Mucositis

Symptoms

Mucositis

What is it?
Common causes
How common is it?
What does it involve?
Tests/examinations and questions you may be asked
Management and treatment

What is it?

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Mucositis is a painful condition in which damage occurs to the lining of the mucous membranes of the mouth and gastrointestinal tract (GI tract), usually following anticancer treatment with chemotherapy and/or radiotherapy. It is a debilitating and distressing side effect of these treatments, and is characterised by extensive pain, ulceration and inflammation of the affected mucosal sites.

Mucositis is a significant side effect associated with anticancer treatments. It can affect your food intake and cause bloating, nausea, vomiting and diarrhoea, all of which can contribute to malnutrition. Moreover, the ulcerative lesions produced by mucositis can be doorways for bacterial infection. Patients who are neutropenic are extremely vulnerable to infections, which can be lethal. In many patients, radiation toxicity is particularly severe on the gut and can lead to intestinal permeability, malabsorption and dysmotility. Severe complications such as perforation, obstruction, and fistula formation can also occur.

Mucositis leads to many hospital admissions and can place a large cost burden on the health system. Patients who experience mucositis are at an increased risk of bleeding and infection, and therefore may have to increase their length of hospitalisation. Most importantly, it can reduce the quality of life of patients already suffering from a severe disease, and can be detrimental to life-saving treatment. Severe mucositis may require lower medication doses and interruptions in treatment, and may lead to delays in cancer chemotherapy. All of these ultimately affect patient survival. Patients receiving treatment with 5-fluorouracil or 5-FU (e.g. Efudix), methotrexate (e.g. Ledertrexate), etoposide, doxorubicin, melphalan (e.g. Alkeran), cytosine, arabinoside and cyclophosphamide (e.g. Cycloblastin) are particularly affected.

Common causes

Mucositis is a side effect of cancer chemotherapy or radiotherapy. There are certain factors, however, that can increase your chance of developing mucositis and which may also affect its severity. These risk factors can be patient related or treatment related.

Patient related factors

Patient related factors include:

Age (patients younger than 20 are at higher risk)
Sex (females are at a higher risk in some cases, such as when recieving treatment with 5-FU)
Kidney and liver function
The presence of any other conditions
Type of cancer (blood or lymphatic cancers pose a greater risk than solid tumours)
Poor oral health (e.g. periodontal disease)
Bodyweight (found to be a risk factor for gastrointestinal mucositis associated with 5-FU)
Genetic problems which affect the ability to metabolise drugs (e.g. defects in the enzyme that breaks down 5-FU in the liver have been shown to increase toxicity to this drug. Only a very small number of people have this defect.)

Treatment related factors

Treatment associated factors refer to the type of drug or combination of drugs being administered. Not all anticancer agents have equal mucosal toxicity. Other factors in radiotherapy include the dose and frequency of administration and location of treatment. Combined treatment regimes of radiotherapy and chemotherapy lead to more severe mucositis.Certain chemotherapeutic agents (including methotrexate and etoposide) are secreted into the saliva, thereby increasing direct toxicity to the oral cavity.

How common is it?

Whether or not a patient develops mucositis is highly dependent on the dose, schedule and sequence of drug administration. Mucositis affects almost all patients undergoing high dose chemotherapy and bone marrow or stem cell transplantation, and 80% of patients with head and neck cancer undergoing radiotherapy.In patients receiving standard doses of chemotherapy, about 40% will develop mucositis, with half of those affected having to modify their treatment regime as a consequence.

The incidence of mucositis is much higher in patients undergoing conditioning therapy for bone marrow transplantation, continuous infusion therapy for breast and colon cancer, and therapy for head and neck cancers which requires both radiotherapy and chemotherapy. More than 60% of patients undergoing such high risk treatments experience severe mucositis.About 40% of patients being treated with 5-FU (with or without leucovorin) will develop oral mucositis, and 10-15% of those cases will be classed as grade 3-4. Around 20% of patients being treated with irinotecan (e.g. Camptosar) can develop severe GI mucositis. Mucositis from radiotherapy depends on the site, dosage and fractionation. Fractionation increases the risk to more than 70%.

Around 15% of patients being treated with radiotherapy to the oral cavity and pharynx will need hospitalisation for treatment related complications.

What does it involve?

There are five steps leading to mucositis. These occur in the cells making up the mucous membranes of the mouth and gastrointestinal tract:

Initiation
Following a dose of radiotherapy or chemotherapy, the initiation phase begins immediately. Damage to the lining of the mouth is caused by the cytotoxic agent, leading to the formation of reactive oxygen species (ROS), which are free radicals capable of causing cell and DNA damage.
Upregulation and message generation
The ROS causes an increase in the number and activity of certain genes, leading to the activation of transcription factors (proteins capable of activating the expression of other genes) NF-kβ.
Signalling and amplification
These transcription factors then activate genes, which stimulate cells to produce cytokines (proteins capable of causing damage to cells) TNF-α, IL-1β. These cytokines can also increase the amount of transcription factors available, thereby acting as a positive feedback loop and amplifying the whole process.
Ulceration
Ulceration occurs as a result of all the cell death and injury caused during the first three stages. This usually begins about 4-5 days following initiation of treatment and peaks at about day 10. Consequently, the lining of the mouth becomes very thin and there may be redness, bleeding and ulcers present. It may be extremely painful, depending on the severity of the mucositis, and may affect your ability to speak and eat. Bacterial infection can occur at this stage, further increasing the amount of cytokines in the surrounding tissues and causing more damage to the mucosal membrane.
Healing
The final healing stage occurs once treatment with the mucotoxic agent has stopped.

Tests and examinations and questions you may be asked

Damage to the mucosal tissues of the body begins immediately following chemotherapy or radiotherapy, even before symptoms appear. Your doctor will assess you for oral mucositis within 12-24 hours after your treatment starts, and will then monitor your progress daily.

There are five steps for classifying the extent of mucositis into grades according to World Health Organisation (WHO) guidelines:

Assess nutrition
Determine level of discomfort
Assess saliva production
Physical examination
Score

Questions regarding diet are asked to determine your ability to consume solid food or liquid and whether or not mucositis has affected this. The level of mouth and oral pain is assessed by determining dryness, difficulty swallowing and taste function. You will also be questioned on how much saliva you produce, and the doctor will conduct a physical examination to inspect any bleeding and ulceration.

Following examination, patients are scaled according to the WHO grading scale:

Grade 0: No ulceration or pain. May have soreness but no erythema.
Grade 1: No ulceration. Erythema and soreness present. May involve buccal mucosal scalloping, with or without erythema.
Grade 2: Ulcers with or without erythema. Can eat solid food.
Grade 3: Ulcers with or without extensive erythema. Can tolerate liquids but not solid food.
Grade 4: Cannot eat or drink. Patient is fed parenterally and receives intravenous analgesia.

Management and treatment

There are currently very few treatments available for mucositis. Management is mainly limited to pain relief, anti-diarrhoea medication, anti-ulcer medication and dose modification. Preventing dehydration, providing adequate nutrition and treating infections are central to management strategies.

The Multinational Association of Supportive Care in Cancer has produced some guidelines for the management, prevention and treatment of mucositis.These recommendations are summarised below.

Oral mucositis

Management of oral mucositis centres on maintaining good oral hygiene to reduce the severity of symptoms. Replacing toothbrushes regularly is recommended, as is frequently cleaning the mouth. This can include the use of rinses and moisturisers.

Patient controlled analgesia with morphine is the treatment of choice in patients with oral mucositis undergoing haematopoietic stem cell transplantation (HSCT).

Radiation therapy - Prevention

Benzydamine (e.g. Difflam) is recommended for preventing radiation induced mucositis in patients with head and neck cancer receiving moderate dose radiation therapy.
Sucralfate (e.g. Carafate) and antimicrobial lozenges are not recommended for preventing radiation induced oral mucositis.
Chlorhexidine is not recommended for preventing oral mucositis in patients with solid head and neck tumours who are undergoing radiotherapy.
Sucralfate is not recommended as a treatment for radiation induced oral mucositis.

Standard dose chemotherapy - Prevention

To prevent mucositis in patients undergoing standard dose chemotherapy with 5-FU, 30 minutes of swishing ice chips in the mouth (cryotherapy) is recommended prior to treatment. This is also recommended for patients being treated with bolus doses of edatrexate.
Acyclovir and its derivatives are not recommended for routine use to prevent mucositis.

Standard dose chemotherapy - Treatment

Do not use chlorhexidine for established oral mucositis.

High dose chemotherapy with or without total body irradiation plus HSTC – Prevention

Palifermin can be used in patients with haematological malignancies receiving high dose chemotherapy and total body irradiation with autologous stem cell transplantion. 60ug/kg/day for three days prior to conditioning treatment and 3 days post transplant for prevention of oral mucositis.
Cryotherapy can be used in patients receiving high dose mephalan to prevent oral mucositis.
Use of pentoxifyllin or GMCSF mouthwashes is not recommended for preventing mucositis in patients undergoing HSCT .
Low level laser therapy (LLLT) can be used to attempt to reduce oral mucositis in patients receiving high dose chemotherapy before HSCT.

GI Mucositis

Basic bowel care involves maintaining adequate hydration.

Radiation therapy – Prevention

Sulfasalazine (e.g. Pyralin) 500mg orally twice daily to reduce incidence and severity of radiation induced enteropathy in patients receiving external beam radiotherapy to the pelvis.
Amifostine (>340mg/m²) may be used to prevent radiation proctitis in those receiving standard dose radiotherapy for rectal cancer.
Do not use oral sucralfate to prevent acute diarrhoea in patients with pelvic malignancies. It is associated with more GI side effects.
Do not use 5-amino salicylic acid and its related compounds mesalazine and olsalazine to prevent GI mucositis.

Radiation therapy – Treatment

Sucralfate enemas can be used to manage chronic radiation induced proctitis in patients who have rectal bleeding.

Standard dose and high dose chemotherapy - Prevention

Ranitidine or omeprazole for prevention of epigastric pain following treatment with cyclophosphamide, methotrexate and 5-FU, or treatment with 5-FU with or without folinic acid chemotherapy.
Do not use systemic glutamine for preventing GI mucositis.

Standard dose and high dose chemotherapy - Treatment

If loperimide fails to control diarrhoea induced by standard or high dose chemotherapy with HSCT, octreotide (e.g. Sandostatin) at a dose of at least 100ug subcutaneously twice daily is recommended.

Combined chemotherapy and radiation therapy - Prevention

Amifostine (Ethyol) is recommended to reduce oesophagitis in patients with non small cell lung cancer.

Reference

Gibson RJ, Bowen JM, Keefe D. Technological advances in mucositis research: New insights and new issues. Cancer Treatment Reviews. 2008 doi:10.1016/j.ctrv.2008.02.001
Sonis ST, Elting LS, Keefe D, Peterson DE, et al. Perspectives on cancer therapy induced mucosal injury: pathogenesis, measurement, epidemiology and consequences for patients. Cancer Supplement. 2004; 100(9): 1995.
Pico JL, Avila-Garavito A, Naccache P. Mucositis: Its occurrence, consequences, and treatment in the oncology setting. Oncologist. 1998; 3: 446–51.
Barasch A, Peterson DE. Risk factors for ulcerative mucositis in cancer patients: Unanswered questions. Oral Oncol. 2003; 39 (2):91–100.
Rubenstein EB, Peterson DE, Schubert M, Keefe D, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy–induced oral and gastrointestinal mucositis. Cancer. 2004; 100 (9Suppl): 2026–46.
Keefe DM, Schubert MM, Elting LS, Sonis ST, et al. Updated clinical practice guidelines for prevention and treatment of mucositis. Cancer. 2007; 109(5): 820-30.
Keefe DM. Intestinal mucositis: mechanisms and management. Current Opinion in Oncology. 2007; 19: 323–7.
Oral mucositis visual assessment guide: Based on the WHO oral toxicity scale [online]. Kepivance. 2005 [cited 8 May 2008]. Available from URL: http://www.kepivance.com/ pdf/ om_assessment_guide.pdf)