Oral Mucositis

Earn CME/CE in your profession:


Continuing Education Activity

Oral mucositis is a debilitating condition, and it presents as erythema, edema, and ulceration of the oral mucosa with subsequent pain and restriction in oral intake. The lesions can also break the skin barrier resulting in local or systemic infection. In severe cases, this can lead to parenteral nutrition, ultimately leading to poor quality of life. This activity reviews the evaluation and treatment of oral mucositis and reviews the role of the interprofessional team in managing complications of oral mucositis to improve patient outcomes.

Objectives:

  • Identify the etiology of oral mucositis.
  • Identify the physical exam findings of oral mucositis as well as its evaluation.
  • Review the management options available for oral mucositis.

Introduction

Oral mucositis is a severely debilitating condition. It can occur due to radiation therapy (RT) to the head and neck, chemotherapeutic agents, high-dose chemotherapy agents, hematopoeitic stem cell transplantation (HSCT). It presents as erythema, edema, and ulcerations within the oral mucosa and pain with subsequent restriction in oral intake. In severe cases, this may even lead to the need for parenteral nutrition. In addition, the lesions weaken the skin barrier resulting in local or systemic infection.[1] It is a debilitating condition for patients due to pain and subsequent decreased oral intake resulting in worsened quality of life.[2] In severe cases, the subsequent cycle of chemotherapy may need to be given in a reduced dose or be delayed.

Etiology

Oral mucositis is a frequent complication in patients receiving radiation therapy (RT) to the head and neck, chemotherapy for solid tumors or lymphoma as well as those who receive high-dose myeloablative chemotherapy prior to hematopoietic cell transplantation. The incidence of oral mucositis varies amongst the different chemotherapy agents.[2] 

Chemotherapeutic agents that affect DNA Synthesis (S-phase), e.g. 5-fluorouracil, methotrexate, and cytarabine have a high incidence of oral mucositis.[3] Anthracyclines, mTOR inhibitors, alkylating agents, and antimetabolites also have a high risk of oral mucositis.[4][5] Chemotherapeutic agents cause mucositis through both direct and indirect mechanisms.

Epidemiology

The incidence and severity of mucositis vary between chemotherapeutic agents, the number of chemotherapy cycles, the dose of chemotherapy, as well as from patient to patient.[3] Patients who receive myeloablative preparations for hematopoeitic stem cell transplant have a higher incidence of oral mucositis.[6] 

One study reported that patients who receive high doses of chemotherapy or undergo bone marrow transplantation have a 76 % risk of getting mucositis. Radiation-induced oral mucositis (RIOM) occurs in 100% of altered fractionation radiotherapy head and neck cancer patients.[7] The frequency of mucositis is higher in patients with poor nutritional status and poor oral care. Younger age patients may have a higher incidence of oral mucositis.[6]

Pathophysiology

The pathophysiology behind the development of RIOM and/or oral mucositis due to chemotherapy is thought to be due to a complex process that starts with injury to the tissue in a five-phase model as suggested by Sonis.[8] 

The five stages (phases) of OM induced by RT and/or chemotherapy include initiation, signaling, amplification, ulceration, and healing. Firstly, tissue injury is induced by chemotherapy by both death of the basal epithelial cells as well as the formation of reactive oxygen species.[2] Secondly, the reactive oxygen species cause direct cellular death as well as upregulate the inflammatory pathway to cause further cellular death.[2] Thirdly, further pathways are amplified such as TNF alpha. Fourthly, mucosal ulcerations occur along with further inflammation. Lastly, the epithelium undergoes healing via epithelial proliferation.

History and Physical

Oral mucositis due to RT starts after RT exposure to the head and neck lasting between 7 and 98 days and starts as acute inflammation in the oral mucosa, tongue, and pharynx.[7]  Similarly, oral mucositis due to chemotherapy has a temporal association with the dose of stomatotoxic chemotherapy usually it develops within 10 to 14 days of the given dose. It starts as erythema with the mucosa which subsequently becomes erosion and ulceration. Next, the ulceration is covered with a white fibrinous pseudomembrane.

In immunosuppressed patients or patients undergoing hematopoietic stem cell transplant, the oral mucositis starts to resolve as the absolute neutrophil count recovers. The patient complains of discomfort/pain with eating or may have increased bleeding while brushing. On physical examination, the mucosa may appear erythematous or have white fibrinous pseudomembrane covering the ulcers. The location of ulcers is usually limited to non-keratinized surfaces of the mouth e.g. buccal mucosa, lateral tongue, ventral tongue, and soft palate.[9]

Evaluation

Evaluating for oral mucositis is dependent upon clinical history and physical exam findings. Laboratory and radiography are not as helpful. If there are ulcers present on the hard palate, attached gingiva, or dorsum of the tongue, cultures should be obtained to rule out viral or fungal etiology.

The severity of the mucositis is measured on a well-defined scale and there are a few different scales that have been developed.[1]

Common Terminology Criteria for Adverse Events (CTCAE)

The CTAE is developed by the National Cancer Institute (NCI) and is rated from 1 to 5. This scale is divided into two parts: a clinical exam and a functional/symptoms-based exam. 

Functional/symptoms - based exam:

  • Grade 1 = Asymptomatic or mild symptoms and Intervention is not indicated as well as the patient is on a normal diet.
  • Grade 2 = Moderate pain or ulcer that does not interfere with oral intake and the patient requires a modified diet. 
  • Grade 3 = Severe pain which interferes with oral intake
  • Grade 4 = Life-Threatening consequences which require urgent intervention
  • Grade 5 = Death

Clinical exam:

  • Grade 1 = mucosal erythema
  • Grade 2 = patchy ulceration or pseudomembranes
  • Grade 3 = Minor trauma resulting in bleeding, confluent ulcers, or pseudomembranes. 
  • Grade 4 = Tissue necrosis, spontaneous bleeding, life-threatening events. 
  • Grade 5 = Death. 

World Health Organization (WHO) 

The World Health Organization (WHO) scale combines both subjective and objective measures of oral mucositis. 

  • Grade 0 = No oral mucositis
  • Grade 1 = Erythema and soreness
  • Grade 2 = Ulcers, able to eat solids
  • Grade 3 = Ulcers, requires a liquid diet (due to mucositis)
  • Grade 4 = Ulcers, alimentation not possible (due to mucositis)

Oral Mucositis Assessment Scale (OMAS)

The Oral Mucositis Assessment Scale (OMAS) is an objective scale that measures erythema and ulceration at nine sites within the oral cavity.[10] A multi-center trial showed that this scale has high interobserver reproducibility and a strong correlation between the OMAS score and patient symptom.[10] According to Sonis et al., the use of concomitant symptomatic measurements appeared to be not needed while using OMAS.[10]

Eastern Cooperative Oncology Group (ECOG) common toxicity criteria are used in oncology trials.

Treatment / Management

There are various options employed by clinicians to manage oral mucositis in the setting of chemotherapy.[11] A brief description is provided here of the different strategies which can be helpful. 

  • Oral Hygiene 
    • Oral hygiene protocols have been shown to help prevent mucositis or decrease the duration and severity of mucositis once it occurs.[12] It also helps reduce the microbial burden which prevents the development of secondary infections.[12][13] The 2020 MASCC/ISOO clinical guidelines for the management of mucositis secondary to chemotherapy states that despite the limited data on both saline and sodium bicarbonate oral rinses, the panel has recognized that these are inert and bland rises that increase oral clearance, which would thus help maintain oral hygiene and improve patient comfort. Routine mouth care includes removal of dentures, gentle cleansing which includes dental flossing and gentle brushing, and oral rinses. In terms of oral rinses, there are several different options including saline water rinse, sodium bicarbonate rinse, a mix of sodium bicarbonate and saline water, hydrogen peroxide (diluted 1:1 with saline or water), and miracle mouthwash. For patients with poor dentition, a dental evaluation may be recommended as well as tooth extraction, if warranted. 
  • Pain management
    • Topical such as lidocaine agents are effective in reducing the severity of lesions as well as the intensitive of pain; however, this effect varies depending on the agent used. Topical agents would be a great at-home treatment option to allow for relief of pain and reduction in inflammation.[14] Also, opioid analgesics are given to alleviate pain. 
  • Chemoprotective agent
    • Palifermin is a keratinocyte growth factor and works as a chemoprotective agent, which has been recommended for severe oral mucositis (mucositis greater than or equal to grade 3) associated with autologous hematopoietic stem cell transplant regimens.[12] In such patients, it has been shown to decrease the incidence and duration of severe oral mucositis.  
    • Prophylactic Dexamethasone mouthwash for patients receiving mTOR inhibitors was shown to prevent oral mucositis and stomatitis. 
  • Low-level laser therapy
    • Another treatment option that is currently being explored is using low-level laser therapy to enhance wound healing with a reduction in pain and tissue swelling; however, standard treatment protocols are not currently present for all chemotherapy agents.[15] A double-blinded study showed that low-level laser therapy was beneficial in the prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT.[16]
  • Cryotherapy
    • For some chemotherapy agents, data suggests the use of placing ice chips in the mouth is beneficial, for example, during bolus of 5-fluorouracil and high dose melphalan.
  • Zinc supplementation
    • Zinc is beneficial to augment tissue repair as well as providing antioxidant effects. It is beneficial in patients with oral cancer undergoing chemoradiation.[17]
  • Diet
    • For moderate to severe mucositis, the diet should be limited to foods that do not aggravate the mucosa or risk injury during chewing. Foods that have less salt, acid, moisture, or require significant chewing should be avoided.

Differential Diagnosis

Differential diagnoses include the infectious process or dermatologic manifestation of another disease. Although infectious processes do not cause oral mucositis, the local infection can complicate the presentation of oral mucositis as well as call for the need for adjuvant treatment.

Viral infections such as herpes simplex virus and fungal infections such as candidiasis can be superimposed. Dermatologic manifestations of systemic inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis can also cause oral ulcers. Oral squamous cell carcinoma may also present similarly.  Nutritional deficiencies such as zinc deficiency can cause oral lesions, for which nutritionists often prescribe zinc supplementation.[18]

Prognosis

The resolution of oral mucositis is temporally related to the timing of chemotherapy. As the time from the given chemotherapy increases, the mucositis heals. Thus, supportive measures aiming towards comfort for the patient are indicated with a possible reduction or cessation of the next dose of chemotherapy.

Complications

Oral mucositis results in pain and its subsequent decrease in oral intake can lead to a significant deterioration in patient quality of life as well as nutritional status. This can also interrupt the chemotherapy treatment cycle, which may worsen cancer outcomes. Mucositis also results in a breakdown of the protective mucosal barrier and thus increasing the susceptibility of the patient to blood infections. Thus, chemotherapy protocols that increase the risk of oral mucositis have a prophylactic oral regimen and antibiotics built into them to prevent the development of oral mucositis and subsequent septicemia.[19]

Deterrence and Patient Education

Every patient who is being treated with radiation or chemotherapeutic agent that can cause oral mucositis should be given detailed information about signs and symptoms to monitor as the development of oral mucositis, treatment options available, and complications of oral mucositis. The patient should be informed about indications requiring a visit to the emergency department and/or inpatient admission, i.e., inability to take oral intake or concern for infection.

Enhancing Healthcare Team Outcomes

The management of oral mucositis is challenging and complex. It requires the coordination of multiple healthcare providers. The identification of oral mucositis may be by a provider in the field of primary care physicians, oncology, pharmacists,  or other specialties. Upon diagnosis of oral mucositis, the patient would require education by the healthcare team for treatment.



(Click Image to Enlarge)
Oral Mucosa, epithelium, lamina propria, submucosa, periosteum, bone, papillary layer, reticular layer
Oral Mucosa, epithelium, lamina propria, submucosa, periosteum, bone, papillary layer, reticular layer
Contributed From StatPearls Publishing Illustration by Emma Gregory
Article Details

Article Author

Andrea Bell

Article Editor:

Anup Kasi

Updated:

4/22/2021 5:48:15 PM

PubMed Link:

Oral Mucositis

References

[1]

Lalla RV,Sonis ST,Peterson DE, Management of oral mucositis in patients who have cancer. Dental clinics of North America. 2008 Jan;     [PubMed PMID: 18154865]

[2]

Sonis ST,Elting LS,Keefe D,Peterson DE,Schubert M,Hauer-Jensen M,Bekele BN,Raber-Durlacher J,Donnelly JP,Rubenstein EB, Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004 May 1;     [PubMed PMID: 15108222]

[3]

Naidu MU,Ramana GV,Rani PU,Mohan IK,Suman A,Roy P, Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer. Neoplasia (New York, N.Y.). 2004 Sep-Oct;     [PubMed PMID: 15548350]

[4]

Valer JB,Curra M,Gabriel AF,Schmidt TR,Ferreira MBC,Roesler R,Evangelista Junior MC,Martins MAT,Gregianin L,Martins MD, Oral mucositis in childhood cancer patients receiving high-dose methotrexate: Prevalence, relationship with other toxicities, and methotrexate elimination. International journal of paediatric dentistry. 2020 Aug 20;     [PubMed PMID: 32815183]

[5]

Barasch A,Peterson DE, Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral oncology. 2003 Feb;     [PubMed PMID: 12509961]

[6]

Vagliano L,Feraut C,Gobetto G,Trunfio A,Errico A,Campani V,Costazza G,Mega A,Matozzo V,Berni M,Alberani F,Banfi MM,Martinelli L,Munaron S,Orlando L,Lubiato L,Leanza S,Guerrato R,Rossetti A,Messina M,Barzetti L,Satta G,Dimonte V, Incidence and severity of oral mucositis in patients undergoing haematopoietic SCT--results of a multicentre study. Bone marrow transplantation. 2011 May;     [PubMed PMID: 20818449]

[7]

Maria OM,Eliopoulos N,Muanza T, Radiation-Induced Oral Mucositis. Frontiers in oncology. 2017     [PubMed PMID: 28589080]

[8]

Sonis ST, Pathobiology of oral mucositis: novel insights and opportunities. The journal of supportive oncology. 2007 Oct     [PubMed PMID: 18046993]

[9]

Lalla RV,Peterson DE, Oral mucositis. Dental clinics of North America. 2005 Jan;     [PubMed PMID: 15567367]

[10]

Sonis ST,Eilers JP,Epstein JB,LeVeque FG,Liggett WH Jr,Mulagha MT,Peterson DE,Rose AH,Schubert MM,Spijkervet FK,Wittes JP, Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer. 1999 May 15     [PubMed PMID: 10326686]

[11]

Rubenstein EB,Peterson DE,Schubert M,Keefe D,McGuire D,Epstein J,Elting LS,Fox PC,Cooksley C,Sonis ST, Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004 May 1;     [PubMed PMID: 15108223]

[12]

Elad S,Cheng KKF,Lalla RV,Yarom N,Hong C,Logan RM,Bowen J,Gibson R,Saunders DP,Zadik Y,Ariyawardana A,Correa ME,Ranna V,Bossi P, MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020 Jul 28;     [PubMed PMID: 32786044]

[13]

Eilers J,Harris D,Henry K,Johnson LA, Evidence-based interventions for cancer treatment-related mucositis: putting evidence into practice. Clinical journal of oncology nursing. 2014;     [PubMed PMID: 25427611]

[14]

Sant Ana G,Normando AGC,De Toledo I,Dos Reis PED,Guerra ENS, Topical Treatment of Oral Mucositis in Cancer Patients: A Systematic Review of Randomized Clinical Trials. Asian Pacific journal of cancer prevention : APJCP. 2020 Jul 1;     [PubMed PMID: 32711408]

[15]

Tam SY,Tam VCW,Ramkumar S,Khaw ML,Law HKW,Lee SWY, Review on the Cellular Mechanisms of Low-Level Laser Therapy Use in Oncology. Frontiers in oncology. 2020;     [PubMed PMID: 32793501]

[16]

Schubert MM,Eduardo FP,Guthrie KA,Franquin JC,Bensadoun RJ,Migliorati CA,Lloid CM,Eduardo CP,Walter NF,Marques MM,Hamdi M, A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2007 Oct;     [PubMed PMID: 17393191]

[17]

Lalla RV,Bowen J,Barasch A,Elting L,Epstein J,Keefe DM,McGuire DB,Migliorati C,Nicolatou-Galitis O,Peterson DE,Raber-Durlacher JE,Sonis ST,Elad S, MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014 May 15;     [PubMed PMID: 24615748]

[18]

Ozler GS, Zinc deficiency in patients with recurrent aphthous stomatitis: a pilot study. The Journal of laryngology and otology. 2014 Jun;     [PubMed PMID: 24849699]

[19]

Al-Taie A,Al-Shohani AD,Albasry Z,Altaee A, Current topical trends and novel therapeutic approaches and delivery systems for oral mucositis management. Journal of pharmacy     [PubMed PMID: 32742107]