Effectiveness of topically applied chamomile in the treatment of oral mucositis: a literature review

Oral mucositis (OM) is one of the main adverse events observed during the treatment of neoplasms, especially in relation to head and neck (H&N) cancer. Complications, initially non-infectious of OM, can significantly compromise the chosen therapy, extend the hospitalization period and decrease the quality of life of patients with H&N cancer. Therefore, the present work presents a narrative review that gathers, presents and discusses studies on the relationship between the topical application of chamomile-based pharmaceutical products and the treatment of oral mucositis, with an emphasis on its effectiveness. A literature search was conducted in August 2021 using PubMed, Scielo and LILACS. From literature search was identified 869 papers, of which 06 were selected to answer the guiding question of this study. Finally, it could be seen that chamomile has great potential to help manage OM, as well as other oral complications, especially in cases of patients undergoing H&N cancer treatments using radiotherapy. Furthermore, formulations containing chamomile have been shown to be effective in slowing the progression of OM grades. However, it is necessary to evaluate in each formulation, the possible impacts of each pharmaceutical adjuvant, as well as the adverse events capable of increasing pharmacotherapeutic adherence.


Introduction
Oral mucositis (OM) is one of the main adverse events observed during the treatment of neoplasms, especially in relation to head and neck (H&N) cancer. It is an inflammatory response of the oropharyngeal mucosa, usually ulcerative and extremely painful, observed in patients undergoing both radiotherapy (RT) and chemotherapy (CT). The process of ulceration and infections of the oral mucosa occur as a result of the treatment of cancer located in regions close to the oral cavity, such as the lips, middle ear, oral and nasal cavities, pharynx and larynx (Hong et al., 2019;Daugėlaitė et al., 2019;Santos et al., 2011;Elad et al., 2020). The treatments in question are not specific and as such regions have high mitotic activity and high cell renewal rate, non-neoplastic cells are rapidly affected, both by radiation and by the cytotoxicity of the therapy. In this particular case, adverse events include OM, dermatitis, hyposalivation and xerostomia, rampant caries, pharyngitis, discomfort, osteoradionecrosis and trismus (Sari et al., 2014). Recent studies show that OM affects 20 % to 40 % of patients who receive conventional CT, over 80 % of those who receive high doses of CT, 100 % of patients with H&N cancer who receive RT plus 75 % to 100 % of patients with hematopoietic stem cell transplantation (HSCT) (Santos et al., 2011;Sari et al., 2014;Elad et al., 2020).
According to the World Health Organization, OM can be classified into five grades, based on the clinical appearance and functional status of the patient, where for grade 0, there are no signs or symptoms, grade 1 (low-moderate) the mucosa is erythematous and painful, in grade 2 (moderate) there are ulcers and the patient eats normally, in grade 3 (severe), the patient has ulcers and only feeds with liquids, and in grade 4 (extremely severe) urgent intervention is needed, as the patient cannot eat orally. This can lead to discontinuation, interruption or reduction of the defined dose for cancer treatment (Medeiros et al., 2013;Kawashita et al., 2020;Bensinger et al., 2008).
The pathogenesis of OM is complex, as factors related to the treatment and the patient are determinant in the severity of this event. These factors are reported by the description of clinical cases, reviews, descriptive studies and some analytical studies (Brown & Gupta, 2020). Its treatment, in general, is only symptomatic and will depend on the degree of severity of the lesion. Among the strategies for managing OM, the use of saline (NaCl 0.9 %), sodium bicarbonate, anti-inflammatory Complications, initially non-infectious of OM, may significantly compromise the chosen therapy, extend the hospitalization period and decrease the quality of life of patients with H&N cancer (Elad et al., 2020). Its sequelae include dysphagia, dysgeusia, weight loss and secondary infections, which clinically manifest as stomatitis, usually caused by Candida albicans and the herpes simplex virus (Comodo et al., 2020).
Currently, the pathophysiology of OM comprised of five stages, namely: (i) Onset of damage to the oral mucosa; (ii) Primary damage due to the generation of reactive oxygen species; (iii) Expansion of lesions related to the patient's inflammatory response; (iv) Mucosal ulceration as a result of epithelial apoptosis and tissue necrosishere, extremely painful lesions stand out, designated as passages for oral bacteria, causing infections; (v) Tissue repair due to suspension or termination of RT or CT treatment (Elad et al., 2020).
The repair or healing process involves several steps, but once complete, symptoms tend to disappear in the following days (Sonis, 2004). Even so, after the end of the healing process, the mucosa may persist with changes in its shape, due to changes in angiogenesis and fibroblasts (Almeida et al., 2009). For all these steps to be possible, cell multiplication and differentiation are necessary, until they become part of the mucosal tissue, without a limiting factor interfering with the repair in question. In the case of patients undergoing RT or CT, this process is complicated, and the role of substances capable of optimizing the stages of healing is therefore important. The ability of a substance to block or modify any of the steps in this process can result in successful prevention or management of mucositis (Sonis, 2004).
According to Verginadis et al. (2016), one of the common risks of RT is the development of lesions in the gastrointestinal mucosa, which lead to intestinal mucositis. In order to alleviate this situation and improve adherence to chemotherapy and radiotherapy treatment of patients, there are products on the market such as Ad-Muc  ointment, registered by the company Biolab Sanus Farmacêutica Ltd., located in Taboão da Serra, São Paulo, Brazil. This, in turn, is primarily indicated for the treatment of gingivitis, stomatitis and other inflammations of the oral cavity, being also indicated for episodes of oral irritation resulting from ill-fitting dentures (Anvisa, 2021a).
Among the constituents of this ointment, with anti-inflammatory property, is the extract of Chamomilla recutita (L) Rauschert 100 mg/g (10 % m/m) as active pharmaceutical ingredient, in addition to glycerol, lanolin alcohols, cetostearyl alcohol, white petroleum jelly, solid petrolatum, xanthan gum, methylparaben, mint essence, myrrh tincture, mineral oil, sodium saccharin and purified water (Anvisa, 2021a). To chemical constituents such as camazulene, alpha-bisabolol, bisaboloxides and flavonoids, characteristic of extracts and essential oil of chamomile and that have anti-inflammatory, antibacterial, spastic, sedative and antifungal activities (Ribeiro et al., 2015;Buono-Core et al., 2011), is that the therapeutic potential of that ointment is attributed.
In this context, the therapeutic potential of chamomile extract is observed in relation to the management of oral sequelae resulting from the treatment of H&N cancer. Therefore, the present work presents a narrative review that gathers, presents and discusses studies on the relationship between the topical application of chamomile-based pharmaceutical products and the treatment of oral mucositis, with an emphasis on its effectiveness.

Methodology
This is a narrative, qualitative review, with the following guiding question: What is the scientific evidence on the use of chamomile in the treatment of OM in patients undergoing chemotherapy and RT?
A literature search was conducted in August 2021 using PubMed, Scielo and LILACS. To search for articles, the following descriptors were used: "oral mucositis", "cancer" and "chamomille", using the Boolean operators "AND" and "OR".
Duplicate articles, comments, theses and dissertations, abstracts published in conference proceedings and scientific journals, letters to the editor, were excluded news, book chapters and review articles.

Results
From literature search was identified 869 papers, of which 06 were selected to answer the guiding question of this study. A flow diagram (Figure 1) was developed to demonstrate the steps in the process of this narrative review. Thus, carefully respecting the previously established inclusion and exclusion criteria, it was observed that, in general, the articles found present information on the use of chamomile in the treatment and prevention of OM, alleviating the symptoms and accelerating the healing process due to its anti-inflammatory properties (Table 1). Assess the dental condition of patients with H&N cancer undergoing surgery associated with RT or exclusive RT, through a protocol able to visualize possible changes in the different phases of treatment, in order, through guidance and/or treatment, to prevent, diagnose and control injuries of the maxillomandibular complex resulting from surgical and RT procedures Observational prospective cohort study The use of mouthwash with chamomile tea (5x/day) plays an important role in the degree and relief of OM symptoms, a fact associated with the anti-inflammatory action of chamomile. The development of grade 1 OM may be related to the application of preventive measures for oral adequacy before the start of treatment, as well as the maintenance of these measures during the period of RT Yes -Legend: "-" = absence. Source: Authors.

Discussion
OM is associated with a set of adverse events that can limit the patient's ability to tolerate anticancer treatment if not properly managed. Thus, it is crucial to develop effective preventive and curative treatment options in relation to this clinical condition. In this regard, it is worth commenting that in Brazil the importance of implementing natural products as a therapeutic alternative for various diseases has been seen since the publication of the National List of Medicinal Plants of Interest to the Unified Health System (RENISUS) (de Almeida et al., 2020).
According to Almeida et al. (2009), chamomile has therapeutic potential in relation to negative adverse events caused by RT and CT.
The Among the various botanical synonyms of chamomile that exist, the most used in studies for medicinal purposes is M.
chamomilla, simply called chamomile, due to its widespread use in traditional medicine and its medicinal potential continuously described in the specialized literature, it has been the target of recurrent phytochemical investigations, which are important for the analysis of their pharmacological activities on the pathology highlighted in this review. Among these actives, we can highlight matricin and its transformation products (camazulene and alpha-bisabolol), whose biological activities are many, with emphasis on their anti-inflammatory and healing process stimulation properties (Anvisa, 2021a).
Among the pharmacological activities of camazulene, present in chamomile essential oil, its potential antiinflammatory action stands out, attributed to inhibition of leukotriene synthesis and additional antioxidant effects (Buono-Core et al., 2011). Spasmolytic, antipeptic and antibacterial effects described from the use of alpha-bisabolol are also reported (Mazokopakis et al., 2005).
A study that evaluated the daily use of chamomile tea as a mouthwash showed a reversal of grade 3 mucositis to grade 2 after 13 days of treatment, leading to complete healing in four weeks (Ribeiro et al., 2015). Of the selected articles, only one referred to adverse events, and the non-verification of their occurrence after the administration of mouthwashes containing chamomile extract was reported (Köstler et al., 2001).
According to Gomes et al. (2018), the anti-inflammatory activities of chamomile, especially the synonymy M. recutita, are mediated by the inhibition of prostaglandin release and induced by lipopolysaccharide and by the reduction of the activity of the type 2 cyclooxygenase enzyme (COX-2). Thus, it is noted that this medicinal plant has a high potential for the treatment of OM, as it can promote the inhibition of pro-inflammatory cytokine actions, influence the chemotaxis of leukocytes and lipopolysaccharides, in addition to promoting the activation of macrophages (Aghamohamamdi & Hosseinimehr, 2015;Ribeiro et al., 2015).
The results presented by Barreto et al. (2020) demonstrate that chamomile tea associated with the provision of information related to correct techniques for oral hygiene, obtained non-significant results. However, in this study only patients undergoing chemotherapy were included. It is known that, according to Santos et al. (2011), the incidence of OM in patients undergoing cancer treatments is higher for those undergoing RT. This fact should be considered in the study by Barreto et al. (2020), for presenting a selection bias when defining the study inclusion criteria.
In Thus, when composing a pharmaceutical form, chamomile extract should be used respecting the usual concentrations that, according to Yarom et al. (2020), should be between 0.5 and 2.0% for topical use products such as mouthwashes. Added to this, the appropriate choice of other inactive pharmaceutical ingredients, which can impact the adherence to pharmacotherapy of the patient, whose oral mucosa is sensitive and inflamed (Ribeiro et al., 2020).
In fact, some substances can cause some discomfort while using the product. In this sense, Ribeiro et al. (2020) mentioned that multifunctional excipients such as sorbitol and glycerol, which have humectant and sweetening properties, however, are polyalcohols capable of interacting with water through hydrogen bonds and favoring tissue dryness. Other adjuvant substances such as azo dyes and sodium saccharin should be avoided as they promote adverse events.
In parallel, different potentially efficient excipients in the treatment of OM are indicated in the literature. Among these, the use of honey, zinc, selenium, topical vitamin E and glutamine stands out as complementary treatment to reduce the risk of developing OM during CT or RT (Gonçalves et al., 2020). It is also reported the use of sodium alginate with the potential to reduce the discomfort and severity resulting from the ulcerative process of this pathology, this by stimulating the synthesis of collagen and cell proliferation from the stimulus in the transformation of secretion of factor Beta 1 (TGFβ1) growth on skin wounds (Braga et al., 2015).
Despite the high therapeutic potential of chamomile, it is important to carefully choose the other pharmaceutical ingredients in the formulation, as well as the pharmaceutical form to be prepared to minimize discomfort during its use and ensure adherence to pharmacotherapy. It is noteworthy the lack of data on the use of sodium alginate and other substances that can help as a synergistic factor in formulations for topical use for the prevention and treatment of OM. In short, it is suggested that dosage forms containing chamomile be strategically optimized so that adjuvants do not interfere in the management of this pathology.
Research, Society andDevelopment, v. 10, n. 14, e433101422081, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i14.22081 8 In 2020, an impacting factor emerged in the treatment of patients with H&N cancer due to the dissemination of the new coronavirus (Sars-Cov-2), responsible for Covid-19. This was due to the reduction in the number of surgeries performed due to the increase in medical demand aimed at controlling the pandemic and due to the increased incidence of this infection in health professionals. It was observed that, on average, 10 % (from 4.8 to 37.5 %) of the H&N cancer surgeons, who worked in reference oncology services, were contaminated with the virus. High contamination rates among health professionals reduced their availability for patient care (Gonçalves et al., 2020).
Furthermore, it is known that delays in diagnosis, surgeries, and treatments for H&N cancer can significantly increase the attributable mortality rate when compared to the management of the Covid-19 pandemic. Both surgeries and treatments are highly impactful in terms of years of life gained by spent resources (Gonçalves et al., 2020).

Final Considerations
In view of the bibliographical survey carried out, it could be seen that chamomile has a great potential to help manage OM, as well as other oral complications, especially in cases of patients undergoing H&N cancer treatments using RT.
Furthermore, formulations containing chamomile have been shown to be effective in slowing the progression of OM grades.
However, it is necessary to evaluate in each formulation, the possible impacts of each pharmaceutical adjuvant, as well as the adverse events that increase the pharmacotherapeutic adherence.
To definitively clarify the effectiveness of chamomile in the treatment of OM, it is suggested to carry out a randomized clinical study in patients undergoing HSCT, RT or RT associated with CT, using different formulations containing exclusively chamomile and appropriate adjuvants.