Mucositis is an adverse event that occurs in 65% of patients receiving radiotherapy for head and neck tumors. Grade 3 or 4 (CTCAE) adverse events occur in about 11% of patients, and oncological treatment should be discontinued as it limits feeding and puts life at risk. To date, there is no universal care protocol to prevent this complication, so the use of toothpaste enriched with spirulina is proposed to prevent severe mucositis as well as a faster recovery. Three cases of tongue cancer with bioradiotherapy are presented, in which patients are instructed regarding oral hygiene, using toothpaste with spirulina, maintaining biofilm control and elimination of irritants in the oral cavity. Although all of them had grade 3 mucositis, with the presence of xerostomia, ulcerations and pain, which led them to change their usual diet to a soft diet, the toothpaste provided a feeling of relief. In no case was any radiotherapy or cetuximab session suspended, achieving a favorable recovery.

Keywords: lingual cáncer, oral mucositis, spirulina, arthrospira

Oral cancer is considered a public health problem, ranking 16th among the most common malignant neoplasms worldwide, increasingly affecting young men and women.^1–3 Of these, more than 90% are squamous cell carcinomas,⁴ with the tongue being the most affected site, followed by the oropharynx, lip, buccal mucosa, floor of the mouth, gingiva and palate.^5,6 The anterior two-thirds of the tongue are considered part of the oral cavity, while the posterior third, the base of the tongue, is a sub site of the oropharynx. Although histologically they are similar, they differ in treatment, prognosis and follow-up.⁷ Unfortunately, tongue cancer, like other oral cancers, is diagnosed in advanced stages, which is associated with an unfavorable prognosis, with 5-year survival rates of around 50% of patients.⁷ Among the implications of lingual cancer, the deterioration in the quality of life stands out, which in turn complicates the pathology itself, coupled with the decrease in quality of life associated with the different treatments, that is, independently, surgery, radiotherapy or chemotherapy, or the combination of these, either due to pain, alterations in chewing, swallowing, taste, phonation, quantity and/or quality of saliva, appearance, which affects mood, recreation, affecting the level of anxiety.⁵ Mucositis is one of the most common effect of chemo-radiotherapy in patients with head and neck cancer. The probability of mucositis is 100%, but only high-grade cases requiring treatment.^8–10 Mucositis is an inflammatory response of both the oral mucosa and the tract. Antineoplastic treatments alter epithelial cell turnover between 7 and 14 days in direct mucositis, and between 10 and 21 days the lesions are associated with a bacterial and/or fungal infection that is a side effect of hyposalivation combined with neutropenia.^8,9

The development of mucositis is divided into five phases or stages:

1. Release of reactive oxygen species (ROS), thus p53-regulated apoptosis, increased caspase 3 and release of endogenous damage-associated pattern molecules (DAMP).
2. Positive regulation or response to primary damage, through different signaling pathways, pro inflammatory cytokines, cell adhesion molecules and metalloproteinase are activated, which cause damage to connective tissue such as endothelial tissue.
3. Signal amplification, a feedback of pro inflammatory cytokines. The signal favors apoptosis, the cell cycle is inhibited and mediated signaling (DAMP) increases.
4. Ulceration. Appears clinically between 3 and 5 days after administration of the drug and resolves within 2 weeks. The loss of mucosal integrity favors infections, which increases mononuclear inflammation.
5. Healing. Cell differentiation allows proliferation, repairing the integrity of the epithelium.^8,9

Other factors that affect the presence of mucositis are the route of administration, advanced age (children under 10 years of age have less severe symptoms and a shorter duration of chemotherapy),¹¹ increased body mass and female gender, which are associated with a higher risk of developing severe mucositis. Genetic factors such as polymorphisms related to the production of TNF-α,^8,9 or genes related to enzymes that metabolize drugs such as 5-fluorouracil (5-FU), since the deficiency to catalyze dihydropyrimidine dehydrogenase, increases the risk of mucositis.^8,11 The oral environment is another risk factor, determined by the state of health. Poor oral hygiene, xerostomia, and changes in the immune response are factors that modify the oral microbiota, which can favor the presence of mucositis;⁹ therefore, adequate dental care is essential, which should include the removal of all mucosal irritants, removal of orthodontic appliances, and minimizing the use of dentures. The periodontium is considered the largest reservoir of microorganisms and therefore, control is essential.¹¹

The only drug approved for the prevention of mucositis, both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), is palifermin, a recombinant human keratinocyte growth factor 1 (KGF-1), which promotes faster tissue regeneration after inducing damage, and has antioxidant, antiapoptotic and anti-inflammatory actions.⁸ Other products used in the prevention and/or treatment of mucositis are caphosol,¹¹ photobiomodulation,^8,11 benzydamine hydrochloride,^9,11 morphine,¹¹ pentoxifylline,⁸ dusquetide, SGX942,⁸ amifostine, glutamine, zinc supplements, vitamin E, vitamin A, N-acetyl-cysteine ​​(NAC),⁸ Camellia sinensis leaf extract (green tea and hydrolyzed palmitoyl wheat protein),⁹ honey,^9,11 clonidine lauriad (Clonidine Lauriad®), turmeric,⁸ indigo root or Rhodiola algida, chamomile (or its components such as chamazulene, α-bisabolol, bisbolol oxides spirometers and flavonoids), Aloe vera,^8,9 essential oils such as peppermint,⁹ combination of manuka (Leptospermum scoparium) and kanuka (Kunzea ericoides),^8,9 Calendula officinalis L. (marigold), Phoenix dactylifera L. (date palm), Catechu, Rhodiola algida Fisch and C. A. Mey (stonecrop), Salvadora persica or miswak or chewing stick, the hydroalcoholic extract of Ziziphus Jujuba.⁹ On the other hand, Arthrospira known as "Spirulina" is a cyanobacteria, formerly blue-green microalgae, with a wide variety of bioactives,^12,13 it is an ancestral food and a nutraceutical with various benefits for human health. Its properties include being antioxidant, anti-inflammatory, immunomodulatory, anticancer, chemopreventive, antiviral, antibacterial, probiotic, antifungal;¹³ in addition, it has shown regression in oral leukoplakia¹⁴ as well as improving the symptoms of oral submucous fibrosis (mouth opening and ulcers/erosions/vesicles)¹⁵ and reducing burning.¹⁶ Kaur and Kaur¹⁷ report that the numerous compounds, more than 70 bioactive, such as C-phycocyanin, β-carotene, calcium spirulan, linoleic and linolenic acids, are important in the prevention of carcinogenesis, especially for its antioxidant, anti-inflammatory and immunomodulatory effects, which favors the apoptosis of tumor cells and improves endonuclease activity, DNA repair. In CAL-27, FaDu and HGF cell lines, Spirulina is considered a natural, safe and effective photosensitizer for photodynamic therapy of oral and hypopharyngeal cancer, with no cytotoxic effect on normal cells.¹² Meanwhile, in colon cancer and liver cancer lines, Spirulina has a dose-dependent antiproliferative effect.¹⁸ Also, Spirulina has a cytotoxic and antiproliferative effect on the non-small cell lung carcinoma cell line, A549¹⁷ (Czerwonka et al., 2018, in Kaur and Kaur, 2021) and inhibits the growth of MCF-7 breast cancer cells,¹⁷ (Ouhtit et al., 2013, in Kaur and Kaur, 2021), a component of Spirulina, phycocyanin, is a potent antiproliferative effect in human melanoma cells A375, as well as, inducer of apoptosis in HeLa cells in vitro.¹⁷ The effects of Spirulina in murine models are related to a modulation of the p53-Bax-Bcl-2 pathway, in addition to an increase in glutathione activity, the negative regulation of several kinases, the selective inhibition of cyclooxygenase-2 and increased activation of various caspases.¹⁷ Spirulina has a bone protective effect against the harmful effects of gamma radiation in the jaws of adult male albino rats,¹⁹ while there is a regression of cancer induced in the hamster buccal pouch, in addition to showing a hepatoprotective effect in the same type of animals when using methotrexate²⁰ and anti-teratogenic when using cyclophosphamide in CD-1 mice.²¹ Currently there is no universally accepted protocol to prevent or treat mucositis, a common disorder in patients with anticancer treatments, which compromise the treatment itself, the quality and even the life of the subject, which is why it is essential to maintain oral hygiene with adequate brushing, as well as with the support of auxiliaries such as interproximal cleaners, the use of mouthwashes and toothpastes. On the other hand, Spirulina is a low-cost cyanobacteria, with beneficial properties for humans, including protection, which can improve and/or maintain the tissues of the oral cavity in adequate condition. The objective of this study is to recognize the effects on the oral mucosa of a toothpaste enriched with Spirulina in patients with lingual cancer under bio-radiotherapy.

The research corresponds to a quasi-experimental study of preventive therapeutic intervention with repeated measures, prospective cross-sectional, with a convenience sample.

Subjects

Patients who presented to the medical oncology service of the ISSSTE “Fernando Quiroz” Hospital, where they were diagnosed with lingual cancer, and who were treated with bio-radiotherapy were selected. From February to December 2024, there were 3 patients. Each patient was given all the information so that they could freely and voluntarily agree to participate, giving their signed informed consent in writing.

Preparation of spirulina toothpaste

For the preparation of the Spirulina toothpaste (TEA), the ingredients used were of food-grade quality, and their selection was based on the consulted literature. The ingredients included sodium benzoate (E211) (NaC₆H₅CO₂), calcium carbonate (CaCO₃), carbopol 940, carboxymethylcellulose (R_nOCH₂-COOH), sodium lauryl sulfate (SLS) (NaC₁₂H₂₅SO₄), menthol, saccharin (E954), sorbitol, and spirulina, in the following proportions: 1:52:1:3:4:2:1:22:13, respectively. Additionally, purified water was added in an amount based on the desired consistency of the mixture. For Arthrospira maxima (Spirulina maxima), the commercial brand Spiral Spring® (Mexico City) in powder form was used, and the other ingredients were purchased from Farmacia Paris® (Mexico City) and Droguería Cosmopolita® (Mexico City). Once the mixture (TEA) was prepared, it was packaged into toothpaste tubes and aluminum cans with screw caps, measuring 6.3 cm x 2.5 cm (60 mL), which were previously sterilized in an autoclave.

Using toothpaste

Each patient was given general recommendations on oral hygiene and provided with information (digital media) on brushing. In addition, they were asked to use only the Spirulina-enriched toothpaste, with the recommended frequency and amount, without making any other changes.

Evaluation of toothpaste

After 15 days of use, a questionnaire was applied on the perception of the spirulina-enriched toothpaste,²² which addresses the way of use, the changes noticed by the patient, as well as the organoleptic characteristics. After this time, patients began radiotherapy, in order to distinguish the changes caused by radiation. The oral status of the patients was clinically evaluated during different periods, with a variation of 15 days to 1 month, when they came for collecting their toothpaste.

The clinical trial included the voluntary participation of 3 female patients diagnosed with lingual cancer. The following table shows the characteristics of the patients (Table 1). The patients received 77 Gy/33 fractions, as well as a weekly dose of cetuximab 250 mg/m2, all patients received 5 weeks of treatment.

Case 1: oral status was maintained with oral hygiene, in the 17th radiotherapy session presented mucositis that evolved to stage III, increasing the frequency of use of toothpaste with Spirulina, resulting in discomfort in ulcers on the tongue in the most acute phase. Even so, she reported that she preferred to use it. Improvement occurred within one week (Figure 1), although improvement of mucous membranes is reported, dental pain persists when chewing.

Figure 1 Photographs of case 1.

(A) Initial panoramic view in occlusion, (B) Initial tongue, (C) & (D) More acute stage of grade III mucositis with erbitux (cetuxumab) in the 17th radiotherapy session, with a larger area of involvement in the tongue, especially on the left lateral edge, so it is recommended to increase the use of Spirulina toothpaste, the use of Hydral® GUM® spray and gel and a soft diet, E; After 15 days, F; After 3 weeks

Case 2: like case 1, continued oral hygiene and tooth 17 was observed, which did not present discomfort or worsening of Mucositis. The mucositis occurs in a more irregular manner, affecting different areas of the oral mucosa, requiring a soft diet and Hydral® GUM® (Figure 2).

Figure 2 Photographs of case 2.

(A) Initial panoramic view in occlusion, (B) Initial tongue, (C) Presence of generalized grade III mucositis

Case 3: Initially, she reports that the toothpaste improves the cleanliness of her teeth. After fifteen days of use, she generally considers that it provides her with better oral hygiene, but when the mucositis begins, she reports that she feels a favorable effect on her gums, halitosis. Grade III oral mucositis (Figure 3) is also accompanied by xerostomia, so the use of Hydral® GUM® is indicated, also leading to a soft diet.

Figure 3 Photographs of case 3.

(A) Mucositis with the main lesions in the tongue, initial, (B) and (C) presence of mucositis

In all cases, oral mucositis was present, which affected the quality of life, especially with regard to eating and pain associated with ulcers. Even at the most acute moments, patients preferred the use of toothpaste with Spirulina since it provided relief. In these cases, xerostomia was also a frequent finding, and hence it was decided to complement the treatment with Hydral as well as dietary recommendations, which allowed them to complete their bioradiotherapy sessions.

Although oral mucositis is a frequent side effect of cancer therapy, there is no universally accepted protocol^8,9,11 and therefore more studies are required with alternatives that improve the quality of life of patients. In this clinical case, natural products (Spirulina) are considered as the alternative that can be used as an adjuvant in the treatment of mucositis. Among the natural products in the food field, there is a group called nutraceuticals that are considered important elements in “proactive medicine”, mainly in the prevention of some disease.²³ An example of a nutraceutical is Spirulina, a cyanobacteria that offers many benefits, since it has multiple biological activities that have been researched and proven.⁹ Spirulina has been shown to have chemopreventive potential, capable of reversing potentially malignant lesions due to its antioxidant, immunomodulatory,²⁴ and anti-inflammatory properties, as well as being antimicrobial with effects against viruses, bacteria, and fungi. It is considered to be an antibiofilm, thus reducing infections, and it promotes healing.²⁵ Spirulina can be considered an option in the complementary treatment against oral mucositis caused by radiotherapy. The three cases presented showed grade II or III oral mucositis according to the WHO classification; in addition, the ulcers and pain present in the pathology led to a decrease in eating and swallowing food. Discontinuing antineoplastic treatment is usually the option mentioned above, and consequently patients may be hospitalized, increasing costs and decreasing quality of life.^8–11,26 Thus, in all three cases, dietary modifications were made, but the use of the Spirulina-enriched toothpaste remained unchanged because its use provided relief to the subjects. Brushing (before radiotherapy), professional cleaning and application of fluoride were used as additional protection.

Menthol is a monoterpenoid and one of the components of mint essential oil. It is used in toothpaste to improve organoleptic characteristics such as the smell and taste of Spirulina as most people find it unpleasant. Menthol promotes refreshing and cool perceptions by stimulating transient potential melastatin 8 (TRPM8) receptors, its absorption and resulting excitation of nerve fibers is inversely proportional to the thickness of the keratinized stratified squamous epithelium and the sensitivity of the trigeminal nerve.²⁷ It is reported to have antibacterial, antiviral, antifungal, thirst-quenching, analgesic and nausea-reducing activities. It also improves perceptual characteristics related to thermal comfort, taste sensation and sensitivity.²⁷ Mouthwashes containing mint in chemotherapy-induced oral mucositis are effective and tolerated by patients.⁹ Clinically, it is reported that in 40 patients with oral submucous fibrosis, where the mucosa presents inflammation, ulcerations, pigmentation, loss of elasticity and flexibility, the use of spirulina was an effective treatment by significantly reducing the burning sensation and opening of the mouth, attributing these results to its anti-inflammatory and antioxidant properties.²⁴ Daily brushing and exploring the use of novel medications or compounds that promote faster recovery of patients in order not to further deteriorate their quality of life has been agreed upon by some authors.⁹ The polysaccharides (glucose, galactose, mannose, and ribose) contained in Spirulina have been suggested as agents in the healing process by maintaining the humidity of the site, promoting the formation of granulation tissue, stimulating proliferation of fibroblasts and keratinocytes, increasing angiogenesis and collagen deposition; likewise, they reduce the inflammation process by decreasing cytokines and transcription factors (TNF-α, NF-B, TlR-4, VEGF), the apoptosis process (AIF, caspase-3) and reducing the expression of the HGMB-1 protein involved in the regeneration of damaged tissues and as an antifibrotic agent.^25,28

Research reports that spirulina promotes fin regeneration in zebrafish (Danio rerio).²⁵ ale Wistar rats, topical application of spirulina on wounds and burns promotes healing,²⁸ as well as increasing the rate of epithelial cell proliferation and vascularization, decreasing inflammation and free radicals, and controlling infection, using a heteropolysaccharide (rhamnose, xylose, glucose, and mannose) isolated from spirulina and enriched with carbon dioxide.²⁵ Other components of spirulina such as phycocyanins have a healing effect when a cream based on them is applied.²⁵ The consumption of spirulina tablets in patients with atrophic lesions associated with geographic tongue, favors the reduction of its size, associated with anti-inflammatory and regenerative activities on the oral mucosa, which coincides with the reduction of ulcers, erosions and vesicles.²⁹ In the case of patients with oral submucous fibrosis after 3 months of use, 500 mg of spirulina with 0.1% triamicolone was significant in the sensations of burning, mouth opening and painful ulcers.³⁰ Although the clinical cases presented in this study are diagnosed with oral mucositis, the use of toothpastes enriched with spirulina requires specific studies on the effects of the mucosa in patients with bioradiotherapy, but it is an indication that it reduces the pain associated with the ulcers present with probable acceleration of the healing of these lesions. The pigments such as chlorophyll, phycocyanin and carotenoids contained in Spirulina, it is used as a natural photosensitizer for photodynamic therapy against oral and hypopharyngeal cancer cells in CAL-27, FaDu and HGF cell lines that are irradiated with a 635 nm diode laser at different energy densities with constant power, the results being encouraging, since it induces death in cancer cell lines, but without cytotoxic effect on normal cells.¹² During the wound healing stage, it is very important to restore the redox balance, which involves increasing antioxidant defenses (enzymatic and non-enzymatic) and decreasing free radicals (mainly oxygen). Spirulina is an excellent antioxidant as it contains phycocyanins, carotenoids, γ-linolenic acid (GLA, 18:3 n-6) and selenium.²⁵ The omega-3 fatty acid (⍵-3), present in spirulina, helps reduce inflammation by altering the cellular functions of polymorphonuclear leukocytes. In addition, it completely inhibits the production of arachidonic acid metabolites by the cyclooxygenase and lipoxygenase pathways, limiting tissue damage.²⁴ Although the use of agents that help treat the complications of the disease is relevant, it is essential to maintain adequate or optimal hygiene in order to keep to a minimum the superinfections and the complications that may occur with oral mucositis, such as bacteremia and sepsis.¹⁰

The periodontium is the largest reservoir of microorganisms,¹¹ which is why in a Sprague Dawley rat model, 12% spirulina gel was applied to the gum and it was observed that it favors angiogenesis and the density of collagen fibers, and therefore, accelerates healing.³¹ Brushing with the spirulina-enriched toothpaste in the cases presented maintained the periodontal status, despite the difficulties in maintaining hygiene and the pain caused by mucositis. Maintaining a micro-ecological balance is ideal in any situation where an injury occurs, such as in the oral cavity, and while most microorganisms are harmless, the presence of Streptococcus mutans, Actinomyces sp., Treponema denticola, Tannerella forsythia, Bacteroides sp., Aggregatibacter actinomycetemcomitans, Staphylococcus intermedius, Porphyromonas gingivalis and Candida albicans³² can promote the accentuation of large infections. Spirulina is a prebiotic and contains phycocyanins that effectively inhibit the growth of Aspergillus fumigatus, A. niger, Candida albicans and Escherichia coli,²⁵ so its potential in the prevention and control of infections may be beneficial in oral mucositis. There is no doubt that damage to oral tissues due to bio-radiotherapy is common in patients with tongue cancer, and hence it is necessary to maintain oral health with the help of low-toxic, accessible and cost-effective products and/or compounds.

The cases presented are an approximation to a natural product spirulina, which, when applied in toothpaste, offers temporary relief that allows patients with oral mucositis to complete their bioradiotherapy, thereby providing a better prognosis and quality of life. In addition to requiring studies that can demonstrate its effectiveness as an antioxidant, anti-inflammatory, antimicrobial and regenerative agent, the positive comments of the patients presented in this case in relation to toothpaste with spirulina favor continuing to promote its use. Undoubtedly, multidisciplinary work is required in the treatment of lingual cancer, exploring treatment alternatives that improve, with a dental approach to the elimination of local factors that further complicate the oral condition.

None.

The authors declare no conflicts of interest.

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