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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 68-73

Management of oral mucositis caused by radiotherapy – A comprehensive review


Department of Oral Medicine and Radiology, KAHERS KLE VK Institute of Dental Sciences, Belagavi, Karnataka, India

Date of Submission21-Feb-2022
Date of Decision07-May-2022
Date of Acceptance07-May-2022
Date of Web Publication20-Jun-2022

Correspondence Address:
Dr. Manisha Singh
Department of Oral Medicine and Radiology, KAHERS KLE VK Institute of Dental Sciences, Nehru Nagar, Belagavi, Karnatakam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/srmjrds.srmjrds_31_22

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  Abstract 

Oral cancer is the malignant neoplasm involving the oral cavity. The treatment of oral cancer is surgery, radiotherapy, and adjuvant chemotherapy. Oral mucositis is the most common side effect when radiotherapy treatment for oral cancer is indicated. High.grade oral mucositis results in the delay of the radiotherapy treatment and increases the cost of maintenance. The preventive measures for radiation.induced mucositis include maintaining oral hygiene, treatment of xerostomia, diet modifications, and low.level laser therapy. This article provides a guide for the practicing oncologists about the current treatment, advances in treatment, and alternative medicine for improving radiation.induced mucositis.

Keywords: Management, oral mucositis, radiotherapy


How to cite this article:
Singh M, Bagewadi A. Management of oral mucositis caused by radiotherapy – A comprehensive review. SRM J Res Dent Sci 2022;13:68-73

How to cite this URL:
Singh M, Bagewadi A. Management of oral mucositis caused by radiotherapy – A comprehensive review. SRM J Res Dent Sci [serial online] 2022 [cited 2022 Jun 30];13:68-73. Available from: https://www.srmjrds.in/text.asp?2022/13/2/68/347816


  Introduction Top


The selection of treatment for oral cancer whether it is surgery or radiotherapy or a combination of treatment modalities depends on several factors such as the general condition of the patient, experience of the surgeon, cost factor, probability of complete excision of the tumor, and anticipated outcomes after the treatment both cosmetically and functionally.[1] In general, the most common treatment option is surgery for oral cancer. Radiotherapy is alone considered for the treatment when an early small primary tumor is present in the oral cavity.[1] Radiotherapy is combined with chemotherapy when the patients are unable to tolerate surgical procedures. Radiotherapy procedure is done with external-beam radiotherapy and brachytherapy. Radiation-induced mucositis causes severe pain which affects the healthy living of patients. The other symptoms caused are difficulty in swallowing, the discrepancy in taste sensation, and sore mouth which may lead to malnutrition. The progressed stage of oral mucositis results in ulceration, secondary infections, bleeding, and thereby affecting the prognosis of the patient. Early prevention and treatment of radiation-induced mucositis are required to improve the quality of life and prognosis of the patient.

According to Sonis, 2004, the pathobiology of oral mucositis induced by radiotherapy includes five stages.[2] They are initiation, primary injury and signal amplification, ulceration, and healing. Initiation starts with DNA damage involving injury to the basal epithelial cells and endothelial cells and the formation of reactive oxygen species (ROS). The signal amplification stages are described as follows ROS activates nuclear factor kappa B (NF-κ B). NF-κ B activates pro-inflammatory cytokines-tumor necrosis factor (TNF-α), interleukin-6 (IL-6), IL-1 β and increases the rate of formation of COX-2.NF-κ B also causes apoptosis of basal epithelial cells and endothelial cells resulting in the ulceration stage. The death of cells results in ulceration and stimulates the production of pro-inflammatory cytokines and lastly healing of oral ulcerations. Extracellular matrix will allow basal epithelial cells proliferation and differentiation.

High-grade oral mucositis results in the delay of the radiotherapy treatment and increases the cost of maintenance. This article discusses the preventive measures, current treatment, advances in treatment, and alternative medicine for improving radiation-induced mucositis. This will guide the practicing oncologists in the proper management of oral mucositis. The treatment of radiation-induced mucositis is categorized into preventive measures, current management, advances in treatment, and lastly current research and alternative medicine [Figure 1].
Figure 1: The treatment of radiation-induced mucositis

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  Preventive Measures Top


Interventions reducing mucosal toxicity

Maintenance of oral hygiene and elimination of dental infections including dental caries, extraction of compromised teeth, and periodontal lesions before radiotherapy may help in reducing radiation-induced mucositis. Patients are advised to brush with a soft toothbrush and fluoride toothpaste twice daily to maintain oral hygiene. The use of a soft toothbrush will prevent trauma to the oral cavity during brushing. The importance of maintaining oral hygiene is to decrease the number of oral bacteria, thereby decreasing the development of secondary infections of the oral mucosa and periodontal tissues.

Prophylactic oral care and management of xerostomia before radiotherapy may decrease the risk of radiation-induced mucositis. Oral xerostomia should be treated with artificial saliva spray and cholinergic agents such as pilocarpine (orally). Chewing sugarless gum may stimulate salivary flow. Salivary glands are sensitive to radiation due to which salivary flow rate reduces during the initial treatment with radiotherapy. Xerostomia primarily contributes to oral mucositis.

Mucosal sparing radiation therapy technique

Radiation shields, namely mouth bite, gauze pack, palatal shield, and retractors are intraoral devices that should be used when required to protect part of mucosa from the radiation. They act at the primary injury stage. The use of midline radiation blocks protects the mucosa covering the lower neck area of the aerodigestive tract during radiation therapy for the treatment of cancer involving the nasopharynx and oropharynx.[3]

Three-dimensional radiation treatment should be designed to decrease radiation-induced mucosal injury. Intensity-modulated radiation therapy procedure spares 30% of the mucosa during the radiotherapy treatment of oral cancer. They reduce radiation scatter. Other factors include field size, interfraction interval, and low dose per fraction helped in reducing radiation-induced mucositis. Total dose, overall treatment duration, and removal of separable prosthetics may affect the extent of mucositis.

Diet modification

The diet helps in maintaining oral health. The patient should be told about the change in taste and difficulty swallowing during radiotherapy and hence instructed on the food which can improve oral health. Food modifications should be balanced to prevent mucositis. Patients are advised to avoid alcohol and smoking during treatment. Spicy, acidic, sharp, and very hot food should be avoided as it can increase the discomfort of mucositis. A liquid diet and a soft diet with low sugar are advised during treatment. This food will not progress mucositis and improve chewing and swallowing.

Low-level laser therapy

The other name for low-level laser therapy is photobiomodulation therapy. They use nonthermal lasers, including red-beam or near-infrared lasers to prevent and manage radiation-induced mucositis.[3] The wavelength associated with lasers is between 600 and 1000 nm, and the use of power is 5–500 mW.[3] These lasers when applied have low absorption by the skin and can penetrate deeply into tissues. This therapy will promote the healing of damaged tissues. The main advantage no heat is transferred to the tissues, only low energy in the form of the monochromatic light source is transferred by photobiomodulation. Lalla et al. 2014 recommended low-level laser therapy for the prevention and suppressing radiation-induced mucositis in head-and-neck cancer patients.[4] Bensadoun, 2018 suggested that low-level laser therapy can be used in the management of radiation-induced mucositis and can be performed each day to decrease the progression of mucositis.[5] Florence Legouté et al. 2019 used low-level laser therapy for high-grade oral mucositis patients treated with chemoradiotherapy and reduced oral mucositis, which provides benefits to them.[6] Low-level laser therapy requires proper training and techniques when used for radiation-induced mucositis patients.


  Current Management Top


Mucositis pain control

The initial stage of mucositis is treated with topical anesthetics such as 2% viscous lidocaine and benzocaine mouthrinse. They are used as 5 ml of mouthrinse, swish, and spit.[7] This procedure is done before meals which help to relieve pain due to radiation-induced mucositis. They help in short-term pain relief for radiation-induced mucositis. Magic mouthwash usually contains anesthetic, antacid, and diphenhydramineare also used for short-term pain relief. These anesthetics when applied to oral ulcerations have the combined effect of anti-inflammatory and antimicrobial which help the patients during eating as well as maintaining oral hygiene.

Doxepin is a tricyclic antidepressant drug with local anesthetic and analgesic properties. Lalla et al., 2014 mentioned that 0.5% doxepin mouthwash was useful in treating pain due to radiation-induced mucositis.[4] Patients had reported drowsiness, unpleasant taste, and stinging or burning sensation on using doxepin mouthwash.[8] Patients should be counseled about the side effects and should be kept under observation.

Morphine mouthwash 0.2% (Opioid) swish and spit are indicated in treating pain for high-grade oral mucositis. The duration of severe pain is decreased with morphine mouthwash and lower systemic analgesia is required for high-grade oral mucositis.[9]

Bey et al., 2010 evaluated patients with high-grade oral mucositis who would requires ystemic analgesics (nonsteroidal anti-inflammatory drugs) with opioids to decrease pain.[3] Opioids played an important role in decreasing the pain due to high-grade oral mucositis during the last weeks of radiotherapy.[10] Gabapentin is an antiepileptic drug used for nerve pain and seizures. Milazzo-Kiedaisch et al., 2016 suggested a high dose of gabapentin (1200 mg) for patients with radiation-induced mucositis for the control of pain and its use helped in the reduction of opioids usage.[11]

Infection control

The antimicrobial agents help to prevent secondary infections (viral, bacterial, and fungal) which may deteriorate the oral mucositis. Polymyxin-B, Tobramycin, and Amphotericin-B paste was used for the prevention of radiation-induced mucositis in patients with head and neck cancer.[4] McGuire et al., 2013 considered chlorhexidine mouthwash a part of basic oral care for the prevention of radiation-induced mucositis in patients with head and neck cancer.[12] Chlorhexidine possesses antiseptic, antifungal as well as antiplaque properties.[3] Roopashri et al., 2011 concluded chlorhexidine when used for the treatment and prevention of radiation-induced mucositis did not show positive results.[13] Povidone-iodine mouthwash is an alternative to chlorhexidine mouthwash due to less cost factor. Povidone-iodine is an antiviral, antibacterial, and antifungal agent. A recent study suggested the use of nonalcoholic mouthwash (Bland rinses) four times a day during the beginning of treatment.[14] Bland rinses included saline and sodium bicarbonate mouthwashes, swish, and spit.

Anti-inflammatory drugs

Benzydamine is a nonsteroidal anti-inflammatory agent that inhibits TNF-α, and it also possesses analgesic, anesthetic, and antimicrobial activities. Sheibani et al., 2015 demonstrated Benzydamine mouth rinse for reducing the signs and symptoms of oral mucositis in patients receiving radiation therapy for the head-and-neck cancer patients.[15] Lalla et al., 2014 suggested Benzydamine 0.15% oral rinse to be used in the prevention of oral mucositis when a moderate dose of radiation treatment was given in head-and-neck cancer patients.[4]

Sonis, 2010 considered the use of local corticosteroids (mouthwash) or systemic corticosteroids in the persistent cases of radiation-induced mucositis.[16] Hydrocortisone and betamethasone are generally used to reduce radiation-induced mucositis. They basically inhibit the inflammatory response to all stimuli. Pentoxifylline has an anti-inflammatory activity that inhibits TNF-α and IL-1 β. Sayed et al., 2019 tried Pentoxifylline with Vitamin E for the reduction of radiotherapy-induced mucositis.[17] Dusquetide (SGX942) modulates immune innate pro-inflammatory response. Kudrimoti et al., 2016 reported intravenous dusquetide administration in head-and-neck cancer patients treated with radiotherapy reduces the duration of oral mucositis and rate of infection.[18]

Topical agents

Sucralfate is made up of sucrose sulfate and aluminum hydroxide and this complex can be used as a mucosal protectant to decrease the intensity of radiation-induced mucositis.[3] They form a complex at the ulcer site which results in a barrier that covers the mucosa. Sucralfate is used in the form of mouthwash for the resolution of mucositis. The advantages of sucralfate include that they are less costly, easy to administer, and with no side effects. Lalla et al., 2014 did not recommend sucralfate mouthwash to treat radiation-induced mucositis.[4]

Gelclair is another mucosal protectant that comprises polyvinylpyrrolidone and sodium hyaluronate and helped in reducing radiation-induced mucositis.[3] They are used in gel form and applied to the oral mucosa. It acts as a bioprotective coat that decreases pain and provides instant comfort to the patients. Lalla et al., 2014 introduced mucoadhesive hydrogel rinses and calcium phosphate rinses for the prevention and treatment of radiation-induced mucositis which showed palliative results.[4]


  Advances in Treatment Top


Growth factors

Palifermin, a recombinant human keratinocyte growth factor, is useful for the management of radiation-induced mucositis. This growth factor reduces Grade 3 and 4 mucositides along with the duration of mucositis after radiotherapy. They are administered systemically. Palifermin stimulates the proliferation and differentiation of epithelial cells and helps in fast tissue regeneration after radiotherapy treatment which reduces the chances of developing oral mucositis.[19] They act with antioxidant, antiapoptotic, and anti-proinflammatory activities. The only disadvantage is that they are costly but have good results when used in radiation-induced mucositis. Granulocyte macrophage colony-stimulating factor (GM-CSF) can be administered systemically as well as topically when used in radiation-induced mucositis patients. They promote the production of neutrophils at the tissue injury site. GM-CSF mouthwash is costly and showed the results same as conventional mouthwashes. When GM-CSF is used systemically, it has controversial results. Transforming growth factor-β3 may help in decreasing radiation-induced mucositis, and hence, further studies should be carried out in patients with radiation-induced mucositis.

Reactive oxygen species inhibitors

Amifostine is a reactive oxygen scavenger that acts as an antioxidant and cytoprotective agent.[20] Amifostine also reduces the production of pro-inflammatory cytokines and is administered subcutaneously and intravenously to prevent radiation-induced mucositis.[20] They are effective in preventing oral mucositis during radiotherapy. They prevent DNA damage and preserve the salivary gland, endothelium, and connective tissue integrity. Conventionally, this reactive oxygen scavenger is given an IV before radiotherapy.[20] The side effects of Amifostine given IV are hypotension and nausea. Hence, the routine use of Amifostine IV is questionable. Even Amifostine can be administered subcutaneously 60 min before radiotherapy in head-and-neck cancer patients. When Amifostine was administered SC, patients showed a decrease in side effects.[21] They are not commonly administered SC due to decreased patient compliance.

N-acetylcysteine (NAC) is an antioxidant that suppresses NF-κB activation. NAC has a radioprotective activity that helps in the prevention of radiation-induced mucositis. Manganese superoxide dismutase (GC4419) acts as a detoxifying agent which helps in removing ROS.[20] Anderson et al., 2018 mentioned that GC4419 can reduce the severity, incidence, and duration of oral mucositis in radiotherapy patients.[22] The daily infusion of this detoxifying agent limits its use by patients.[10] Blakaj et al., 2019 stated this compound was used to prevent oral mucositis in radiotherapy patients.[23]


  Current Research and Alternative Medicine Top


Glutamine

Glutamine is a nonessential amino acid that possesses antioxidant properties. Pachón Ibáñez et al. 2018 evaluated oral glutamine for the prevention of radiation-induced mucositis. The results were in favor of decreased oral mucositis and severity.[24]

Zinc supplements

Zinc possesses antioxidant properties as well as a wound-healing mechanism. Chaitanya et al., 2019 mentioned the use of Zinc in decreasing the severity of radiation-induced mucositis in patients with head and neck cancer.[25]

Vitamin-E

Vitamin E (tocopherol) reduces the oxidative destruction of the oral tissues caused due to release of ROS.[20] Alcantara et al., 2020 concluded that topical or oral use of Vitamin E is safe and nontoxic for the treatment of radiation-induced mucositis.[26]

The following are the drugs under clinical trials, which can be used for the management of radiation-induced mucositis.

GC4419

Anderson et al., 2019 demonstrated the potential of GC4419 for the reduction of incidence, duration, and severity of radiation-induced mucositis.[27] Phase III trial has been initiated to confirm that GC4419 can be used for the management of radiation-induced mucositis.

SGX942

SGX942 is found to decrease the duration of severe oral mucositis in patients with concomitant chemoradiation in clinical trials.

AG013

A phase II trial is initiated to evaluate the efficacy and safety of topically applied AG013 for the reduction of oral mucositis in patients with concomitant chemoradiation. AG013 is used in the form of mouth rinses with Lactococcus lactis strain which produces human Trefoil Factor 1. This factor helps in protecting and healing mucosal tissues.

RRx-001

RRx-001 drug has been tried with cisplatin and radiotherapy to decrease the duration, incidence, and time of onset of severe oral mucositis in head and neck cancer patients.

EC-18

A small molecule oral immunomodulator EC-18 has been for the reduction of severe oral mucositis in patients receiving concomitant chemoradiation treatment.

Ectoin

Ectoin mouth wash (EML03) is found to be efficacious for the prevention and treatment of radiation-induced mucositis.

Chlorine dioxide

Chlorine dioxide oral rinse is under phase II trial to decrease the incidence and duration of severe oral mucositis in patients receiving radiotherapy.

Brilacidin

Brilacidin oral rinse can be given thrice daily for 7 weeks to reduce the severity of oral mucositis.

The following are the alternative medicine used for the prevention and treatment of oral mucositis:

Natural honey

Natural honey is an antibiotic, a nutritional supplement, and a ROS scavenger and suppresses the production of proinflammatory cytokine IL-6 and TNF alpha. The advantage of using honey is cost-effective and easily available. Xu et al., 2016 used honey before radiotherapy to reduce the incidence of oral mucositis.[28] Amanat et al., 2017 showed that oral intake of honey reduced the severity of oral mucositis in radiotherapy patients.[29] Patients were given 20 ml of Ziziphus honey, 15 min before and after the radiotherapy. They were also advised to take 20 ml of Ziziphus honey before sleeping at night. This treatment was started from day 1 of radiation to the end of the 6th week.

Herbal drugs

Several studies have been done on herbal drugs, Aloe vera, essential oils of manuka, and kanuka, for the prevention of oral mucositis in radiotherapy patients.[30] Rao et al., 2014 stated turmeric which belongs to Curcuma longa of the ginger family can decrease the severity of oral mucositis in radiotherapy patients.[31] Elkerm and Tawashi, 2014 evaluated date palm pollen as useful in decreasing incidence, severity, and pain in radiation-induced mucositis.[32] Date palm pollen has antioxidant and anti-inflammatory properties. Mamgain et al., 2020 observed that Yashtimadhu (Glycyrrhiza glabra) was useful in decreasing pain and resolution of radiation-induced mucositis.[33]

Others

Podlesko et al., 2018 showed the topical use of sodium salt-based polydeoxyribonucleotide to be beneficial for oral mucositis in radiotherapy patients. Polydeoxyribonucleotide drug comprises anti-inflammatory and regenerative properties.[34] Shumsky et al., 2019 showed the improvement of symptoms of oral mucositis with the use of an Oncoxin nutritional supplement.[35] Sun et al., 2019 used a compound Vitamin B mixture combined with Gene Time (a recombinant form of human epidermal growth factor) for oral mucositis in radiotherapy patients. This combination was helpful in improving the healing of ulcers associated with oral mucositis.[36] A study done by Agha-Hosseini et al., 2021 introduced mouthwash that contains Vitamin E, hyaluronic acid, and triamcinolone acetonide for the effectiveness of oral mucositis in radiation-induced mucositis. In this study, positive results were found considering the antioxidant property of Vitamin E, anti-inflammatory properties of triamcinolone acetonide, and improved healing property of hyaluronic acid.[37]


  Conclusion Top


This article provides different treatment modalities for radiation-induced mucositis in head-and-neck cancer patients. The different treatment modalities have helped the patients in improving their quality of life and providing comfort to them. There are important factors that should be considered before starting the treatment such as its side effects, the cost factor, availability of the drug, and route of administration. Hence, there is no specific treatment advised for patients with radiation-induced mucositis. The oncologists, as well as oral health professionals, should workhand in hand to decrease the severity of radiation-induced mucositis. The involvement of oral health professionals will help in evaluating the damage to the oral mucosa and the necessary oral hygiene procedures to be done. Together they should provide the treatment depending upon the suitability of patients and explain the various treatment modalities which will be most effective and benefit them.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Preventive Measures
Current Management
Advances in Trea...
Current Research...
Conclusion
References
Article Figures

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