Oral mucositis and stomatitis

Definition

Oral mucositis

Erythematous and/or ulcerative lesions of the mucosal lining of the oral cavity secondary to anti-cancer agents, radiation therapy, particularly to the head, neck or oesophagus, or high dose chemotherapy followed by blood and marrow transplant (BMT).^r

Stomatitis

Any inflammatory condition of the oral tissues. Stomatitis can include oral ulceration, xerostomia, altered taste and taste loss, oral sensitivity, and oral pain with or without lesions being clinically present.^r​

Pathophysiology

Oral mucositis

The mucosal lining of the mouth is a prime target for treatment related toxicity by virtue of its rapid cell turnover rate. Chemotherapy and radiation therapy cause direct cell damage to basal epithelial cells impairing their ability to replicate. This is thought to initiate a pathogenic process that includes other contributing factors, such as reactive oxygen species, proinflammatory cytokines, and metabolic products of bacteria, which can lead to loss of mucosal integrity resulting in clinically painful lesions.^r

Stomatitis

These conditions occur secondary to targeted therapies, e.g., tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin (mTOR) inhibitors. The oral ulcerations resemble aphthous stomatitis, and their pathogenesis is not well understood.

It is thought to be multi-factorial and distinct from conventional mucositis, based on differences in clinical presentation. mTOR inhibitors may cause an autoimmune-like inflammatory response which could contribute to the development of mTOR inhibitor-associated stomatitis (mIAS). mTOR inhibitors may also induce an increase in glucose levels, and this, combined with its anti-angiogenic properties, would have a negative impact on wound healing.^r

There is consensus the term mTOR inhibitor-associated stomatitis (mIAS) be used to describe these lesions.^r

Incidence/prevalence

Oral mucositis

Radiation therapy- All patients receiving radiation therapy to the head and neck, and more than 96 per cent of patients receiving total body irradiation (TBI) develop some level of mucositis.^rr

Blood and marrow transplant (BMT) - The WHO figures for the incidence of mucositis in patients undergoing BMT can be as high as 75 per cent depending on the conditioning regimen used, and whether methotrexate prophylaxis is used to prevent graft-versus-host disease.^r​

Chemotherapy - Mucositis occurs in approximately 20-40 per cent of patients receiving conventional chemotherapy. In particular chemotherapy with bleomycin, fluorouracil, methotrexate, cytarabine, doxorubicin, etoposide, melphalan, capecitabine and irinotecan can lead to a clinically significant incidence of mucositis.^r​

Targeted therapies - Additionally 10-40 per cent of patients treated with molecularly targeted agents, such as sunitinib, sorafenib, regorafenib and cetuximab, are reported to have developed mucositis.^r

Stomatitis

In a systematic review of 44 studies of mTOR inhibitors, mIAS was the most frequent side effect, with 73.4 per cent of patients developing some level of stomatitis, and was the most frequent dose-limiting toxicity (52.5 per cent).^r

Onset/duration

Oral mucositis

Radiation therapy - Radiation-induced mucositis is more severe and of longer duration (3­12 weeks) when compared to chemotherapy-induced mucositis. Mucositis usually appears about two weeks into radiation treatment and peaks by the end of treatment. The peak can continue for at least two weeks after treatment completion and can persist for up to eight weeks .^r

For patients undergoing combined radiation therapy and chemotherapy treatments, onset can be sooner, and concurrent treatment can exacerbate the severity, and prolong the duration of mucositis.^r

Blood and marrow transplant (BMT) – Mucositis can appear at around 5 days after BMT, and may last for 2 to 3 weeks after completion of treatment.^r

Chemotherapy - Typically occurs 2 to 3 weeks from the commencement of conventional chemotherapy.^r

Stomatitis

mIAS lesions usually appear within 4-5 days of commencing treatment, and most cases resolve spontaneously within 7-10 days of onset, despite continuing mTOR inhibitor treatment.^r​

Risk factors

Table 1. Risk factors for development/severity of oral mucositis and stomatitis

Signs and symptoms

Oral mucositis

Signs and symptoms can include:

• erythema
• bleeding
• altered taste.

Oral mucositis lesions are characterised by:

• their non-uniform shape and depth
• the presence of a fibrinous pseudo-membrane.

Oral mucositis often occurs concurrently with damage to other areas of the gastrointestinal tract.^r

Stomatitis

Stomatitis signs and symptoms can include:

• single or multiple ulcerations resembling aphthous stomatitis
• distinct ovoid ulcers with a central white/grey area surrounded by an erythematous margin or halo
• small in size in comparison to other types of mucosal trauma that are secondary to chemotherapy and radiation therapy
• altered taste/taste loss
• xerostomia
• thick ropey secretions
• nonulcerated oral lichenoid or hyperkeratotic lesions^r
• oral sensitivity and pain without the presence of oral lesions.

mIAS is not associated with other gastrointestinal trauma.

Investigations and diagnosis

Patients should be assessed using a scale that incorporates the measurement of oral symptoms, clinical signs, and functional disturbances. Each patient should be assessed for:

• pain and/or dysphagia - including response to any analgesia administered
• erythema and/or ulceration of the oral cavity
• xerostomia (dry mouth)
• thick ropey saliva
• signs and symptoms of oral candidiasis, viral or bacterial infection
• signs and symptoms of aspiration
• altered speech or voice changes, including hoarseness
• dysgeusia (altered taste)
• nutritional intake
• hydration status and changes in fluid intake
• patient compliance with mouth care
• presence of ill-fitting dentures or jewellery (mouth piercings)
• effects (both as subjectively reported by the patient, and objectively assessed) of interventions administered to treat adverse events.

Grading

A number of scales have been developed specifically for the assessment of oral mucositis secondary to chemotherapy and radiation therapy, e.g., the Common Terminology Criteria for Adverse Events (CTCAE). However, the use of such a scale to assess the effects of targeted therapies on the mouth could lead to the inaccurate measurement of stomatitis - its incidence, progression and severity.^r

The mIAS Scale was developed for the assessment of stomatitis secondary to the use of targeted therapies (a clinical measurement of the duration of lesions, and symptomatic and functional assessments).^r See Table 2 for a comparison of the CTCAE scores and the mIAS scale.

Both mucositis and stomatitis can be extremely painful. Mucositis has been reported by cancer patients as the most debilitating of symptoms.^r It is also a clinically significant risk factor for febrile neutropenia, and may compromise the airway. Additionally there is a risk of sepsis secondary to mucositis during the aplasia period following BMT.

Basic oral care is crucial in preventing and reducing the severity of both mucositis and stomatitis. Educating the patient about effective oral hygiene is essential. Reducing and/or removing sources of trauma (such as ill-fitting dentures) and avoiding painful stimuli (hard and/or spicy foods, hot drinks, smoking, and alcohol) are also very important.

The involvement of a multidisciplinary team in the management of sequelae associated with cancer therapy is recommended. Patients should have appropriate access and care-pathways to supporting health services.

Oral mucositis

Based on MASCC/ISOO current evidence there is no recommendation either in support of, or against the use of normal saline, or sodium bicarbonate, in the prevention or treatment of oral mucositis in patients undergoing cancer treatment.^r If normal saline or sodium bicarbonate are not well tolerated, plain water mouthwashes can be used for this group of cancer patients, to help promote compliance with basic oral care.^r

As the radiation dose received by the oral cavity is a risk factor for mucositis, radiation therapy treatment techniques which minimise the radiation dose to the oral cavity may help minimise the severity of mucositis.^r

MASCC/ISOO guidelines recommend:^r​

• 30 minutes oral cryotherapy to prevent mucositis in patients receiving bolus fluorouracil (5FU), or high dose melphalan with/without TBI as conditioning for BMT
• benzydamine mouthwash to prevent mucositis in patients with head and neck cancer receiving moderate dose radiation therapy (up to 50 Gy), without concomitant chemotherapy
• benzydamine is currently only routinely available as an alcohol-based preparation in Australia and is rarely used in practice. It is not recommended by the eviQ radiation oncology head and neck reference committee
• patient-controlled analgesia with morphine be used to treat pain.

MASCC/ISOO guidelines suggest:^r​

• benzydamine mouth wash may be used to prevent oral mucositis in patients with head and neck cancer receiving radiation therapy with concomitant chemotherapy
• benzydamine is currently only routinely available as an alcohol-based preparation in Australia and is rarely used in practice. It is not recommended by the eviQ radiation oncology head and neck reference committee
• oral glutamine (at a dose range of 10-30 g/day) for head and neck patients receiving radiation therapy with concomitant chemotherapy, administered throughout treatment to prevent mucositis
• morphine 0.2 per cent mouthwash for oral-mucositis associated pain in patients with head and neck cancer receiving radiation therapy with concomitant chemotherapy
• honey (topical and oral) as a natural remedy may be used to prevent oral mucositis in patients with head and neck cancer receiving radiation therapy with/without concomitant chemotherapy.

MASCC/ISOO guidelines recommend against:^r​

• IV glutamine be used to prevent mucositis in patients undergoing BMT
• sucralfate (combined topical and systemic) be used for prevention or treatment of oral mucositis associated pain in head and neck cancer patients undergoing radiation therapy or patients with solid tumours receiving chemotherapy.

Stomatitis

Prevention

Expert opinion has suggested that due to the elevated risk of bacterial infection in patients receiving targeted agents (increasing the risk of oral injury), saline mouthwashes should be used instead of plain water.^r

Steroid-based mouthwash has been shown to reduce the incidence and severity of mIAS lesions.^r

Treatment

Based on expert opinion, a number of interventions have been suggested for treating targeted therapy-associated stomatitis and pain, including:^r

• increasing the number of mouthwashes, up to hourly if necessary
• sugarless chewing gum or salivary substitutes to treat oral dryness
• anaesthetic mouthwashes (e.g., viscous lidocaine 2 per cent) or coating agents to treat mild to moderate pain
• systemic or topical analgesics to treat pain (studies have shown transdermal fentanyl and short-acting opiates for breakthrough pain have been effective)
• topical steroids, e.g., dexamethasone mouth rinse to treat mIAS lesions
• systemic or intralesional steroids to treat highly symptomatic mIAS ulcers, e.g., oral prednisolone, triamcinolone injection.^r

Educate all patients to immediately report the development of symptoms such as pain, difficulty swallowing, thrush, mouth ulcers, bleeding or difficulty talking.

With this in mind, patients must be educated to:

• inspect their mouth daily and immediately report any adverse changes
• if possible, see a dentist prior to commencing treatment to eliminate possible sources of oral mucosal injury, e.g., ill-fitting dentures, broken teeth
• drink adequate amounts of water to keep the mouth moist (within limitations of fluid restrictive diets where necessary)
• keep lips lubricated, e.g., with lip balm or lip cream
• avoid using lip balms or creams that are hydrophobic or water-repelling (e.g., have a high content of paraffin or petroleum jelly)
• use a soft toothbrush or swab four times a day, after meals and before sleep (change the toothbrush monthly)
• use a mild, fluoride-containing toothpaste
• if in the habit of using dental floss or inter-dental brushes, continue to do so daily; if this is not already habitual, do not start it while on cancer therapy as it can damage the epithelial barrier, thus increasing the risk of developing mucositis/stomatitis
• rinse mouth with an alcohol-free mouthwash following brushing; and try to avoid eating/drinking for about 30 minutes after rinsing
• remove dentures before performing oral care; brush dentures with toothpaste and rinse with water; clean/swab the gums
• avoid painful stimuli, e.g., smoking, alcohol, acidic foods (such as tomatoes and citrus), hot drinks, spicy, hot, raw and crusty foods, fizzy drinks and too much salt.^r

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