|Year : 2016 | Volume
| Issue : 2 | Page : 66-72
New Treatment Approaches of Oral Mucositis: A Review of Literature
Narges Gholizadeh, Nafiseh Sheykhbahaei, Maryam-Sadat Sadrzadeh-Afshar
Department of Oral and Maxillofacial Medicine, Dental Faculty, Tehran University of Medical Sciences, Tehran, Iran
|Date of Web Publication||12-Sep-2016|
Department of Oral and Maxillofacial Medicine, Dental Faculty, Tehran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
Oral mucositis (OM) is described as inflammation of the mucosa in the oral cavity which is caused by destruction of the oral mucosal epithelial cells and growth suppression secondary to cancer treatment in the form of radiotherapy or chemotherapeutic drug substances. It is the most debilitating condition and the most common complication in cancer patients. It appears first by thinning of oral tissues which leads to erythema. As these tissues become thinner, ulceration eventually occurs. Potential complications include pain, increased risk of local and systemic infections, bleeding and insufficient food intake and may lead to breaks in treatment sessions. It is usually associated with pain, increased risk of infection and dysphasia and may lead to inadequate hydration and impaired nutritional status. Traditional management of OM has involved patient compliance and education, hydration, nutritional support, use of saline rinses, topical and systemic pain relief and infection surveillance and treatment. The PubMed, Medline, Ovid, Science Direct and Google were searched from 1998 to 2015. The search terms used for medical subject heading were 'oral mucositis' and 'new treatments of mucositis'. Unfortunately, there is not a single method which is capable of preventing or eliminating OM in an efficient way. In this article, we reviewed new therapeutic methods of OM including cryotherapy, honey and coffee, propolis, low-level laser therapy, growth factors, stem cell therapy, hyaluronic acid-based substances and matrix metalloprotease blockers.
Keywords: Adverse effect, new treatments, oral mucositis
|How to cite this article:|
Gholizadeh N, Sheykhbahaei N, Sadrzadeh-Afshar MS. New Treatment Approaches of Oral Mucositis: A Review of Literature. Adv Hum Biol 2016;6:66-72
|How to cite this URL:|
Gholizadeh N, Sheykhbahaei N, Sadrzadeh-Afshar MS. New Treatment Approaches of Oral Mucositis: A Review of Literature. Adv Hum Biol [serial online] 2016 [cited 2020 Aug 14];6:66-72. Available from: http://www.aihbonline.com/text.asp?2016/6/2/66/190319
| Introduction|| |
Oral mucositis (OM) is described as inflammation of the mucosa in the oral cavity which is caused by destruction of the oral mucosal epithelial cells and growth suppression secondary to cancer treatment in the form of radiotherapy or chemotherapeutic drug substances., Although it is less common, OM also can occur secondary to chemotherapy of various solid tumours. It is the most debilitating condition and the most common complication in cancer patients. Typical manifestations are atrophy, erythema, ulceration and swelling of the mucosa. It appears first by thinning of oral tissues which leads to erythema. As these tissues become thinner, ulceration eventually occurs. Potential complications include pain, increased risk of local and systemic infections, bleeding, insufficient food intake and may lead to breaks in treatment sessions.
Myeloablative (bone marrow-suppressing) chemotherapy is associated with 60%–100% risk of mucositis induction, while the combination of radiotherapy and chemotherapy is associated with a risk of almost 100%. OM and xerostomia commonly occur in patients with cancer, particularly squamous cell carcinoma in the head and neck region treated with radiotherapy directed at the oral, submandibular and pharyngeal areas. The aetiology of OM is directly due to the effect of chemotherapy and radiotherapy on the oral mucosa. There are also several risk factors influencing on the development of this complication including patients' age and gender. Some researches indicated that older peoples appear to be at an increased risk due to insufficient DNA repair mechanisms, while another study suggested that younger populations seem to be at greater risk that may be related to the more rapid rate of proliferation of the epithelial cells. Female gender, smoking, excessive alcohol use, defective restorations, orthodontic appliances, ill-fitting prostheses and any source of mucosal irritation are associated with an increased possible risk of developing OM during anticancer treatment. Treatment-related risk factors including daily, repetitive radiation treatment, radiation source, dose intensity, cumulative dose, type of chemotherapeutic agents and the volume of irradiated mucosa. In general, risk of developing OM increases directly as a function of medical agents used in the antineoplastic treatment, with the highest risk occurring with more aggressive chemotherapeutics such as cisplatin and 5-fluorouracil (5-FU) with or without radiation therapy and the lowest risk occurring with 'gentler' agents such as gemcitabine (Gemzar ®). Chemotherapy-induced OM usually begins within the 1st week after the initiation of treatment and the peak is in the 2nd week. Radiation-induced mucositis typically develops after about 10 days, at a cumulative dose of about 15 Gy and usually peaks full severity at a dose of 30 Gy, and lasts for several weeks or even months. It is usually associated with pain, increased risk of infection and dysphasia and may lead to inadequate hydration and impaired nutritional status.,,, These complaints are getting further complicated by xerostomia and taste alterations that may lead to anorexia, nutritional deficiencies, weight loss and weakness.
OM also can increase the risk of poorer outcome of antineoplastic treatment because of the need for treatment interruptions in some patients. Traditional management of OM has involved patient compliance and education, hydration, nutritional support, use of saline rinses, topical and systemic pain relief and infection surveillance and treatment. Palliative treatments also have been used including palifermin and benzydamine. Briefly, cancer therapy-related OM is usually described as the most debilitating and significant acute complication associated with chemotherapy and radiation therapy. In this article, we reviewed new therapeutic methods of OM.
The PubMed, Medline, Ovid, Science Direct and Google were searched from 1998 to 2015. The search terms used for medical subject heading were 'oral mucositis' and 'new treatments of mucositis'.
| Discussion|| |
OM is a common, painful and debilitating side effect of radiation therapy and chemotherapy noted by varying degrees of erythema, atrophy and ulceration of the mucosa. It has a significant negative impact on the quality of life (QOL) and produces pain and discomfort, poor oral intake, delays in administration of radiotherapy and or chemotherapy, dose reduction of the chemotherapy drugs, increased length of hospital stays, associated economic burdens and in some cases life-threatening infections (septicaemia in neutropenic cases). Few medical interventions are efficient in reducing the duration or severity of mucositis, and up to now, there are no universally accepted medical treatment protocols. Unfortunately, there is not a single method which is capable of preventing or eliminating OM in an efficient way. According to evidence-based clinical guidelines for mucositis management by the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) which were published in May 2004, traditional management of OM has involved patient compliance and education, using non-medicated saline rinses, hydration, nutritional support, topical and systemic pain control measures and infection control and treatment. Furthermore, enhanced understanding of the precise pathologic basis of OM is leading to the development of new targeted agents that will subsequently allow single-agent or combination strategies which is based on patient risk. Phases in the development of OM include destruction of these tissue compartments, including cellular signalling, messaging and amplification processes that can lead to the upregulation of pro-inflammatory cytokines; epithelial cell apoptosis; ulceration (and potential sepsis in severe neutropenic patients); and, finally, healing. However, within each of these phases, there are a number of pathways which can serve as suitable targets for new treatment approaches. Novel treatments designed to combat processes involved in the initiation of OM or to accelerate healing process are now in development.
| Cryotherapy|| |
It has been traditionally hypothesised that topical use of ice chips in the oral cavity during chemotherapy can result in decreased delivery of the anticancer chemotherapeutic drugs to the oral mucosa. Presumably, this process is mediated through local vasoconstriction leading to reduced blood flow. Several researches have demonstrated that cryotherapy can reduce the severity of OM in patients under chemotherapeutic treatment. The MASCC/ISOO guidelines suggested the use of cryotherapy in patients who are receiving bolus doses of melphalan, 5-FU and edatrexate 51 to reduce OM. Five minutes before the administration of chemotherapy, ice chips should be placed in the mouth and replenished if needed for up to 30 min. Cryotherapy is only effective for short-bolus chemotherapeutic infusions, and in some patients, it may not be well tolerated, so it does not have any role in radiation-induced OM. However, this intervention becomes ineffective, although oral cryotherapy can significantly reduce OM in melphalan/fluorouracil conditioning receiving allogenic stem cell transplantation. Salvador et al. in 2012 suggested that oral cryotherapy and an oral care protocol seem to be successful in reducing the severity of OM compared with an oral care program alone. In this article, the primary outcome of OM severity and secondary outcomes of OM-related functional intake of food and beverage and pain were evaluated at days 1, 3, 6, 9 and 12. Another study in 2012 suggested that oral cryotherapy has a great contribution to the protection of patient's oral health by reducing OM score according to the mucositis scale of the WHO, especially on the 7th–14th days. Patients were instructed to hold ice cubes just before, during and just after the infusion of leucovorin with 5-FU in their mouth. In 2013, Vokurka et al. found that incidence of OM was greatly lower in the cryotherapy group. They noted that reduced oral tissue damage which is mediated by oral cryotherapy did not appear to lead to reduction in the fevers of unknown origin and intravenous antibiotic use. In one research which was done in 2014, the efficacy of oral cryotherapy plus laser on decreasing OM severity to laser therapy alone was compared. The cryotherapy/laser therapy group had lower OM scores and also the lower mean number of days with mucositis in comparison with the other groups (P < 0.001). In 2015, Svanberg et al. investigated the effects of combining Caphosol ® to cryotherapy to further protect against OM, but they did not find any additional effect of adding Caphosol ® with oral cryotherapy. Caphosol ® is a supersaturated neutral calcium phosphate (Ca2/PO4) mouthwash. It has been proposed to exert a prophylactic action against chemotherapy-induced OM and also diffusion of ions to intracellular spaces of the epithelium to permeate mucosal lesions.
| Honey and Coffee|| |
It has been found that honey constitutes of more than 200 substances including sugars, minerals, some vitamins, proteins, organic acids and antioxidants such as phenolic compounds, flavonoids, enzymes, carotenoid-like substances, amino acids and other phytochemicals. According to several studies, honey by its antioxidant properties can increase cytokine release and also has antimicrobial effects. Furthermore, it can prevent tissue cells from oxidative damage that leads to ageing, disease susceptibility and death. Honey can reduce inflammation and oedema, stimulate epithelialisation and tissue regeneration and therefore may improve granulation and debridement which accelerate tissue repair and wound healing results. Sweet substances of the honey stimulate saliva secretion in the oral cavity and also mucus secretion in the airways. Caffeine is a natural alkaloid which is found in coffee, tea, cocoa and cola drinks. Bronchodilators such as methylxanthines (caffeine and theophylline) stimulate breathing and can be used in the prevention of apnoea. Caffeine also has hypoalgesic, antioxidant and anti-inflammatory properties. It is the most commonly used psychoactive substance that stimulates the central nervous system. Moreover, caffeine improves psychomotor performance, increases self-reported alertness and also decreases self-reported sleepiness and weariness. Coffee or coffee-specific compounds which contain antioxidant properties also have some protective effects against tissue damage, oxidative DNA damage and liver lesions such as hepatotoxicant-induced fibrosis. Coffee consumption also diminishes liver-induced insulin resistance.
The mechanism of action of 'honey' in the management of OM is not definitely known, but acidity, osmolality and hydrogen peroxide production have been suggested to be the main factors. By decreasing prostaglandin synthesis at the area of application, honey reduces plasma prostaglandin concentrations. It also has anti-inflammatory and antioxidant effects and increases the level of nitric oxide in the lesions. Furthermore, honey and coffee are both have been mentioned in complementary medicine and also their combination is acceptable and safe.
OM can be successfully treated by the 'mixture of coffee and honey' in a short time. Compared with topical steroids, it can be used as an alternative treatment modality in the management of OM.
| Propolis|| |
Propolis is a resinous substance which is produced by honey bees. They also collect it from the exudates of plants and is used to seal holes of the beehive. Propolis also forms part of folk medicine, and chemical evaluation has revealed at least 300 components in its composition. It has many biological properties, such as antioxidant, anti-tumour, anti-inflammatory, anti-microbial and immunomodulatory effects, as well as other biological properties of honey. Propolis is mainly because of the phenolic compounds such as flavonoids which have been reported to have a wide range of biological properties, including antibacterial, antiviral, anti-allergic, anti-inflammatory and vasodilatory actions. Furthermore, flavonoids inhibit lipid peroxidation, capillary permeability, platelet aggregation and fragility and the activity of cyclo-oxygenase and lipoxygenase. Noronha et al. reported that honey produced faster wound healing in patients with Grade 2 and 3 chemotherapy-induced OM.
In addition, Noronha et al. showed that mucoadhesive propolis gel can be considered as an effective topical medication for preventing radiation-induced OM. However, a comparative Phase III clinical trial study with larger number of cases should be done to confirm the efficacy of the product. Moreover, in one study, it was demonstrated that propolis is effective in delaying and reducing radiation-induced OM in an animal model, nevertheless, further study and evaluation are required.
| Low-Level Laser Therapy|| |
Multiple researches have shown that low-level laser therapy (LLLT) can reduce the severity of OM, although the exact mechanism of action is not known. It has been assumed that LLLT may reduce the levels of pro-inflammatory cytokines and/or reactive oxygen species (ROS) which contribute to the pathogenesis of OM. It is difficult to compare the studies due to different laser types and parameters including wavelength and power. However, based on the successful results, the MASCC/ISOO guidelines also suggest the use of LLLT in OM at medical centres that are able to support the required training and technology.
The continued investigation of new treatment modalities to attenuate OM for improving both the efficacy and tolerability of the radiotherapy in head and neck cancer has been introduced by LLLT which is thought to have anti-inflammatory, analgesic and wound healing effects, without any known clinical toxicity.
Optimal details of this technology such as type of light source, dose schedule and wavelength are not worked out yet, and its use requires special training and certification. LLLT is atraumatic, non-invasive and well tolerated by patients that explain why the use of this technique in the oral cavity of cancer patients is increasing. Several studies have indicated that the LLLT can minimise the severity and pain in OM.
The outcome produced by the LLLT depends on the capacity to regulate different metabolic pathways, via conversion of the light energy through photophysical and biochemical processes, which convert the laser light energy into useful energy to the cell. Visible laser light is absorbed in the respiratory cycle of the mitochondria by chromophores that increase the ATP production which results in more cellular proliferation and protein synthesis, facilitating tissue repair. LLLT also increases collagen synthesis and cell activity throughout healing period that ultimately leads to decreased levels of inflammation and pain.,
For pain relief, it has been indicated that stimulation of peripheral nerve by laser changes polarisation of the neuron membrane and increases the concentration of ATP, thereby contributing to the maintenance of membrane stability and increasing the pain threshold. Furthermore, the LLLT can raise peripheral endogenous opioid and enkephalin secretion and serum prostaglandin E2. However, pain relief also results in significant improvements of basic oral functions, including eating, drinking, swallowing and speaking., Optimum wavelength to promote healing in ulcerative and inflamed tissue is between 680 and 880 nm. Previous investigations have shown that application of He-Ne laser in hematopoietic cell transplantation receiving patients can significantly reduce the duration and severity of ulcerations in OM.
| Ozonated Water|| |
Ozone is a molecule with clinical applications in medicine and dentistry due to its anti-inflammatory, antimicrobial, biosynthetic (activator of lipid, protein and carbohydrate metabolism), antihypoxic, bioenergetic, hemostatic and analgesic properties. Ozone is very successful in lysing bacteria, fungi, yeast and mould. Ozone directly attacks inflamed cells, with loss of enzyme layer, therefore ensuring that the attack is solely targeted on these cells. In the study of Yildirim et al., ozonated water was used in stress-associated gastric ulcer cases. They reported a significant reduction in the occurrence of Type I–III ulcers. In another study, Volpato et al. have reported faster wound healing when ozone is used in comparison with other disinfectants. It also helps in the reduction of the pain associated with OM and enables faster recovery of the patient and sooner returns to daily activities. Nonetheless, there are very few studies of the administration of ozonised water in the management of OM. Therefore, ozonised water can be applied as an option for the existing treatment methods.
| Growth Factors|| |
Growth factors which may have an impact on OM are granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), keratinocyte growth factor (KGF) and Interleukin 11. Some studies suggest that GM-CSF or G-CSF can reduce the severity of OM by accelerating neutrophil recovery. Both agents have been applied as topical and parenteral agents.
Recombinant human keratinocyte\growth factor-1 or palifermin is the other compound shown to reduce OM induced by cytotoxic chemotherapy and radiation therapy. This molecule is the first inventive 'target-based' biologic agent to prevent OM. Palifermin has several mechanisms of action, such as inhibition of DNA damage and apoptosis in the epithelial cell; downregulation of pro-inflammatory cytokines and also stimulation of epithelial cell proliferation, growth, differentiation and migration.
Stiff et al. in 2016, evaluated long-term safety outcomes (disease progression, incidence of secondary malignancies and overall survival) between palifermin and placebo in the prevention of OM in patients with haematological malignancies and undergoing autologous HSCT. They found that after a follow-up period of about 15 years, comparable long-term safety results were observed for palifermin and control groups undergoing autologous HSCT.
Repifermin or human KGF-2 has been investigated in phase II clinical trial, in which patients experienced conditioning chemotherapy before autologous hematopoietic stem cell transplantation. Repifermin notably reduced the incidence of Grades 2, 3 and 4 of OM.
Decreased glutamine concentrations are seen frequently in many malignancies and can support and protect keratinocyte proliferation to replenish the mucosa. Saforis (AES-14) is a swish and swallow oral suspension containing L-glutamine designed to increase local and systemic glutamine levels to serve as a mucoprotective. Glutamine is an amino acid which is necessary for cell mitosis and only acts in the prevention from OM by decreasing the production of pro-inflammatory cytokines responsible for cell apoptosis.
| Regorafenib|| |
Regorafenib is an oral multikinase inhibitor which targets factors involved in oncogenesis (RET, KIT, B-RAF and RAF-1), angiogenesis and modulation of the tumour microenvironment. However, in preclinical studies, anti-tumour activity of regorafenib was seen in different tumour models, such as models of gastrointestinal stromal tumour (GIST) and colorectal carcinoma (CRC). Therefore, this substance holds promise as a new accepted standard of care for GIST and CRC patients after disease progression following other approved therapies. Although the most common side effects of regorafenib include mucosal and dermatologic toxicities (particularly hand–foot–skin reaction, OM and rash), constitutional symptoms such as nausea, weight loss and fatigue, vascular effects (mainly hypertension) and gastrointestinal symptoms (especially diarrhoea).
| Stem Cell Therapy|| |
The principal properties of stem cell that make it distinct from any other various cells in the body are first, self-renewal, which is the ability to participate in multiple cycles of cell division while remaining in their undifferentiated state and the second property is differentiation, which is the potential to evolve into specialised cell type. Stem cells have anti-inflammatory property, immunomodulatory functions and regenerative properties. However, their therapeutic efficacy can be increased by transgenic approach and also preconditioning them with certain factors such as pro-inflammatory cytokines.
In the study of Zhang et al., gingiva-derived mesenchymal stem cells (GMSCs) were injected to mice with chemotherapy-induced OM and subsequently they found that treatment with GMSCs reduced the incidence and severity of ulcerations and also restored the lining and thickness of the mucosal epithelial layer, as compared with control group. The improved therapeutic advantages of GMSCs may be because of their increased potential of engraftment and survival at the injured sites, preconditioning to oxidative and hypoxic challenges and transdifferentiation into epithelial cells. Hence, GMSCs could prove to be a reliable shot therapy in OM following the cancer therapies.
| Episil|| |
Episil, which is a preservative free liquid, has been provided in a convenient pocket-sized, ready-to-use, spray device for intra-oral administration. It gives pain relief by mechanical barrier action. This product contains a patented combination of phospholipids and glycerol dioleate, and after administration, quantities of aqueous fluid present rapidly in the oral cavity; the liquid–lipid mixture self-assembles to form a robust protective membrane which strongly adheres all over the oral mucosa. The intended use of episilis is the treatment of pain induced by OM caused by radio- and chemotherapy. It causes no systemic adverse effects and does not have any interactions with other treatments.
| Advantages of Episil|| |
- Clinically demonstrated acceptable pain reduction
- Long-acting effect with duration of at least 8 h
- High-level bioadhesion demonstrated in clinical trials
- Lipid-layer protection of injured oral mucosa
- Revealed safety with no systemic effects
- Ready to use, multi-dose device and pocket-sized.
| Hyaluronic Acid|| |
In the submucosa, the production of ROS can be involved in the onset of mucositis. Cirillo et al. suggested a probable protective effect of a joinery formulation of hyaluronic acid rich with amino acids; in vitro and in vivo studies showed that spray of mucosamin is effective versus the injury induced by oxidative stress. Breaking down the ROS is the main mechanism of mucosamin to barricade the dissemination of oxidative stress. They thought that oxidative stress can induce senility in stromal fibroblasts; this phenomenon can play a key role in damaging effects in the epithelium. The evidences support this hypothesis that irreversibly senile fibroblasts through paracrine mechanisms were able to change migration, metabolic activity and function of keratinocytes. The use of Gelclair ® (OSI Pharmaceuticals, Melville, New York, USA), hyaluronic acid gel, promotes pain relief because it forms a protective layer that covers the ulcerations, providing less discomfort during the ingestion.
| Matrix Metalloproteases Blockers|| |
All chronic ulcers are known to contain excessive amounts of proteolytic enzymes such as matrix metalloproteases (MMPs). MMPs is responsible for proteolysing protein debris which is a natural physiological mechanism to clean the ulcer and produce a favourable ground for cells to growth, but unluckily they also proteolyse cell matrix proteins. For healing process, young mucosal cells should attach onto a matrix that is secreted before cell division by the mother cells to form a basis for the daughter cells. However, this matrix is cell-specific and comprises various proteins such as laminin, elastin, hyaluronic acid, collagen, fibronectin and other proteins in specified proportions. In the absence of this matrix, daughter cells cannot grow and attach, so ulcers cannot heal. In fact, as MMPs destroy cellular matrix, they hamper daughter cell attachment and therefore block cell growth in the OM ulcers. In one study, an osmotically active hypertonic solution comprising specific protease-inhibiting plant procyanidins (OROSOL) was applied which is capable of cleaning the ulcers, removing the contaminants and also stimulating cell growth as a new therapeutic approach for the management of OM. Compared to the traditional treatment groups, OROSOL group showed notably higher improvement in burning sensation, pain, grade of infection, eating abilities and overall mucositis, but the rate of new ulcer formation was not decreased.
| Other Treatments|| |
Jin-Xiang Lin et al. in 2015, compared the efficacy of iodine glycerine cream and dioctahedral smectite (DS) with topical mouth rinse which is composed of gentamicin, saline and Vitamin B12, in the treatment of chemotherapy-induced OM. DS that is natural adsorbent clay and formed of sheets of aluminomagnesium silicate is efficient in protecting gastrointestinal mucosa. Natural clay acts to enhance the intestinal barrier, reduce microbe and prevent the mucosal damage. Non-antibiotic topical antiseptics, including gentian violet, silver coordination polymers and iodine solutions, are effective in the treatment of mucosal injuries and have strong antimicrobial properties. They showed that DS cream dramatically decreased the Oral Assessment Guideline score and also shortened the OM duration.
Another study evaluated the effect of Achillea millefolium distillate solution as a treatment option in the treatment of chemotherapy-induced mucositis. According to conclusions, A. millefolium distillate promoted healing much more than the general routine solution. Hence, it is suggested for the treatment of patients with chemotherapy-induced OM. Of course, this herbal medication has been used in ancient medicine for the treatment of different diseases in general, and injuries, burns and infections, in particular. In addition, it has anti-allergic, antibacterial, anti-congestion, anti-inflammatory and anti-spasmodic effects and also exerts beneficial effects on cardiovascular, nervous and digestive systems.
In 2014, Hadjieva et al. compared the analgesic effect of CAM2028 plus benzydamine with unmedicated CAM2028 for the treatment of OM. CAM2028 is a vehicle which forms a bioadhesive lipid barrier layer when applied to the oral mucosa and actually was developed as a carrier system to the local delivery of non-steroidal anti-inflammatory drugs and benzydamine, which are used for pain relief in OM. They concluded that there was no significant difference in pain deduction between the two interventions. Both treatments were well tolerated and safe.
In 2016, Chen et al. in an animal study evaluated the effect of a new peptide on radiation-induced OM and tumour growth. Twenty-one amino acid peptides which are derived from Antrum mucosal protein (AMP)-18 can mediate growth promotion of the normal-cultured epithelial cells and mitigate radiation-induced OM. Synergism between AMP peptide and radiotherapy has been suggested by the findings that tumours in the AMP peptide and radiotherapy cohort demonstrated inhibited growth versus radiotherapy only treated tumours, while AMP peptide treatment delayed the initiation and decreased the severity of radiotherapy-induced OM. A differential effect on apoptosis seems to be one of the mechanisms by which AMP-18 can induce growth and repair of damaged mucosal epithelial cells. These findings confirm the notion that tumour cells and normal cells can respond differently to biological stimuli, and that leveraging the above-mentioned findings in the case of AMP-18 can provide a clinically relevant opportunity. A brief review of recent clinical trials has been demonstrated in [Table 1].
|Table 1: Summary of randomised clinical trials evaluating the new treatment modalities of oral mucositis|
Click here to view
| Conclusion|| |
OM is a very debilitating and painful condition for patients who undergo chemotherapy and radiotherapy. It may cause a change in treatment regimen. Therefore, prevention of this problem is essential especially with the approach of addressing the treatment of the underlying oral disease and improve oral hygiene. There are several supportive and palliative treatments for mucositis; however, a standard treatment for this disease has not been confirmed. Today, there are pharmacologic and non-pharmacologic methods for treating mucositis, particularly a combination of these methods together can create greater therapeutic effects. In recent years, researchers have suggested new promising methods for the treatment of mucositis, most important of which are stem cell transplantation and growth factors. These techniques can be very effective and have fewer side effects than previously used. We hope that in the near future, more controlled clinical trials need to be designed to assess the effectiveness of these methods on pain reduction, nutrition improvement and increase the QOL in patients with mucositis.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Alvariño-Martín C, Sarrión-Pérez MG. Prevention and treatment of oral mucositis in patients receiving chemotherapy. J Clin Exp Dent 2014;6:e74-80.
Rohani B, Pourfar K, Pourshahidi H, Ebrahimi SH. Oral manifestation of hematologic malignancies. Jundishapur Sci Med J 2015;14:477-85.
Redding SW. Cancer therapy-related oral mucositis. J Dent Educ 2005;69:919-29.
Jadaud E, Bensadoun R. Low-level laser therapy: A standard of supportive care for cancer therapy-induced oral mucositis in head and neck cancer patients? Laser Ther 2012;21:297-303.
Silverman S Jr. Diagnosis and management of oral mucositis. J Support Oncol 2007;5 2 Suppl 1:13-21.
Khan M, Gupta N. Oral mucositis. E J Dent 2013;3:405-11.
Köstler WJ, Hejna M, Wenzel C, Zielinski CC. Oral mucositis complicating chemotherapy and/or radiotherapy: Options for prevention and treatment. CA Cancer J Clin 2001;51:290-315.
Cirillo N, Vicidomini A, McCullough M, Gambardella A, Hassona Y, Prime SS, et al.
A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro
and prevents oral mucositis in vivo
. J Cell Physiol 2015;230:1421-9.
da Mota Vasconcelos Brasil C, Serpa MS, Tenório de França TR, Lisboa de Castro JF. Management of oral mucositis. Arch Oncol 2011;19:57-61.
Quinn B, Potting CM, Stone R, Blijlevens NM, Fliedner M, Margulies A, et al.
Guidelines for the assessment of oral mucositis in adult chemotherapy, radiotherapy and haematopoietic stem cell transplant patients. Eur J Cancer 2008;44:61-72.
Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A, et al.
Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011;4:CD000978.
Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol 2006;4(2 Suppl 1):9-13.
Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008;52:61-77, viii.
Raeessi MA, Raeessi N, Panahi Y, Gharaie H, Davoudi SM, Saadat A, et al.
“Coffee plus honey” versus “topical steroid” in the treatment of chemotherapy-induced oral mucositis: A randomised controlled trial. BMC Complement Altern Med 2014;14:293.
Salvador P, Azusano C, Wang L, Howell D. A pilot randomized controlled trial of an oral care intervention to reduce mucositis severity in stem cell transplant patients. J Pain Symptom Manage 2012;44:64-73.
Katranci N, Ovayolu N, Ovayolu O, Sevinc A. Evaluation of the effect of cryotherapy in preventing oral mucositis associated with chemotherapy – A randomized controlled trial. Eur J Oncol Nurs 2012;16:339-44.
Vokurka S, Chvojkova I, Svoboda T, Brandejsova R, Jungova A, Bystricka E, et al.
The impact of oral cryotherapy and oral and gastrointestinal mucositis after autologous stem cell transplantation. Eur J Oncol Nurs 2014;18:228-9.
de Paula Eduardo F, Bezinelli LM, da Graça Lopes RM, Nascimento Sobrinho JJ, Hamerschlak N, Correa L. Efficacy of cryotherapy associated with laser therapy for decreasing severity of melphalan-induced oral mucositis during hematological stem-cell transplantation: A prospective clinical study. Hematol Oncol 2015;33:152-8.
Svanberg A, Öhrn K, Birgegård G. Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation. A pilot study. Eur J Oncol Nurs 2015;19:50-3.
Viuda-Martos M, Ruiz-Navajas Y, Fernández-López J, Pérez-Alvarez JA. Functional properties of honey, propolis, and royal jelly. J Food Sci 2008;73:R117-24.
Abdulrhman M, Elbarbary NS, Ahmed Amin D, Saeid Ebrahim R. Honey and a mixture of honey, beeswax, and olive oil-propolis extract in treatment of chemotherapy-induced oral mucositis: A randomized controlled pilot study. Pediatr Hematol Oncol 2012;29:285-92.
Noronha VR, Araujo GS, Gomes RT, Iwanaga SH, Barbosa MC, Abdo EN, et al.
Mucoadhesive propolis gel for prevention of radiation-induced oral mucositis. Curr Clin Pharmacol 2014;9:359-64.
Ghassemi L, Zabihi E, Mahdavi R, Seyedmajidi M, Akram S, Motallebnejad M. The effect of ethanolic extract of propolis on radiation-induced mucositis in rats. Saudi Med J 2010;31:622-6.
Simões A, Eduardo FP, Luiz AC, Campos L, Sá PH, Cristófaro M, et al.
Laser phototherapy as topical prophylaxis against head and neck cancer radiotherapy-induced oral mucositis: Comparison between low and high/low power lasers. Lasers Surg Med 2009;41:264-70.
Yildirim C, Akgun OM, Atas E, Ozdemir A, Acar O. Mucositis treatment using ozonated water. Int J Adv Case Rep 2015;2:161-3.
Volpato LE, Silva TC, Oliveira TM, Sakai VT, Machado MA. Radiation therapy and chemotherapy-induced oral mucositis. Braz J Otorhinolaryngol 2007;73:562-8.
Stiff PJ, Leinonen M, Kullenberg T, Rudebeck M, de Chateau M, Spielberger R. Long-term safety outcomes in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation treated with palifermin to prevent oral mucositis. Biol Blood Marrow Transplant 2016;22:164-9.
Trucci VM, Veeck EB, Morosolli AR. Current strategies for the management of oral mucositis induced by radiotherapy or chemotherapy. Rev Odontol Ciênc 2009;24:309-14.
Grothey A, George S, van Cutsem E, Blay JY, Sobrero A, Demetri GD. Optimizing treatment outcomes with regorafenib: Personalized dosing and other strategies to support patient care. Oncologist 2014;19:669-80.
Suma GN, Arora MP, Lakhanpal M. Stem cell therapy: A novel treatment approach for oral mucosal lesions. J Pharm Bioallied Sci 2015;7:2-8.
Pettita L, Sangheraa P, Glaholma J, Hartley A. The use of MuGard™, Caphosol® and Episil® in patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck. J Radiother Pract 2014;13:218-25.
Shrivastava R, Deshmukh S. A new therapeutic approach to treat oral mucositis using specific MMP blockers in an osmotically active solution. J Cancer Res Treatment 2013;1:4-11.
Lin JX, Fan ZY, Lin Q, Wu DH, Wu XY, Chen YR, et al.
A comparison of dioctahedral smectite and iodine glycerin cream with topical mouth rinse in treatment of chemotherapy induced oral mucositis: A pilot study. Eur J Oncol Nurs 2015;19:136-41.
Miranzadeh S, Adib-Hajbaghery M, Soleymanpoor L, Ehsani M. Effect of adding the herb Achillea millefolium
on mouthwash on chemotherapy induced oral mucositis in cancer patients: A double-blind randomized controlled trial. Eur J Oncol Nurs 2015;19:207-13.
Hadjieva T, Cavallin-Ståhl E, Linden M, Tiberg F. Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution. Support Care Cancer 2014;22:1557-62.
Chen P, Mancini M, Sonis ST, Fernandez-Martinez J, Liu J, Cohen EE, et al.
A novel peptide for simultaneously enhanced treatment of head and neck cancer and mitigation of oral mucositis. PLoS One 2016;11:e0152995.
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