to treat radiotherapy-induced oral mucositis. However, there is still a need for additional studies focusing on the safety of these traditional medicines and their efficacy and safety when used in combination with other conventional and/or naturopathic therapies.

References

  1. 1. Pulito C, Cristaudo A, Porta C, Zapperi S, Blandino G, Morrone A, et al. Oral mucositis: the hidden side of cancer therapy. J Exp Clin Cancer Res. 2020;39(1):210. Epub 20201007. pmid:33028357; PubMed Central PMCID: PMC7542970.
  2. 2. Brown TJ, Gupta A. Management of Cancer Therapy-Associated Oral Mucositis. JCO Oncol Pract. 2020;16(3):103–9. Epub 20200203. pmid:32048926.
  3. 3. Elting LS, Keefe DM, Sonis ST, Garden AS, Spijkervet FK, Barasch A, et al. Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer. 2008;113(10):2704–13. pmid:18973181.
  4. 4. Pranadwista ZF, Nur’aeny N. Effectiveness of natural-based products for radiation-induced oral mucositis therapy: A systematic review. Cancer Treat Res Commun. 2023;36:100720. Epub 20230516. pmid:37209466.
  5. 5. Villa A, Sonis ST. Pharmacotherapy for the management of cancer regimen-related oral mucositis. Expert Opin Pharmacother. 2016;17(13):1801–7. Epub 20160803. pmid:27477002.
  6. 6. Russo G, Haddad R, Posner M, Machtay M. Radiation treatment breaks and ulcerative mucositis in head and neck cancer. Oncologist. 2008;13(8):886–98. Epub 20080813. pmid:18701763.
  7. 7. Colella G, Boschetti CE, Vitagliano R, Colella C, Jiao L, King-Smith N, et al. Interventions for the Prevention of Oral Mucositis in Patients Receiving Cancer Treatment: Evidence from Randomised Controlled Trials. Curr Oncol. 2023;30(1):967–80. Epub 20230110. pmid:36661723; PubMed Central PMCID: PMC9858113.
  8. 8. Nagi R, Patil DJ, Rakesh N, Jain S, Sahu S. Natural agents in the management of oral mucositis in cancer patients-systematic review. J Oral Biol Craniofac Res. 2018;8(3):245–54. Epub 20171206. pmid:30191118; PubMed Central PMCID: PMC6107930.
  9. 9. Sonis ST. Oral mucositis. Anticancer Drugs. 2011;22(7):607–12. pmid:21709615.
  10. 10. Eubank PLC, Abreu LG, Violante IP, Volpato LER. Medicinal plants used for the treatment of mucositis induced by oncotherapy: a systematic review. Support Care Cancer. 2021;29(11):6981–93. Epub 20210514. pmid:33988743.
  11. 11. Baharvand M, Jafari S, Mortazavi H. Herbs in Oral Mucositis. J Clin Diagn Res. 2017;11(3):Ze05–ze11. Epub 20170301. pmid:28511530; PubMed Central PMCID: PMC5427456.
  12. 12. Lima I, de Fátima Souto Maior L, Gueiros LAM, Leão , Higino fivennameS, Carvalho AAT. Clinical applicability of natural products for prevention and treatment of oral mucositis: a systematic review and meta-analysis. Clin Oral Investig. 2021;25(6):4115–24. Epub 20210107. pmid:33409696.
  13. 13. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol. 2021;134:178–89. Epub 20210329. pmid:33789819.
  14. 14. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019;366:l4898. Epub 20190828. pmid:31462531.
  15. 15. Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. Bmj. 2020;368:l6890. Epub 20200116. pmid:31948937; PubMed Central PMCID: PMC7190266.
  16. 16. Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis: a preliminary study. Support Care Cancer. 2003;11(4):242–8. Epub 20030219. pmid:12673463.
  17. 17. Shirazian S, Manifar S, Kazemian A, Pourshahidi S, Rashtiani A. Effectiveness of green tea mouthwash on radiation-induced mucositis in patients with head and neck cancer: a randomised clinical trial. Australian Journal of Herbal and Naturopathic Medicine. 2023;35(1):74–8.
  18. 18. Martins AFL, Pereira CH, Morais MO, de Sousa-Neto SS, Valadares MC, Freitas NMA, et al. Effects of a mucoadhesive phytomedicine (Curcuma longa L. and Bidens pilosa L.) on radiotherapy-induced oral mucositis and quality of life of patients undergoing head and neck cancer treatment: randomized clinical trial. Support Care Cancer. 2023;31(9):517. Epub 20230811. pmid:37566179.
  19. 19. Mansourian A, Amanlou M, Shirazian S, Moosavian Jahromi Z, Amirian A. The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer. International journal of radiation research. 2015;13(3):269‐74. CN-01102027.
  20. 20. Shah S, Rath H, Sharma G, Senapati SN, Mishra E. Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res. 2020;31(5):718–27. pmid:33433509.
  21. 21. Delavarian Z, Pakfetrat A, Ghazi A, Jaafari MR, Homaei Shandiz F, Dalirsani Z, et al. Oral administration of nanomicelle curcumin in the prevention of radiotherapy-induced mucositis in head and neck cancers. Special care in dentistry: official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2019;39(2):166–72. http://dx-doi-org-443.beijingxiehe.tsg211.com/ pmid:30761565
  22. 22. Soni TP, Gupta AK, Sharma LM, Singhal H, Sharma S, Gothwal RS. A Randomized, Placebo-Controlled Study to Evaluate the Effect of Bio-Enhanced Turmeric Formulation on Radiation-Induced Oral Mucositis. ORL J Otorhinolaryngol Relat Spec. 2022;84(2):103–13. Epub 20210623. pmid:34161952.
  23. 23. Arun P, Sagayaraj A, Azeem Mohiyuddin SM, Santosh D. Role of turmeric extract in minimising mucositis in patients receiving radiotherapy for head and neck squamous cell cancer: a randomised, placebo-controlled trial. J Laryngol Otol. 2020:1–6. Epub 20200207. pmid:32029014.
  24. 24. Arantes DAC, da Silva ACG, Freitas NMA, Lima EM, de Oliveira AC, Marreto RN, et al. Safety and efficacy of a mucoadhesive phytomedication containing curcuminoids and Bidens pilosa L. extract in the prevention and treatment of radiochemotherapy-induced oral mucositis: Triple-blind, randomized, placebo-controlled, clinical trial. Head Neck. 2021;43(12):3922–34. Epub 20211015. pmid:34655135.
  25. 25. Motallebnejad M, Akram S, Moghadamnia A, Moulana Z, Omidi S. The effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial. J Contemp Dent Pract. 2008;9(3):40–7. Epub 20080301. pmid:18335118.
  26. 26. Jayachandran S, Balaji N. Evaluating the effectiveness of topical application of natural honey and benzydamine hydrochloride in the management of radiation mucositis. Indian J Palliat Care. 2012;18(3):190–5. pmid:23439942; PubMed Central PMCID: PMC3573473.
  27. 27. Rashad UM, Al-Gezawy SM, El-Gezawy E, Azzaz AN. Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head and neck cancer. J Laryngol Otol. 2009;123(2):223–8. Epub 20080519. pmid:18485252.
  28. 28. Hawley P, Hovan A, McGahan CE, Saunders D. A randomized placebo-controlled trial of manuka honey for radiation-induced oral mucositis. Supportive care in cancer. 2014;22(3):751‐61. CN-24221577.
  29. 29. Charalambous M, Raftopoulos V, Paikousis L, Katodritis N, Lambrinou E, Vomvas D, et al. The effect of the use of thyme honey in minimizing radiation—induced oral mucositis in head and neck cancer patients: A randomized controlled trial. Eur J Oncol Nurs. 2018;34:89–97. Epub 20180430. pmid:29784145.
  30. 30. Sahebjamee M, Mansourian A, Hajimirzamohammad M, Zadeh MT, Bekhradi R, Kazemian A, et al. Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation-induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial. Oral Health Prev Dent. 2015;13(4):309–15. pmid:25431805.
  31. 31. Su CK, Mehta V, Ravikumar L, Shah R, Pinto H, Halpern J, et al. Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms. Int J Radiat Oncol Biol Phys. 2004;60(1):171–7. pmid:15337553.
  32. 32. Putwatana P, Sanmanowong P, Oonprasertpong L, Junda T, Pitiporn S, Narkwong L. Relief of radiation-induced oral mucositis in head and neck cancer. Cancer Nurs. 2009;32(1):82–7. pmid:19104205.
  33. 33. Yuce Sari S, Beduk Esen CS, Yazici G, Yuce D, Cengiz M, Ozyigit G. Do grape and black mulberry molasses have an effect on oral mucositis and quality of life in patients with head and neck cancer? Support Care Cancer. 2022;30(1):327–36. Epub 20210720. pmid:34283318.
  34. 34. Demir Doğan M, Can G, Meral R. Effectiveness of Black Mulberry Molasses in Prevention of Radiotherapy-Induced Oral Mucositis: A Randomized Controlled Study in Head and Neck Cancer Patients. J Altern Complement Med. 2017;23(12):971–9. Epub 20170705. pmid:28677999.
  35. 35. Elyasi S, Hosseini S, Niazi Moghadam MR, Aledavood SA, Karimi G. Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res. 2016;30(11):1879–85. Epub 20160823. pmid:27555604.
  36. 36. Elyasi S, Hosseini S, Razaei S, Karimi G. Evaluation of oral nano-silymarin formulation efficacy on prevention of radiotherapy induced mucositis: A randomized, double-blinded, placebo-controlled clinical trial. Annals of oncology. 2020;31:S672–S. WOS:000573469101227.
  37. 37. addocks-Jennings W, Wilkinson JM, Cavanagh HM, Shillington D. Evaluating the effects of the essential oils Leptospermum scoparium (manuka) and Kunzea ericoides (kanuka) on radiotherapy induced mucositis: a randomized, placebo controlled feasibility study. Eur J Oncol Nurs. 2009;13(2):87–93. Epub 20090318. pmid:19297246.
  38. 38. Javadzadeh Bolouri A, Pakfetrat A, Tonkaboni A, Aledavood SA, Fathi Najafi M, Delavarian Z, et al. Preventing and Therapeutic Effect of Propolis in Radiotherapy Induced Mucositis of Head and Neck Cancers: A Triple-Blind, Randomized, Placebo-Controlled Trial. Iran J Cancer Prev. 2015;8(5):e4019. Epub 20151027. pmid:26634113; PubMed Central PMCID: PMC4667229.
  39. 39. Aghamohammadi A, Moslemi D, Akbari J, Ghasemi A, Azadbakht M, Asgharpour A, et al. The effectiveness of Zataria extract mouthwash for the management of radiation-induced oral mucositis in patients: a randomized placebo-controlled double-blind study. Clin Oral Investig. 2018;22(6):2263–72. Epub 20180108. pmid:29313134.
  40. 40. Ebert N, Kensche A, Löck S, Hadiwikarta WW, Hänsch A, Dörr W, et al. Results of a randomized controlled phase III trial: efficacy of polyphenol-containing cystus® tea mouthwash solution for the reduction of mucositis in head and neck cancer patients undergoing external beam radiotherapy. Strahlenther Onkol. 2021;197(1):63–73. Epub 20200924. pmid:32970162.
  41. 41. You WC, Hsieh CC, Huang JT. Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis. J Altern Complement Med. 2009;15(7):771–8. pmid:19534614.
  42. 42. Soltani GM, Hemati S, Sarvizadeh M, Kamalinejad M, Tafazoli V, Latifi SA. Efficacy of the plantago major L. syrup on radiation induced oral mucositis in head and neck cancer patients: A randomized, double blind, placebo-controlled clinical trial. Complement Ther Med. 2020;51:102397. Epub 20200430. pmid:32507421.
  43. 43. Luo Y, Feng M, Fan Z, Zhu X, Jin F, Li R, et al. Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study. Evid Based Complement Alternat Med. 2016;2016:8692343. Epub 20160607. pmid:27375766; PubMed Central PMCID: PMC4914730.
  44. 44. Naidu MU, Ramana GV, Ratnam SV, Sudhavani T, Naidu KJ, Roy P, et al. A randomised, double-blind, parallel, placebo-controlled study to evaluate the efficacy of MF 5232 (Mucotrol), a concentrated oral gel wafer, in the treatment of oral mucositis. Drugs R D. 2005;6(5):291–8. pmid:16128599.
  45. 45. Fasanaro E, Del Bianco P, Groff E, Riva A, Petrangolini G, Busato F, et al. Role of SAMITAL in the Prevention and Treatment of Chemo-Radiotherapy-Induced Oral Mucositis in Head and Neck Carcinoma: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial (ROSAM). Cancers (Basel). 2022;14(24). Epub 20221215. pmid:36551677; PubMed Central PMCID: PMC9776559.
  46. 46. Pawar D, Neve RS, Kalgane S, Riva A, Bombardelli E, Ronchi M, et al. SAMITAL® improves chemo/radiotherapy-induced oral mucositis in patients with head and neck cancer: results of a randomized, placebo-controlled, single-blind Phase II study. Support Care Cancer. 2013;21(3):827–34. Epub 20120904. pmid:22945882.
  47. 47. Marucci L, Farneti A, Di Ridolfi P, Pinnaro P, Pellini R, Giannarelli D, et al. Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer. Head Neck. 2017;39(9):1761–9. Epub 20170531. pmid:28560780.
  48. 48. Zheng B, Zhu X, Liu M, Yang Z, Yang L, Lang J, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Shuanghua Baihe Tablets to Prevent Oral Mucositis in Patients With Nasopharyngeal Cancer Undergoing Chemoradiation Therapy. Int J Radiat Oncol Biol Phys. 2018;100(2):418–26. Epub 20171013. pmid:29353657.
  49. 49. Wang C, Wang P, Ouyang H, Wang J, Sun L, Li Y, et al. Efficacy of Traditional Chinese Medicine in Treatment and Prophylaxis of Radiation-Induced Oral Mucositis in Patients Receiving Radiotherapy: A Randomized Controlled Trial. Integr Cancer Ther. 2018;17(2):444–50. Epub 20170904. pmid:28870095; PubMed Central PMCID: PMC6041911.
  50. 50. Wu MH, Yuan B, Liu QF, Wang Q. Study of qingre liyan decoction in treating and preventing acute radioactive oral mucositis. Chin J Integr Med. 2007;13(4):280–4. pmid:18180893.
  51. 51. Hamzah MH, Mohamad I, Musa MY, Abd Mutalib NS, Siti-Azrin AH, Wan Omar WA. Propolis mouthwash for preventing radiotherapy-induced mucositis in patients with nasopharyngeal carcinoma. Med J Malaysia. 2022;77(4):462–7. pmid:35902936.
  52. 52. Mamgain RK, Gupta M, Mamgain P, Verma SK, Pruthi DS, Kandwal A, et al. The efficacy of an ayurvedic preparation of yashtimadhu (Glycyrrhiza glabra) on radiation-induced mucositis in head-and-neck cancer patients: A pilot study. J Cancer Res Ther. 2020;16(3):458–62. pmid:32719251.
  53. 53. Pulito C, Mori F, Sacconi A, Casadei L, Ferraiuolo M, Valerio MC, et al. Cynara scolymus affects malignant pleural mesothelioma by promoting apoptosis and restraining invasion. Oncotarget. 2015;6(20):18134–50. pmid:26136339; PubMed Central PMCID: PMC4627240.
  54. 54. Pulito C, Korita E, Sacconi A, Valerio M, Casadei L, Lo Sardo F, et al. Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma. J Exp Clin Cancer Res. 2019;38(1):349. Epub 20190809. pmid:31399037; PubMed Central PMCID: PMC6689183.
  55. 55. Almuhayawi MS. Propolis as a novel antibacterial agent. Saudi J Biol Sci. 2020;27(11):3079–86. Epub 20200914. pmid:33100868; PubMed Central PMCID: PMC7569119.
  56. 56. Przybyłek I, Karpiński TM. Antibacterial Properties of Propolis. Molecules. 2019;24(11). Epub 20190529. pmid:31146392; PubMed Central PMCID: PMC6600457.
  57. 57. Sánchez M, González-Burgos E, Iglesias I, Gómez-Serranillos MP. Pharmacological Update Properties of Aloe Vera and its Major Active Constituents. Molecules. 2020;25(6). Epub 20200313. pmid:32183224; PubMed Central PMCID: PMC7144722.
  58. 58. Chambers CS, Holečková V, Petrásková L, Biedermann D, Valentová K, Buchta M, et al. The silymarin composition… and why does it matter??? Food Res Int. 2017;100(Pt 3):339–53. Epub 20170712. pmid:28964357.
  59. 59. Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res. 2019;33(6):1627–38. Epub 20190508. pmid:31069872.