Mucositis
Encyclopedia
Mucositis is the painful inflammation
and ulceration
of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy
and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.
Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary tract mucositis increases mortality and morbidity and contributes to rising health care costs.Cancer. 1 May 2004;100(9 Suppl):2026-46. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Rubenstein EB, et al. [PMID15108223]
Free full text Expert panel reviewed literature published January 1966 to May 2002, to create evidence-based guidelines for the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology.
For most cancer treatment, about 5-15% of patients get mucositis. However, with 5-fluorouracil
(5-FU), up to 40% get mucositis, and 10-15% get grade 3-4 oral mucositis. Irinotecan
is associated with severe GI mucositis in over 20% of patients. 75-85% of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well.
Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation.
patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks.
As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema
is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful. The degree of pain is usually related to the extent of the tissue damage. Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth.
Dysgeusia
, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness," or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste.
of mucositis can be divided into its 5 stages; including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokine
s are responsible for the various stages. The initiation phase is caused by the production of free radicals caused by the chemo- or radio- therapy, which damages cell DNA
. This causes the production of cell transcription factors such as NF-κB, which upregulates inflammatory cytokines, marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1 and TNF-alpha. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers.
, bone marrow
transplants or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis.
The severity of oral mucositis can be evaluated using several different assessment tools.
Two of the most commonly used are the World Health Organization (WHO) Oral Toxicity score and the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Oral Mucositis. While the NCI system has separate scores for appearance (erythema and ulceration) and function (pain and ability to eat solids, liquids, or nothing by mouth), the WHO score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition). Another scale developed in 1999, the Oral Mucositis Assessment Scale (OMAS) has been shown to be highly reproducible between observers, responsive over time, and accurate in recording symptoms associated with mucositis. The OMAS provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth.
is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocain for relief of pain. Palifermin
is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation
(eg, IL-1, IL-11, TGF-beta3), amino acid
supplementation (eg, glutamine), vitamins, colony-stimulating factors, cryotherapy
, and laser therapy. Symptomatic relief of the pain of oral mucositis may be provided by barrier protection agents such as concentrated oral gel products (eg Gelclair
). Caphosol
is a mouth rinse which has been shown to prevent and treat oral mucositis caused by radiation and high dose chemotherapy. MuGard™ is a FDA-approved mucoadhesive oral protectant, developed by Access Pharmaceuticals, Inc., that is designed to form a protective hydrogel coating over the oral mucosa while a patient is undergoing chemotherapy and/or radiotherapy cancer treatments to the head and neck. Additionally, the efficacy of MuGard™ for the prevention or treatment of mucositis has been tested by a prospective, randomized clinical trial in which 43% of head and neck cancer patients using MuGard™ prophylactically never got oral mucositis.
NeutraSal® is an FDA-approved calcium phosphate mouth rinse which has been shown in a open-label, observational registry trial to prevent and reduce the severity of oral mucositis caused by radiation and high dose chemotherapy. In the trial, 56% of the radiotherapy patients reported 0 (WHO score) or no mucositis, which is significantly lower than historical rates.
, bacteria
or fungus
.
Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss.
Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicemia (especially in immunosuppressed patients). Approximately half of all patients who receive chemotherapy develop such severe oral mucositis that becomes dose-limiting such that the patient's cancer treatment must be modified, compromising the prognosis.
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and ulceration
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.
Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary tract mucositis increases mortality and morbidity and contributes to rising health care costs.Cancer. 1 May 2004;100(9 Suppl):2026-46. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Rubenstein EB, et al. [PMID15108223]
Free full text Expert panel reviewed literature published January 1966 to May 2002, to create evidence-based guidelines for the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology.
For most cancer treatment, about 5-15% of patients get mucositis. However, with 5-fluorouracil
Fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...
(5-FU), up to 40% get mucositis, and 10-15% get grade 3-4 oral mucositis. Irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
is associated with severe GI mucositis in over 20% of patients. 75-85% of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well.
Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation.
Signs and symptoms
CancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks.
As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful. The degree of pain is usually related to the extent of the tissue damage. Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth.
Dysgeusia
Dysgeusia
Dysgeusia is the distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is the decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be...
, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness," or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste.
Pathophysiology
The pathophysiologyPathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of mucositis can be divided into its 5 stages; including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s are responsible for the various stages. The initiation phase is caused by the production of free radicals caused by the chemo- or radio- therapy, which damages cell DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. This causes the production of cell transcription factors such as NF-κB, which upregulates inflammatory cytokines, marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1 and TNF-alpha. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers.
Diagnosis
Diagnosis is based on the symptoms the patient is experiencing and the appearance of the tissues of the mouth following chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplants or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis.
The severity of oral mucositis can be evaluated using several different assessment tools.
Two of the most commonly used are the World Health Organization (WHO) Oral Toxicity score and the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Oral Mucositis. While the NCI system has separate scores for appearance (erythema and ulceration) and function (pain and ability to eat solids, liquids, or nothing by mouth), the WHO score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition). Another scale developed in 1999, the Oral Mucositis Assessment Scale (OMAS) has been shown to be highly reproducible between observers, responsive over time, and accurate in recording symptoms associated with mucositis. The OMAS provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth.
Treatment
Treatment of mucositis is mainly supportive. Oral hygieneOral hygiene
Teeth cleaning is part of oral hygiene and involves the removal of dental plaque from teeth with the intention of preventing cavities , gingivitis, and periodontal disease. People routinely clean their own teeth by brushing and interdental cleaning, and dental hygienists can remove hardened...
is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocain for relief of pain. Palifermin
Palifermin
Palifermin is a human recombinant keratinocyte growth factor produced in Escherichia coli...
is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
(eg, IL-1, IL-11, TGF-beta3), amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
supplementation (eg, glutamine), vitamins, colony-stimulating factors, cryotherapy
Cryotherapy
Cryotherapy is the local or general use of low temperatures in medical therapy or the removal of heat from a body part. The term "cryotherapy" comes from the Greek cryo meaning cold and the word therapy meaning cure...
, and laser therapy. Symptomatic relief of the pain of oral mucositis may be provided by barrier protection agents such as concentrated oral gel products (eg Gelclair
Gelclair
Gelclair is an oral gel that coats the surface of the mouth forming a thin protective film over painful oral lesions, such as those caused by radiotherapy or chemotherapy treatment for cancer.-Uses:...
). Caphosol
Caphosol
Caphosol is a mouth rinse designed to moisten, lubricate and clean the oral cavity including the mucosa of the mouth, tongue and oropharynx which has been shown to prevent and treat oral mucositis in patients receiving radiation therapy or chemotherapy in the treatment of cancer.-Uses:Caphosol can...
is a mouth rinse which has been shown to prevent and treat oral mucositis caused by radiation and high dose chemotherapy. MuGard™ is a FDA-approved mucoadhesive oral protectant, developed by Access Pharmaceuticals, Inc., that is designed to form a protective hydrogel coating over the oral mucosa while a patient is undergoing chemotherapy and/or radiotherapy cancer treatments to the head and neck. Additionally, the efficacy of MuGard™ for the prevention or treatment of mucositis has been tested by a prospective, randomized clinical trial in which 43% of head and neck cancer patients using MuGard™ prophylactically never got oral mucositis.
NeutraSal® is an FDA-approved calcium phosphate mouth rinse which has been shown in a open-label, observational registry trial to prevent and reduce the severity of oral mucositis caused by radiation and high dose chemotherapy. In the trial, 56% of the radiotherapy patients reported 0 (WHO score) or no mucositis, which is significantly lower than historical rates.
Complications
Sores or ulcerations can become infected by virusVirus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
or fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
.
Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss.
Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicemia (especially in immunosuppressed patients). Approximately half of all patients who receive chemotherapy develop such severe oral mucositis that becomes dose-limiting such that the patient's cancer treatment must be modified, compromising the prognosis.