Introduction

Radiotherapy has been an effective method in the treatment of cancer in the head and neck region [1, 2]. However, this therapy type causes orofacial comorbidities during and after treatment, such as oral mucositis (OM), saliva change, dental caries, osteoradionecrosis, and radiodermatitis in more than 80% of cases [3, 4]. OM is a painful pathology that generates nutritional impacts, decreases the quality of life, changes cancer therapy, and increases economic costs for public health [5]. Radiotherapy in the head and neck region usually causes changes in the function of the salivary glands and cell death in the oral mucosa and oropharynx, evidencing hyposalivation (dry mouth) and consequently, OM [6, 7].

The most recent studies on OM mainly used the classification proposed by the World Health Organization (WHO) [8]. The development of OM is considered in four stages: vascular, epithelial, ulcerative, and repair. The first phase is due to the release of cytokines as a tumor necrosis factor that induces an increase in subepithelial vascularization. Soon after, in the second phase, an unwanted effect occurs in the cells with the inhibition of cellular DNA synthesis, being directly linked to epithelial renewal. The ulcerative phase is the one that harms the patient’s quality of life since there is a greater susceptibility to infections due to the breakdown of the mucosal barrier [9].

OM is the most common comorbidity observed during chemoradiotherapy in virtually all patients with oral squamous cell carcinoma (SCC), being classified by the WHO from grade zero to grade V, according to the observed clinical severity [10–12]. The complex origin of OM involving local and systemic predisposing factors makes it difficult to adopt treatments that are at the same time effective, easy to use, and inexpensive for patients. In this context, products containing medicinal plant extracts have been proposed for the treatment of OM [13]. Several forms of treatment for OM have been proposed, considering the anti-inflammatory and antimicrobial properties of drugs, since the breakdown of the mucosal barrier is the gateway to colonization by fungi such as Candida albicans and bacteria from the oral microbiome [14].

The use of natural products for the treatment of diseases that affect human beings was one of the first forms of medicine in the world [15]. Propolis is a natural product resulting from the mixture of chemical components collected from plants with the saliva of the bees. Brazilian green propolis has different botanical and regional origins: Baccharis dracunculifolia, Vernonia rubriramea (savannah region), and Mimosa tenuiflora (dry region), and has a complex chemical constitution of chalcones, flavonoids, triterpenes, prenylated phenylpropanoids, chlorogenic acids, and condensed tannins [16–19]. The biological properties, quality, and origin of propolis have been proven through several methods, including high performance liquid chromatography (HPLC) and gas chromatograph-mass spectrometer (GC-MS), by identifying its chemical components [16, 17]. Several works have proven the potent anti-inflammatory action of one of the compounds of propolis, artepillin C (3,5-diisopentenyl-4-hydroxycinnamic acid), and also its various antioxidant, antibiotic, and cytotoxic actions, which act synergistically among its more than 400 components [19]. The biological activities of propolis seem to be associated with the synergism between its chemical compounds, which give it anti-inflammatory, antimicrobial, healing, immunoprotective, anesthetic, and antioxidant characteristics [20–26]. The main chemical components found in Brazilian green propolis are shown in Table 1. The objective of this work is to report a series of three clinical cases of cancer patients diagnosed with grade IV OM and treated with mucoadherent gel content of 5% green propolis.

Cases report

Mucoadherent gel formulation and prescription

The study with the mucoadhesive propolis gel was previously approved by the Human Research Ethics Committee of Federal University of Minas Gerais (No.0249.0.203.000-10) in Noronha et al. [22]. The propolis mucoadherent gel (OncOralcare^®, lot reference number GD030717.DV, manufactured on July 2017 and expiry date on July 2019) was produced by Néctar Pharmaceutica Ltda (Belo Horizonte, Brazil), according to required standards by the Brazilian National Health Surveillance Agency (ANVISA), working license (MS 0.48631.1), under ISO 9001: 2000-good manufaturing practices (resolution No. 275/2002), National Institute of Metrology (certificate No. 54448-A-2009-AQ-BRA-INMETRO), Det Norske Veritas (certificate No. 54507-2009-nb) certified company (Figure 1). Green propolis chemical components were identified for scientific studies by HPLC and reverse phase [27–30]. The gel final composition was composed of Brazilian green propolis (5%), propylene glycol, hydroxypropyl methylcellulose, polysorbate 20, and purified water. The final concentration of 5% is justified by the in vitro experiments against microorganisms and previous clinical trial studies [24, 27]. Patients applying it three times a day every 8 h were instructed to use a portion equivalent to a coffee spoon (10 g). It was recommended to apply the gel to the entire mucosa with finger wearing latex gloves provided to the patient or companion [22]. Patients were encouraged to apply the gel at night before going to bed, that is, sleeping with the gel inside their mouth.

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Figure 1. 

The physical aspect of the propolis OncOralcare^®—mucoadherent gel content of 5% green propolis

Case report 1

Patient A.D.S., male, melanoderm (dark skinned), 62 years old, presenting grade IV OM (Figure 2) in which oral feeding was no longer possible, given that the medical recommendation was to suspend the radiotherapy treatment. The patient came with a companion, he was unable to speak and already in the initial anorexia phase, with low self-esteem and suffering. The patient was in the fourteenth session when the radiotherapy was interrupted. He signed the free and informed consent form in the first clinical consultation, after completing the clinical form and taking the anamnesis. Adjustment of the oral cavity was performed by removing the fibrinopurulent pseudomembrane with sterile gauze and successive washes with 10% hydrogen peroxide diluted in sterile deionized water, followed by washing with saline solution until the free, hygienized ulcerated mucosa was observed. The mucoadhesive propolis gel was applied with the finger throughout the mucosa, wearing sterile gloves. The patient received a tube containing 100 g of gel for daily use, free of charge. Monitoring was done weekly and through daily contact via cellphone so that the patient did not interrupt or forget to use the gel three times a day, every 8 h. There was regression of approximately 70% of the ulcerations (Figure 3) after 7 days, and with total regression of the lesions after 15 days of using the gel (Figure 4). There was a significant improvement in the quality of life and appearance of the patient who could already speak without the presence of a companion. With the improvement of his clinical condition, it should be highlighted that A.D.S. shaved his mustache and beard, showing up at the clinic with a more groomed and elegant personal appearance on the 7th and 15th day after the application of the gel. The patient was forwarded to the hospital and the oncologist of origin, and radiotherapy was restarted. The constant use of the propolis gel was indicated throughout the radiotherapy period and for six months after the end of the oncological treatment to avoid recurrences, keep the mouth lubricated, and prevent caries and periodontal disease. The patient was followed up for 6 months after the oncological treatment and no mucositis recurrence was observed. However, A.D.S. returned after 1 year, presenting a new ulcerated lesion on the tongue dorsum suggesting SCC recurrence. A biopsy confirmed the diagnosis. The use of propolis gel was suggested throughout the duration of the new cancer treatment, with no signs of OM being observed.

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Figure 2. 

Patient A.D.S.: oral mucosa clinical aspect presenting grade IV OM before gel content propolis application

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Figure 3. 

Oral mucosa clinical aspect 7 days after the gel content propolis application

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Figure 4. 

Oral mucosa clinical aspect 15 days after the gel content propolis application

Discussion

In order to treat grade IV OM lesions in three patients, mucoadhesive gel content green propolis was used as the therapy of choice due to the anti-inflammatory, antimicrobial, antitumor, immunostimulatory, and healing properties of propolis [27, 31] and also due to the fact that it is a natural product, which does not have side effects that prevent its use and being well accepted by patients. Propolis gel is easy to apply and inexpensive, which is another positive point for its prescription [32, 33]. In this clinical study, patients received the gels free of charge in bottles containing 100 g of the product and it is worth emphasizing the need to adapt already proven treatments in the literature to the reality of each patient. Most patients who seek dental care at Faculty of Dentistry of Federal University of Minas Gerais have low purchasing power and belong to a discriminated social class. Therefore, the biodiversity and the high production of Brazilian green propolis help in the final costs and the gel is inexpensive, making it accessible to patients in general. The therapeutic choice selected was effective and favored nutrition and the consequent improvement in the quality of life of these patients, who were in a situation of physical and psychological frailty. Several clinical studies have reinforced the effectiveness of propolis originating from both Brazil and other countries [6, 8, 34–36], however, there are few clinical cases published on the use of mucoadherent gel for the treatment of grade IV OM. Patients A.D.S., M.T.O., and M.A.S. received treatment for OM for 2 months in a hospital environment, with no regression of the lesions being observed when artificial saliva, antifungal, analgesic, and anti-inflammatory drugs were used. The success in the treatment with the propolis gel was due to biological activities and also, in part, to monitoring and assistance through telephone contact on a daily basis, to encourage use and avoid forgetfulness, as well as face-to-face clinical care once or more times a week, if necessary. Conducting a clinical, double-blind, and randomized study using the same propolis gel is needed for scientific proof of the treatment against grade IV OM.