DEFINITION
Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract. From a clinical point of view mucositis is similar to aphthous stomatitis, but the causes are different. Mucositis is usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. There are a lot of complications if the mucositis affects also the gastrointestinal tract, such as nausea, vomiting, abdominal pain, diarrhoea, blood loss and even sepsis. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Oral mucositis is particularly profound and prolonged among patients who receive total-body irradiation. Another treatment used in case of cancer is the one with fluorouracil (chemiotherapy).
Fluorouracil is the responsable of many oral damages and adverse effects mainly in the gastro-enteric tract: in fact, it blocks the synthesis of thymidine.
A patient with oral mucositis
EPIDEMIOLOGY
- People with head-neck cancers (solid tumors) who follow a radiotherapy or a chemiotherapy
- Traditionally has been associated more with hematologic malignancies; 98% of patients undergoing hematopoietic stem cell transplantation.
- Mainly people with neutropenia, too
SYMPTOMS
- Difficulty in speaking, swallowing and eating. Even opening the mouth may became not so easy.
- Dysgeusia
- Pain and soreness (throat soreness too)
- It is necessary a liquid diet, opioid analgesia (hydratation and parenteral nutrition)
DIAGNOSIS
- Clinical diagnosis as a result of the direct observation of the patient: presence of ulcerations, lesions that describe a situation with a epithelial, mucosal and submucosal damage
- Onset of typical symptoms
- Previous radiotherapy or chemotherapy
- If we block the Radio or chemotherapy the disease regresses
PATHOGENESIS
In case of hematologic malignancies, patients follow the chemotherapy and then there might be necessity of a bone marrow graft. In this situation IL-6 induces an increase of fibrinogen. In a physiological situation, this fibrinogen is metabolized by specific cells into D-dimer. After this, there is the white cells-proliferation that is the signal of a correct body response. If not, the increase of fibrinogen, as one of the element in the coagulation process, causes thrombosis all-over the body. Some symptoms may be: mucositis and stomatitis, micro-infarctions, cutaneous rashes. If the situation is more diffused there might be big tissue infarctions and death.
coagulation and fibrinogen
Mucositis is an epithelium-mediated event as a result of a direct damage by chemotherapy or radiotherapy to the basal epithelial cell layer. (Most recent theories say that also the mucosa and the submucosa are involved in this disorder.) As a consequence there is the loss of renewal capacity and subsequent clonogenic cell death, atrophy and ulceration. However, it is a series of complex and dynamic events involving the endothelium, the extracellular matrix, connective tissue and submucosal cells. Mucositis is more problematic in case of neutropenia. The pathophysiology of mucositis can be divided into its 5 stages: an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokines 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 NFkB, which upregulates inflammatory cytokines marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1beta, IL-6, TNF-alfa. Radiation and chemotherapy also activate the pro-apoptotic ceramide and sphingomyelinase pathways. There is a the destruction of the fibroblasts that generates fibronectin, metalloproteinases and further apoptosis. The ulcers do not usually develop until at least day 7 after starting chemiotherapy or RT, although the pain develops 1-2 days earlier. During the signal-amplification phase, active proteins targets the submucosal tissue and, some of them, induce feed-back loops that amplify the primary damage response. And so TNF-alfa activates: caspase, MAPK, COX-2, tyrosine kinase pathways, while on the other side NF-kB induces an increased production of IL-1beta, IL-6, TNF-alfa During the ulceration phase, there is a local bacterial colonization, the breakdown of the mucosa and mononuclear cells infiltrated that release additional pro-onflammatory cytokines. In the specific situation of the mouth ulcers we can also find a fibrinous exudate. This is the phase in which there is the risk of complications and this is the symptomatis and painfull stage. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers. A great number of cytokines, chemokines and growth factors are involved in this phase, such as: EGF (epidermal growth factor), TGF-alfa(trasforming), IL-1beta, IFN-gamma, platelet-derived growth factors.
Oral mucositis usually resolves within 2-3 weeks, but the oral mucosa does not return completely to its preinjury state.
phases of mucositis
The Pathobiology of Mucositis
HOW RADIATIONS CAUSE CELL-DAMAGE
Radiations, as we know, are responsible of many cell-damages. First of all we must define the concept of absorbed dose.
Which kind of radiation is the most dangerous for our health? Ionizing Radiation.
This kind of radiations cause a DNA damage that can develop in three ways:
- Cells experience DNA damage and are able to detect and repair the damage.
- Cells experience DNA damage and are unable to repair the damage. These cells may go through the process of programmed cell death, or apoptosis, thus eliminating the potential genetic damage from the larger tissue.
- Cells experience a nonlethal DNA mutation that is passed on to subsequent cell divisions. This mutation may contribute to the formation of a cancer.
There may be also cytoplasmatic, cellular membranes and nuclear damages that causes cellular death:
1. cytoplasm: in the E.R. there is the distruction of ribosomes, that causes a block in the protein-synthesis; activation of lysis enzymes that causes autofagia; mitochondria distruction and no more energy production
2. membranes: lipidic peroxydation
3. nucleus: pycnosis, vacuolation, carioressis, cariolisi (a rest nucleus); a block in the replication, chromosome breaks, mutations (if during mitosis)
PATIENT RISK FACTORS
Genetic
neutropenia ( a situation of neutropenia means that no fibrinogen is metabolized into D-Dimer and so there is an increase in thrombosis and infarction risk)
Acquired
exposure to radiation
radiotherapy
chemotherapy
Risk factors for oral mucositis in children undergoing chemotherapy: A matched case-control study
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
epithelia exposed to radiations
COMPLICATIONS
Sores or ulcerations can become infected by virus, bacteria or fungus. 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).
TREATMENT
Mucositis is a real problem and it is really important to find new and successful therapies. In fact, frequently, when mucositis compares as a result of a radio or chemio therapy, the first solution is to stop the main treatment: this is a big mistake. Here below some of the most frequent treatments:
- Oral hygiene.
- 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. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocain for relief of pain.
See more at this link: pubmed
- 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.
- Palifermin, brand name "Kepivance", 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.
See more at this link: pubmed
- Symptomatic relief of the pain of oral mucositis is provided by barrier protection agents such as "Gelclair." This viscous oral gel can be diluted and used as an oral rinse. The film forming agents within Gelclair coat the oral mucosa shielding ulcerated tissues and protecting exposed nerve endings.
- Analgesia
- In case of a lower GI mucositis histamine H2 blockers and proton pump inhibitors are normally used.
- Allopurinol gel mitigates radiation-induced mucositis and dermatitis (see more at pubmed)
IN THE FUTURE…
- Saforis: a new formulation of glutamine that is absorbed more efficiently.
- Velafermin: a member of the fibroblast growth factor family.
- Granulocyte-macrophage colony-stimulating factor are used mainly in case of neutropenia.
More info at: pubmed
EVIDENCE-BASED INTERVENTIONS FOR THE MANAGEMENT OF ORAL MUCOSITIS
PALIFERMIN
Palifermin is now-a-day used for mucositis treatment. It is a keratinocyte growthfactor, member of the fibroblast growth factor family.
As a result of scientific experimentations, Palifermin is really usefull in both the prevention and the treatment of oral mucositis in patients with neck and oral cancer ( so before and after the radiotherapy). In fact it reduced the incidence and the median duration severe. There are also improvements in swallowing, eating, talking and sleeping. Cosequently Palifermin induces significally less transdermal opioid analgesics. Palifermin appears well tolerated at the dosages studied, but more than 80microg/kg/day x doses may cause oral and cutaneus toxic effects (and also rash, pruritus, erythema, cough and oedema in the 50%of patients ). Given that many epithelial cancers express the KGF receptor, and the reported effects of palifermin on apoptotic pathways, there are concerns that it might compromise the effects of chemotherapy and radiotherapy.
