Oral mucositis

Oral mucositis (OM) is caused by the effects of cancer therapy on the oral mucosa.

Some chemotherapy drugs (e.g., fluorouracil) are associated with mucositis more than others. Regimens involving bolus dosing of fluorouracil are also more likely to cause mucositis than those involving infusion over longer periods of time. Additionally, chemotherapy regimens involving docetaxel plus doxorubicin plus cyclophosphamide (TAC) for breast cancer are known to confer a greater risk of OM.[4]

OM is particularly common among patients undergoing hematopoietic stem cell transplantation (HSCT), with incidence and severity associated both with transplant type and conditioning regimen used. Severe OM is more likely in patients receiving allogeneic HSCT compared with autologous HSCT, and in patients treated with myeloablative regimens for allogeneic HSCT.[7][8]

Radiation toxicity is typically limited to the area included in the field of radiation. Therefore, OM is more common among patients with a primary malignancy involving the oral cavity or oropharynx, compared with those with a primary malignancy in other head and neck sites (e.g., larynx).[12][13] Severity of mucositis is dose- and schedule-dependent.[13] Most patients who receive greater than 50 Gy radiation develop ulcerative mucositis, and this condition is more likely in patients receiving altered fractionation schedules than in those receiving conventional radiation therapy.[6][13] Furthermore, patients who receive chemotherapy concurrent with head and neck radiation therapy (chemoradiation) are significantly more likely to develop OM than those who do not.[13]

More uncommonly, OM has also been associated with targeted therapies and immunotherapies.[14][15] Mucositis has been more frequently reported with programmed cell death-1 inhibitors than with cytotoxic T-lymphocyte associated protein-4 inhibitors.

The pathophysiology of OM is multifactorial. A 5-stage model has been proposed, although it is important to note that these events are not wholly linear and often occur simultaneously.[16][17]

Initiation of tissue injury: radiation and/or chemotherapy, directly and via the generation of reactive oxygen species, induce cellular damage resulting in death of the basal epithelial cells of the oral mucosa. The release of endogenous damage-associated pattern molecules from injured cells can activate an inflammatory cascade.
Upregulation of inflammation: free oxygen radicals activate secondary messengers that transmit signals from the receptors on the cellular surface into the cell, leading to upregulation of proinflammatory cytokines, tissue injury, and cell death.
Signaling and amplification: upregulation of proinflammatory cytokines, such as tumor necrosis factor-alpha, causes direct injury to epithelial cells and activates molecular pathways that amplify mucosal injury.
Ulceration and infection: oral ulcerations are secondarily colonized by the oral microflora, causing further upregulation of proinflammatory cytokines and infiltration of inflammatory cells.
Healing: epithelial proliferation and tissue differentiation contribute to the healing process.

Cancer therapy-induced shifts in the oral microbiome may have a role in the development and severity of OM, but the exact mechanisms are still unclear.[18][19]

Based on cancer therapy

Chemotherapy-induced OM
- Secondary to standard-dose oncology therapy
- Secondary to high-dose chemotherapy given prior to hematopoietic stem cell transplant
Radiation-induced OM

Pathophysiology

Classification

Based on cancer therapy