Radiation-Induced Oral Mucositis

Abstract

Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment.

Keywords: chemotherapy; mesenchymal stromal/stem cells; normal tissue injury; oral mucositis; pathobiology; radiation; radiotherapy.

Figure 1

Pathobiology of oral mucositis (OM) (10). Sonis has suggested five stages (phases) of OM injury induced by radiotherapy (RT) and/or chemotherapy (CT): initiation, signaling, amplification, ulceration, and healing. The pathogenesis of each phase is illustrated.

Figure 2

Redding’s summary of RT and/or chemotherapy (CT)-induced oral mucositis pathobiology (11). Redding has summarized the pathobiology phases of radiation-induced oral mucositis induced by RT and/or CT. In brief, initiation phase with RT and/or CT results in direct and lethal DNA damage, which leads to release of reactive oxygen species (ROS) from epithelial, vascular endothelial, fibroblasts, and tissue macrophages with cycles of amplifications. Within such primary damage response, the DNA damage and ROS lead to three major steps: (1) fibronectin breakdown that activates macrophages ending with stimulation of matrix metalloproteinase; (2) nuclear factor-κB (NF-κB) activation that stimulates the gene expression and release of pro-inflammatory cytokines, e.g., TNF-α, interleukin (IL)-1β, and IL-6; and (3) ceramide pathway through sphingomyelinase and ceramide synthase. The result will be more tissue injury and stimulated apoptosis. During the signal amplification phase, there is restimulation of tissue damage and apoptosis by the major pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), NF-κB-mediated gene expression, and ceramide and caspase pathways. During the ulceration and loss of the protective barrier, secondary infection adds more pro-inflammatory reactions and complicates the already existing inflammation before the healing phase starts by matrix signaling to basal epithelial cells to migrate, proliferate, and differentiate. Republished with the permission of Dr. Redding. (A) Initial phase, (B) primary damage phase, (C) signal amplification phase, and (D) ulcerative phase.

Figure 3

Signal amplification during OM induced by RT and/or CT (10). Signal amplification during RT- and/or CT-induced OM is mediated by activation of NF-κB that is reactivated by IL-1β. NF-κB induces the expression of genes responsible for the MAPK, COX-2, and tyrosine kinase pathways to finally activate the MMP1 and MMP3 signaling at the injured tissue cells. TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; NF-κB, nuclear factor-κB; MAPK, mitogen-activated protein kinase; COX-2, cyclooxegenase-2; MMP1, matrix metalloproteinase 1; MMP3, matrix metalloproteinase 3; OM, oral mucositis; CT, chemotherapy. Republished with the permission of Dr. Sonis.

Figure 4

World Health Organization’s Oral Toxicity Scale. Republished with the permission of Dr. Patrick Stiff, Loyola University Medical Center, Maywood, IL, USA.

Figure 5

Differential diagnosis of radiation-induced oral mucositis. Republished with the permission of Dr. Patrick Stiff, Loyola University Medical Center, Maywood, IL, USA. (A) Local, denture-related lesion, (B) aphthous ulcer, (C) oral mucositis, and (D) oral thrush.