The World Health Organization (WHO) conceptualizes cancer as a generic term which includes a wide group of diseases that can affect any part of the organism. They are also called “malignant tumours” or “malignant neoplasms”. A defining characteristic of cancer is the rapid division of abnormal cells that extend beyond the common limits and can invade adjacent parts of the body or spread to other organs, a process called metastasis. Metastasis is the main cause of death due to cancer disease [1]. It is indispensable to highlight the word “group” of diseases, considering that they are different entities with common characteristics, such as their genetic origin, uncontrolled proliferation, resistance to cell death, and capability of invading adjunctive tissues or metastasizing in distant organs [2]. Based on this definition, we can indicate the global situation on morbidity and mortality on account of cancer. From the data reported by the international agency for cancer research (IARC, Lyon) in 2018, we can elucidate that the incidence went up to 18.1 million cases, and the mortality climbed to 9.6 million. Additionally, lung, colorectal, and mammary cancers are still the most incident of all. Furthermore, death rates for women are lower than death rates for men [3]. When neoplastic processes are diagnosed, they come along with a treatment. Whether chemotherapy or radiotherapy is used, adverse events are found, with oral mucositis being one of the most common among others, such as diarrhoea or vomiting [4]. It is estimated that conditioning regimens for stem cell transplantation are the treatments that generate the highest rates of oral mucositis incidence, followed by radiotherapy and lastly by chemotherapy ^{[5][6][7][8][9]}[5,6,7,8,9].

All things considered, it is now possible to define oral mucositis more specifically as the inflammation of the oral mucosa, with clinical consequences such as ulcers or erythema secondary to radiotherapeutic or chemotherapeutic treatments [10]. This term differs from the unit “mucositis”, which is considered to be damage and inflammation of oral, pharyngeal, laryngeal, and oesophageal mucosa, together with other areas of the gastrointestinal tract, secondary to antineoplastic treatments such as radiotherapy and chemotherapy [8]. Likewise, sometimes the word “stomatitis” is used as a synonym for oral mucositis (OM) even though it is a different entity because it defines the inflammation in the oral mucosa as being due to another specific aetiology that is unrelated to antineoplastic treatments (e.g., infections) ^[10][11][10,11].

Multiple scales are used to assess OM, but none of them have achieved agreement in the field as being the standard scale. The scales have been classified as general scales (e.g., WHO scale), scales with multiple variables (e.g., Beck, Eliers, and Walsh scales), and those that are specific to OM treatment (e.g., Oral Mucositis Rating, National Cancer Institute, Bethesda, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scales, Brussels) ^[12][13][14][12,13,14].

After OM is evaluated, it is possible to find either mild erythema and a burnt mouth sensation or profound mouth ulcers and the inability to eat. Independent of the clinical presentation, the cause of OM relies on a matrix of heterogeneous processes. There is not one physiopathological mechanism that is the direct cause of OM, but there are instead many complex biological routes. OM is typically based on five stages [8]. The first two of stages have an immediate appearance after chemotherapy, radiotherapy, or chemoradiotherapy. The first phase is the so-called “initiation” phase, and it is based on the death of basal epithelial cells (as a consequence of damage to the DNA in cells as a result of treatment) along with the secretion of reactive oxygen species (ROS) and endogenous damage-associated pattern molecules (CRAMPs), the last of which binds to specific receptors and sets in motion the second stage. This second stage is designated as the “primary damage response” and involves a cascade of biological events that interact with one another and that conclude by activating various transcription factors (nuclear factor kappa-B (NF-κB), Wnt, p53, and their associated canonical pathways) ^{[8][10][11][12]}[8,10,11,12]. For example, NF-κB route activation can occur directly (by antineoplastic treatments) or indirectly (because of ROS and CRAMPs), showing evidence of the complexity of OM physiopathology. The activation of transcription factors produces the expression of a large number of genes, some of them being related to the production of molecules (e.g., COX-2, inducible NO-synthase, superoxide dismutase, etc.) that take part in the secondary emergence of OM. Other routes directly linked with the onset of this pathology exist, such as the nitrogen metabolism pathway, ceramide and fibrinolysis route, and the stimulation of matrix metalloproteinases (MMPs) ^[11][12][11,12].

The third stage is called “signal amplification” and occurs when the primary response molecules have positive or negative feedback on the local tissue. Throughout this period there is no visible injury even though the submucosal tissues and basal membrane are already damaged. Four to five days after antineoplastic treatment, the destructive processes of the three first stages triggers the fourth stage, called the “ulceration stage”. This phase implies the ulceration of the oral mucosa (transecting the full epithelial thickness), with patients being more prone to infections when this happens. Moreover, the ulcers are colonized by oral bacteria, which worsens the initial injury and makes it last longer due to infiltrating macrophages that generate pro-inflammatory cytokines. The “healing stage”, or the last phase, consists of the spontaneous remission of the oral cavity injuries. This event happens as a result of activation from signalling molecules (extracellular matrix) that direct the migration, proliferation, and differentiation of the epithelium bordering ulcerative areas ^[11][12][11,12].

Managing OM is complex. Clinical practice guidelines (CPG) on this topic are scarce and the vast majority are not recent, although there are exceptions. The Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO, Toronto, ON, Canada) have published the most recent clinical practice guideline on the topic of oral mucositis prevention and treatment.

Strategies such as basic oral care are beneficial practices, but they have a low grade of evidence. Therefore, procedures such as a multiagent combination of oral care protocols (providing guidance on the time, frequency, and products that patients with cancer should use every day) are considered beneficial for preventing OM from appearing, and other treatments such as chlorhexidine rinses are contraindicated for the prevention of OM (grade III evidence); nevertheless, saline or bicarbonate sodium rinses, patient education, and professional oral care have insufficient evidence with which to determine whether they positively or negatively impact OM. The use of benzydamine rinses is recommended to prevent OM in patients with head and neck cancers undergoing radiotherapy (RT) or chemotherapy (CT) (grade I and II evidence respectively); on the other hand, with level II evidence, photo-biomodulation (PBM) is recommended in patients with hematopoietic stem cells transplantation (HSCT) for the prevention of OM. Other anti-inflammatory drugs were studied and none of them had enough evidence to present a recommendation ^[8][15][16][8,15,16].

Regarding other drugs, sucralfate is not recommended as prevention or treatment, whereas topical morphine (0.2%) is suggested for OM treatment when it is associated with pain (low evidence grade III) in patients with head and neck cancer undergoing CT and RT. In order to prevent OM onset, oral cryotherapy (ice therapy) is recommended thirty minutes before patients receive 5-fluorouracil (5-FU) boluses when undergoing CT, or when a patient is treated with melphalan in high doses prior to an autologous stem cell transplantation (which means that the donor and receptor are the same human) ^[8][15][16][8,15,16].

In patients affected by haematologic cancer, the use of intravenous keratin growth factor (KGF-1) is recommended for the prevention of OM before an autologous stem cell transplantation with conditioning regimens including high dose CT and total body irradiation (TBI). In this context, neither topical granulocyte-macrophage colony-stimulating factor (GM-CSF) nor parenteral glutamine should be used in the prevention of OM in stem cell transplantation in contrast to what has been said about KFG-1. Oral glutamine plus disaccharide was shown to significantly help mucositis during chemotherapy and autologous BMT in randomized, placebo-controlled trials. However, experts suggest using oral glutamine to prevent OM from appearing in patients with head and neck cancer who are undergoing CT and RT (grade II evidence). Finally, the use of honey has been considered to prevent OM in patients with head and neck cancer who are treated with RT or CT and RT ^{[15][16][17][18]}[15,16,17,18].

The existing clinical practice guidelines about OM do not address, or poorly address, a nutritional treatment approach, leaving unresolved doubts and evidence voids regarding which interventions should be implemented.

2. Nutritional Management and Prevention of Oral Mucositis in Haematology and Oncology Cancer Patients Undergoing Antineoplastic Treatments

2.1. Paediatric Evidence

Al Jaouni et al. (2017) ^[19][47], through an open clinical trial, determined that honey diminished the incidence of the worst oral mucositis grades and delayed its onset. It was also found that honey helped to decrease pain and infections and to reduce the length of hospital stay. Furthermore, honey increased patients’ weight compared with the control group. In contrast, Widjaja et al. (2020) ^[20][27], with their double-blind randomized controlled trial showed a lower incidence of OM in their treatment group with glutamine, proving other results such as a decrease in the severity of OM due to the glutamine and a reduction in treatment duration and lower sanitary costs.

Alternatively, Thornley et al. (2004) ^[21][63] demonstrated an OM incidence and severity reduction along with lower regimen-related toxicity (especially in high-risk patients) thanks to a preparation made of ursodeoxycholic acid, vitamin E, folinic acid and administered as parenteral nutrition as prevention. In contrast, Pattanakitsakul et al. (2020) ^[22][68] proved in their preliminary quasi-randomized trial that vitamin A did not prevent OM.

Oosterom et al. (2019) ^[23][29] in their cohort study provided evidence that basal vitamin D levels were not related to MTX-induced OM, but an association was found (OR = 1.26) between the reduction in vitamin D levels during MTX treatment and severe OM (grade 3 or more). Finally, a case series (3) reported the benefits of honey as an OM treatment in patients undergoing chemotherapy ^[24][44]. Sung et al. ^[25][69] carried out a clinical practice guideline in which they collected all the available evidence about glutamine (and other treatments) for preventing OM in paediatric patients undergoing a conditioning regimen prior to HSCT, and they determined that there was no consistent reduction in OM in more than one study. The only retrieved study that was reviewed in this paper about glutamine in paediatric patients revealed a positive change, with the clinical trial presenting consistent evidence of the effectiveness of glutamine in decreasing the incidence of OM, highlighting the need for more studies before recommending the administration of glutamine (Widjaja et al., 2020) ^[20][27].

In addition, Sung et al. (2015) ^[25][69] established in their review that there was a study of a topical vitamin E treatment that did not demonstrate an effective reduction in OM. In the present study, it was not possible to compare the retrieved article with the Sung et al. (2015) ^[25][69] review since it applied a combination of agents. Nevertheless, it must be emphasised that because of the huge lack of studies with vitamins, it is necessary to identify their effect and implement recommendations based on sufficient data (Thornley et al., 2004) ^[21][63].

The cohort study with vitamin D was not possible to compare with others because additional papers did not exist, corroborating the assertion in the previous paragraph about the lack of evidence on this subject (Oosterom et al., 2019) ^[23][29].

Friend et al., (2018) ^[26][70] clarified in their review that honey could be effective in the treatment and prevention of OM in paediatric patients in limited resources areas but determined that there was no available evidence that compared whether honey was as effective or more effective than other established treatments. The evidence found in this study supported this assertion since the open clinical trial showed the efficacy of honey in OM, but there were no comparative studies between honey and other treatments. Moreover, case series do not have strong enough evidence to be able to reasonably compare them with clinical trials or to state conclusions if additional evidence does not exist (Al Jaouni et al., 2017) ^[19][47].

2.2. Glutamine

Regarding adults and the use of glutamine, Nihei et al. (2018) ^[27][40], Chattopadhyay et al. (2014) ^[28][41], and López-Vaquero et al. (2017) ^[29][48] in their scientific studies did not show a reduction in the total incidence of OM. In contrast, Huang et al. (2019) ^[30][19] and Tanaka et al. (2016) ^[31][21] showed evidence of a reduction in the total incidence of OM; this matches the contribution of a cohort study made by Pachón-Ibañez et al. (2018) ^[32][22], except for the fact that they did not report lower incidence in the severity of OM (grade ≥ 2). The trials conducted by Huang et al. (2019) ^[30][19] and López-Vaquero et al. (2017) ^[29][48] obtained the same result on this matter, contrasting with the results of Tsujimoto et al. (2015) ^[33][20], Tanaka et al. (2016) ^[31][21], Nihei et al. ^[27][40], and Chattopadhyay et al. (2014) ^[28][41] who observed less severity of OM in patients treated with glutamine.

Concerning the time of onset of OM, only three papers addressed this topic, and two of them determined an absence of delay in the onset of OM, contrary to what the Chattopadhyay et al. (2014) ^[28][41] study addressed ^[33][29][20,48]. As for the duration of OM, it was studied in four trials, with a reduction in the duration of the most severe OM proven in two of them ^[28][34][41,64].

Other nutritional factors, such as weight, were studied in five scientific articles, showing a slightly minor tendency in weight loss in those groups with glutamine ^{[31][35][36][37][34]}[21,23,25,33,64]. Additionally, Tanaka et al. (2016) ^[31][21] proved that weight of cancer patients could be maintained by a mixed glutamine and elemental diet ^{[35][36][37][34]}[23,25,33,64].

Quality of life (QoL) was evaluated by López-Vaquero et al. (2017) ^[29][48] through an adapted questionnaire for this topic, but without observing a link between the use of glutamine and OM patients’ quality of life. Other factors such as pain and the use of analgesia (three articles) ^[33][32][38][20,22,51], dysphagia (one article) ^[39][55], and odynophagia (one article) ^[39][55] were studied. The results provided determined that treatment with glutamine improved dysphagia, odynophagia, and pain, showing in two of the studies a pain decrease with analgesia use too ^{[33][32][37][27][39]}[20,22,33,40,55].

Four of the trials delved into a product called Elental ^{® [40][41][42][43]}[28,32,35,38], a liquid dietetic formula enriched with amino acids and a source of L-glutamine. The results showed at large a reduction in the severity of OM in groups treated with Elental ^®, highlighting the investigation of Harada et al. (2019) ^[42][35] that also showed a decrease in the administered analgesia and CRP levels (4–6 weeks of CRT). These results concurred with those obtained by Harada et al. (2018) ^[40][28] in their in vivo study in which rats treated with Elental ^® healed more rapidly from OM ulcers ^[41][43][44][32,38,46].

Regarding its combination with other products, Peterson et al. (2007) ^[45][54] analysed a compound called Saforis ^® (an oral formulation that increases the availability of glutamine in the oral cavity), which proved to decrease the severity of antineoplastic-induced OM. Even though not currently available, a commercially available glutamine + trehalose powder for use as a suspension is now accessible ^[46][71]. Finally, Bateman et al. (2013) ^[47][58] used a combination of whey protein, fatty acid, and glutamine, showing that the combination does not protect against OM in rats. Nevertheless, Anderson and Lalla (2020) ^[46][71] performed a review in which they suggested glutamine rinses (liquid formula) in patients with head and neck cancers undergoing CRT since they found that the rinses decrease the severity and duration of OM and esophagitis. This is comparable with five of the found studies in the bibliographic search, even though all of them studied oral glutamine for rinsing and swallowing afterwards, revealing the same benefits reported in the commented review. Oral glutamine might be beneficial by topical absorption or ingestion if local uptake can be facilitated with a disaccharide. Although other studies have also shown modest benefits for glutamine rinses or ingestion, it would appear that achieving a local effect may possibly increase effectiveness ^{[30][33][32][28][29][46]}[19,20,22,41,48,71].

In addition, Shuai et al. (2020) ^[48][72] recently published a meta-analysis affirming that oral glutamine had no clinical benefits in the prevention and/or treatment of CRT- or RT-induced OM in patients with head and neck cancers. Therefore, glutamine should be studied further in order to obtain more consistent results.

2.3. Honey

Severity is the most studied outcome of honey use. It has been proven that honey is effective in the eventual reduction in the severity of OM, as Howlader et al. (2019) [49], Rao et al. (2017) ^[50][36], and Amanat et al. (2017) ^[51][43] point out in their scientific publications.

Along the same lines, Raeessi et al. (2014) [52] indicated that the efficacy of the combination of honey and coffee for decreasing the severity of OM exceeded the same capacity of honey by itself and steroids. On the other hand, Fogh et al. (2016) ^[39][55] delved into the severity of esophagitis, and they did not find a link between honey and the decrease in OM stage. This same study did not highlight an association between honey and a reduction in late forms of odynophagia (it does not occur in the same way in precocious forms).

Rao et al. (2017) ^[50][36] approached the incidence of OM and proved the benefits of honey in the prevention and delay of the onset of OM. In addition, they showed a reduction in weight loss in their treatment group with this compound. Jayachandran and Balaji (2012) ^[53][59] also observed a delay in the onset of OM in patients treated with honey in comparison with those who were treated with benzydamine; in fact, no effects were found on the duration.

Regarding other parameters analysed, only the study by Howlader et al. (2019) [49] assessed the influence of honey on quality of life (QoL) during OM, observing a late improvement in OM because of the administration of honey. The trial performed by Samdariya et al. (2015) ^[54][56] showed a consistent decrease in the severity of pain, resulting in fewer discontinuances of RT.

As a final remark, Anturlikar et al. (2019) ^[55][24] in their in vitro and in vivo study with a combination of turmeric, Triphala, and honey (HTOR-091516) showed positive results such as low product toxicity, inflammation inhibition (TNF-α), and a protective effect against CT-induced OM.

Münstedt and Männle (2019) ^[56][73] in their review evaluating the use of honey as an OM treatment showed a decrease in the severity of the ulcers, which harmonized with the scientific articles found in the present paper and in the systematic review and meta-analysis conducted by Tian et al. (2020) ^[57][74].

Other aspects mentioned by Tian et al. (2020) ^[57][74] include the indication of a potential decrease in the incidence of OM during the treatment with honey; however, from the present study, only one study proved significant prevention.

There exist other interesting findings, such as OM pain reduction and the inhibition of the inflammatory pathways (in vitro study with “HTOR-091516”), that are not comparable with the mentioned reviews since there is no evidence to suggest or recommend the use of honey under these circumstances. Even though honey could be useful for reducing mucositis severity, the rest of its uses should be studied more in-depth to provide reliable data and to determine suggestions and recommendations on this matter.

2.4. Vitamins and Amino Acids

The most important results of the three retrieved clinical trials showed a reduction in the severity of OM in patients treated with a combination of GeneTime© ^[58][30], group B vitamin complex, Oncoxin© ^[59][26] (combination of vitamin C, B6, and amino acids), and vitamin B9 ^[60][37], proving a reduction in mucositis incidence too. Nevertheless, Branda et al. (2004) ^[60][37] in their cohort study did not find a link between the quantity of vitamins B12, B9, and multivitamins supplements and OM severity.

Specifically, Oncoxin© was related to a weight increase and a normal food intake too ^[59][26]. On the one hand, the combination of GeneTime© and vitamin B proved to result in less pain and quicker healing of OM ulcers ^[58][30]. Finally, treatment with vitamin B9 coincided with the effect of Oncoxin© in the improvement in food intake capacity, but it did not show a reduction in the amount of time using parenteral nutrition; however, it did show a reduction in opioid use ^[59][58][61][26,30,60].

On the other hand, Nejatinamini et al. (2018) ^[62][31] showed that the decrease in the blood levels of vitamins A and D during RT were related to OM. In the same way, an in vitro study determined relevant information since it showed that vitamin E (γ-tocotrienol) in CT fostered the survival of oral human keratinocytes through the inhibition of reactive oxygen species (ROS), probably by the suppression of the Nrf2 route ^[63][65].

Recently, a clinical trial published by Agha-Hosseini et al. (2021) ^[64][66] with a rinse made of vitamin E, hyaluronic acid, and triamcinolone proved to be useful in the treatment of OM. Similarly, another scientific group did a clinical trial with folinic acid for the prevention of OM. However, their results did not prove to be very successful ^[65][67].

Related to the use of complete protein, the study of Perrone et al. (2017) ^[66][45] proved that there was not a link between the intake of concentrated whey protein and the incidence, severity, and duration of OM. However, the individuals who took a higher quantity of whey protein presented less severity and duration of OM compared with those who took a lower quantity of protein. Finally, an in vivo study by De Sousa et al. (2018) ^[67][39] indicated that glycine promoted major and better tissue restructuring.

Regarding non-combined amino acids, a clinical trial and an in vivo laboratory study were highlighted. The rest of the studies related to amino acids (three in total) appeared in combination with other nutritional compounds and have already been mentioned.

Yarom et al. (2019) ^[68][75] considered that vitamin B9 could not be effective in the prevention of OM in patients who received therapy for a posterior HSCT, highlighting a cohort study (which was also analysed in this study) that proved efficacy in the reduction of both total incidence of OM and OM severity in patients undergoing CT for a posterior stem cell transplantation. There exist few studies related to vitamin B9 that have attempted to seek evidence about its benefit.

An evidence void also occurs when studying the treatment of OM with vitamins E and D since both have some studies (four about vitamin E ^{[62][21][63][64]}[31,63,65,66], one about vitamin A ^[22][68], and one about vitamin D ^[23][29]) that determined different effects of the vitamins on OM and thus cannot be compared due to the characteristics used to analyse each study (they used different laboratories, cohorts, clinical trials, etc.). Therefore, supporting what Yarom et al. (2019) ^[68][75] mention in their review, it is not possible to determine consistent evidence for the use of vitamins in the treatment of OM.

In this section, when it comes to analysing the use of amino acids, the fact that there are no reviews about the use of glycine and concentrated WHEY protein was highlighted. As a result, there was a lack of evidence found in this study (two articles, one on each of the topics) for determining whether amino acids could be useful in treating OM.

2.5. Glycyrrhiza Glabra

On the one hand, the study of Mamgain et al. (2020) ^[69][34] and Das et al. (2011) ^[70][62] found both a reduction in the incidence and severity in those groups treated with liquorice (Glycyrrhiza glabra), with more effect than those treated with honey in the same trial. Contrastingly, Matsuda et al. (2015) ^[71][57] proved that the use of Hangeshashinto (mixed with seven medicinal plants, Glycyrrhiza glabra among them) did not affect the incidence and stage of OM, but it did affect the duration of severe OM.

Finally, it should be highlighted that Das et al. (2011) ^[70][62] also found fewer interruptions in the treatment and persistence of xerostomia despite liquorice administration.

OM therapy with liquorice is novel and not often researched. In the present study, there were only a few articles analysed about this compound, making it insufficient for determining clear evidence in support of the compound’s preventive and/or healing effect in OM. Richard (2021) ^[72][76] proved in a review that glycyrrhizin and glycyrrhetinic acids have anti-inflammatory properties, specifically inhibiting interleukin secretion (IL-6, IL-2, IL-12, etc.), the expression of TNF-α, and cytokine cascade, among others.

Even though this literature review did not focus on OM specifically, attention could be drawn towards this matter, since physiopathologically many inflammatory routes are involved in the production of oral ulcers, and compounds such as liquorice (with anti-inflammatory properties) could give results showing the inhibition of inflammatory routes if further research is carried out in the future.

2.6. Others

Elkerm and Tawashi (2014) ^[38][51] delved into the effect of date pal pollen in OM treatment through a preliminary study. Such research showed a reduction in the incidence and severity of RT-induced OM. A reduction in the pain and dysphagia during OM was also proven.

Second, deoxyribonucleic acid was studied by Podlesko et al. (2018) ^[24][44], using it as a topical spray in a case series. The results showed pain relief and quicker healing of OM ulcers in two cases and a deterioration in a third case.

López-González et al. (2021) ^[73][77] proved the efficacy of oral cryotherapy for preventing and treating OM. This evidence was also found in several clinical practice guidelines, highlighting its best utility in the prevention of OM in patients treated with CT. The present study cannot compare the results of the given evidence due to the scarceness of the analysis (two articles ^[74][75][53,61]), but it does agree with the results found in the evidence retrieved from other reviews and clinical practice guidelines ^[8][15][16][8,15,16].

3. Conclusions

In paediatric ages, positive results were found for the treatment and/or prevention of OM, but more investigation is needed since an evidence void exists when it comes to the use of all of the studied nutritional compounds.

Regarding the adult population, glutamine and honey could be the most useful treatment for OM, but more evidence is needed to confirm a reduction in OM severity. In vitamins and amino acids (different from glutamine), little evidence exists. It seems like vitamins could serve as a treatment, but there is scarce evidence, and generally, the investigated formulations did not only include vitamins, making it difficult to prove vitamins’ effects on their own.

It was not possible to present the usefulness of Glycyrrhiza glabra, date palm pollen, and polydeoxyribonucleotides in the prevention and/or treatment of OM in oncological patients due to a lack of evidence. Moreover, cryotherapy was also analysed insufficiently in this study, contrasting with what was found in the scientific literature.

In general, very few scientific publications exist on the nutritional approach to CT- and/or RT-induced OM in cancer patients, even though there is great interest in the study of alternative OM treatments and such studies are highly attainable and easily available.