Oral Mucositis

Etiology

Oral mucositis is a frequent complication in patients receiving radiation therapy (RT) to the head and neck, chemotherapy for solid tumors or lymphoma, and high-dose myeloablative chemotherapy prior to hematopoietic cell transplantation. The incidence of oral mucositis varies amongst the different chemotherapy agents.[3] Chemotherapeutic agents that affect DNA synthesis (S-phase), e.g., 5-fluorouracil, methotrexate, and cytarabine, have a high incidence of oral mucositis.[5] Anthracyclines, mTOR inhibitors, alkylating agents, and antimetabolites also have an increased risk of oral mucositis.[6][7]

The basal epithelial layer of the oral mucosa has a rapid cellular turnover, making the oral epithelium susceptible to radiation injury.[1] Cell death and the incapacity of the oral mucosa to heal lead to the development of oral mucositis.[1]

Epidemiology

Between 20% to 40% of patients with solid tumors receiving chemotherapy develop mucositis, usually within five to fourteen days of starting treatment.[8] The incidence and severity of mucositis vary between chemotherapeutic agents, the number of chemotherapy cycles, the dose of chemotherapy, and from patient to patient.[5] Patients who receive myeloablative preparations for hematopoeitic stem cell transplant have a higher incidence of oral mucositis.[9]

One study reported that patients who receive high doses of chemotherapy or undergo bone marrow transplantation have a 76% risk of mucositis. Radiation-induced oral mucositis (RIOM) occurs in 100% of altered fractionation radiotherapy head and neck cancer patients.[10] The frequency of mucositis is higher in patients with poor nutritional status and inadequate oral care. Younger age patients may have a higher incidence of oral mucositis.[9]

Pathophysiology

The pathophysiology of oral mucositis due to radiation therapy, chemotherapy, or radiotherapy-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.[11]

The five stages of OM induced by RT and chemotherapy occur consecutively, including initiation, signaling, amplification, ulceration, and healing. Firstly, tissue injury is caused by radiotherapy or chemotherapy, resulting in the death of the basal epithelial cells and the formation of reactive oxygen species.[3] Then, the reactive oxygen species cause direct cellular death and upregulate the inflammatory pathway to cause further cellular death.[3] Thirdly, other 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

Radiotherapy-induced oral mucositis results from tissue damage by the radiation beam, usually appearing in the third week of treatment [8] and lasting between 7 and 98 days.[10] The mucositis starts as acute inflammation in the oral mucosa, tongue, and pharynx.[10] The soft palate is most seriously damaged, followed by the hypopharynx, mouth floor, cheeks, tongue, and lips.[1] Radiation-induced mucositis pain is usually severe, and, in many cases, the radiation treatment must be interrupted.[8] Patients also complain of eating or speaking difficulty and may have increased bleeding while brushing.

Oral mucositis due to chemotherapy usually develops within five to fourteen days of treatment.[8] It starts as erythema in the mucosa, which subsequently becomes eroded and ulcerated. A white fibrinous pseudomembrane may cover the ulcerations. The location of ulcers is usually limited to non-keratinized surfaces of the mouth (buccal mucosa, lateral tongue, ventral tongue, and soft palate).[12]

The oral mucositis starts to resolve as the absolute neutrophil count recovers in immunosuppressed patients or patients undergoing hematopoietic stem cell transplants.

Evaluation

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

The severity of mucositis is measured on a well-defined scale, and several different scales have been developed.[4]

Common Terminology Criteria for Adverse Events (CTCAE)

The CTAE was 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 maintains 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 that 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.[13] A multi-center trial showed that this scale has high interobserver reproducibility and a strong correlation between the OMAS score and patient symptoms.[13] According to Sonis et al., using concomitant symptomatic measurements appeared to be unnecessary while using OMAS.[13]

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

Treatment / Management

Clinicians employ various options to manage oral mucositis in the setting of cancer therapy.[14] A brief description is provided here of the different recommended treatment strategies.(A1)

Basic Oral Care

Basic oral care (BOC) is suggested by the 2020 Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) clinical guidelines for managing oral mucositis secondary to cancer therapy.[2] BOC refers to all the interventions done by patients and clinicians to prevent oral infections and alleviate patient discomfort, including mechanical cleaning of teeth, mouth rinses, and lubricating the oral mucosa.[2] Furthermore, frequent assessment of the oral tissues before and during cancer treatment reduces infection risk and helps identify the initial stages of oral mucositis.[15](A1)

Oral hygiene protocols prevent oral mucositis and decrease its duration and severity once it occurs by reducing the microbial burden, hence, avoiding secondary infections.[2][16] (A1)

Prophylactic dental interventions, such as extracting compromised teeth and restoring carious lesions before initiating cancer therapy, can decrease mucositis risk by >25% and are particularly beneficial in high-risk patients.[8]

Mechanical Cleaning

Patients should be encouraged to enhance their regular mechanical cleaning practices, including increasing the frequency of tooth brushing, using a soft toothbrush, replacing the toothbrush regularly, and cleaning interproximally.[1]

Oral Rinses

Rinsing the oral cavity with non-medicated oral rinses - saline water rinse, sodium bicarbonate rinse, or a combination of sodium bicarbonate and saline water- is recommended every four hours.[1] The MASCC/ISOO clinical guidelines state that despite the limited data on both saline and sodium bicarbonate oral rinses, the panel has recognized that these are inert and bland rinses that increase oral clearance, helps maintain oral hygiene and improve patient comfort.[2] (A1)

Chlorhexidine is not recommended to prevent radiotherapy-induced oral mucositis as no available data supports its benefit.[2][1][2](A1)

Antiinflamatory Agents

The MASCC/ISOO guidelines recommend benzydamine mouthwash for preventing oral mucositis in head and neck cancer patients receiving less than 50 Gy radiation dose (moderate dose) and in those receiving radiotherapy-chemotherapy (RT-CT).[2](A1)

Hydration And Lubrication Of The Oral Mucosa

Patients should be advised to maintain adequate hydration and avoid irritants like tobacco and alcohol (as a beverage and alcohol-containing mouth rinses).[1][8][1] Mousses and topical barrier gels can be used to lubricate the oral mucosa surfaces.[1]

Diet

The diet should be limited to food that does not aggravate the mucosa or risk injury during chewing. Food that may induce unintended trauma to the oral mucosa, such as spicy, sharp, and hard food, should be avoided.[8]

Pain Management

Topical morphine 0.2% mouth rinse is recommended by the MASCC/ISOO guidelines for managing pain in head and neck cancer patients receiving radiotherapy and chemotherapy.[2](A1)

Other oral rinses have been formulated to manage pain, including the so-called “magic mouthwash.” This oral rinse usually contains an anesthetic, antacid, and diphenhydramine and may have steroids and anti-micotics.[15] However, a study of 26 patients receiving a dual treatment of RT and CT concluded that patients using topical morphine 0.2% mouth rinses had a shorter duration of severe pain and needed less systemic analgesic treatment than those using the magic mouth rinse containing lidocaine, diphenhydramine, and magnesium aluminum hydroxide.[15]

Low-Level Laser Therapy

The local use of low-level light and laser therapy to induce a biological response is known as photobiomodulation (PBM).[2] PBM promotes the regeneration of affected tissue and prevents inflammation in animal models.[15] Furthermore, clinical studies showed that low-level laser therapy (LLLT) reduces mucositis severity in patients receiving chemo-radiotherapy before hematopoietic stem cell transplantation.[15](A1)

The MASCC/ISOO guidelines recommend intraoral low-level laser therapy for the prevention of oral mucositis in the following clinical settings:

• Adult patients undergoing hematopoietic stem cell transplantation conditioned with high-dose chemotherapy, with or without total body irradiation.[2]
• Adult patients undergoing radiation therapy to the head and neck without chemotherapy - clinicians must take into account the safety considerations relevant to patients with oral cancer.[2]
• Adult patients undergoing radiotherapy-chemotherapy for head and neck cancer - clinicians must take into account the safety considerations relevant to patients with oral cancer.[2]
(A1)

It is worth noting that although clinical evidence supports the use of LLLT in head and neck cancer patients, in vitro studies showed that LLLT can induce pro-tumorigenic signaling pathways in cancerous cells.[15] Low-level laser therapy should not be applied to cancerous tissue, and patients must be closely followed.[15]

Cryotherapy

Cryotherapy refers to placing a source of cold in the oral cavity, usually ice or cold water, during the delivery of a cytotoxic agent (chemotherapy).[17] Cooling the oral mucosa induces vasoconstriction, preventing the influx of cytotoxic drugs in the oral tissues and preventing oral mucositis.[17] Low temperatures may also decrease the metabolism of the basal epithelial layer – making the epithelium less prone to the damage caused by cytotoxic drugs.[18](A1)

The cooling of the oral mucosa is only temporary; therefore, this measure is indicated in conjunction with short chemotherapy protocols or when short half-life cytotoxic agents are used.[2] The MASCC/ISOO guidelines recommend 30 minutes of oral cryotherapy during the administration of bolus 5-fluorouracil.[2] Oral cryotherapy is also recommended for patients conditioned with high-dose melphalan undergoing autologous hematopoeitic stem cell transplantation.[2](A1)

Chemoprotective Agent

Palifermin is a keratinocyte growth factor and works as a chemoprotective agent, recommended for severe oral mucositis (mucositis greater than or equal to grade 3) associated with autologous hematopoietic stem cell transplant regimens.[2] Palifermin decreases the incidence and duration of severe oral mucositis in such patients.(A1)

Zinc Supplementation

Zinc enhances tissue repair and provides antioxidant effects. The 2014 MASCC/ISOO guidelines recommended systemic zinc supplements to prevent OM in oral cancer patients undergoing radiotherapy or chemoradiation.[19] However, in the 2020 update of the guidelines, the panel reversed this recommendation to no guidelines possible.[2](A1)

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 and require adjuvant treatment. Viral infections such as herpes simplex virus and fungal infections such as candidiasis can be superimposed. Dermatologic manifestations of systemic inflammatory diseases like 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.[20]

Prognosis

Symptomatic treatment and palliative care may be sufficient to treat uncomplicated cases of mucositis, which are usually self-limiting.[8] However, nearly 20% of head and neck cancer patients treated with chemo-radiotherapy require hospitalization and a delay in cancer therapy due to high-grade mucositis.[15] This will disrupt patients' quality of life, worsen prognosis, and increase the use of health care resources.

Complications

Oral mucositis results in severe pain and the 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, potentially worsening cancer outcomes. Mucositis also results in a breakdown of the protective mucosal barrier and thus increasing the susceptibility of the patient to infections. Therefore, 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.[21]