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| Etiology |
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The development of oral mucositis is a complex process. Severe oral mucositis (Figure 1)
results from injury to rapidly dividing epithelial cells that line the oral cavity,
causing physiological changes that range from mild atrophy to severe ulceration.
This injury occurs as a consequence of chemotherapy (CT) and radiotherapy (RT) regimens,
the roles of which are to target and eliminate rapidly dividing cancer cells.1 The oral
cavity is lined with rapidly dividing epithelial cells that have a finite life cycle due
to
the mechanical and chemical aspects of alimentation. While rapid cell
division is
imperative for maintaining a healthy oral mucosal epithelium,
it is this normal function
that renders the oral epithelium an unintended
target for CT and RT regimens used
to treat cancer patients with
hematologic malignancies undergoing hematopoietic
stem cell
transplants (HSCT).1,2
Figure 1. Severe Oral Mucositis3
Data on file.
Typically, oral mucositis symptoms develop 5 to 8 days following the
administration of CT and last approximately 7 to 14 days.4 Oral mucositis was previously
thought to be a 4-phase biological process involving an inflammatory/vascular phase,
an epithelial phase, an ulcerative/bacterial phase, and a healing phase.5
The pathobiology of mucositis is currently defined as a 5-phase process: initiation,
signaling with generation of messengers, amplification, ulceration, and, finally, healing.
Although this model is described in a linear way, injury occurs quickly
and simultaneously in all mucosal tissues (Figure 2).1,2
Figure 2. The 5 Phases of Mucositis1
Adapted from Sonis. Nat Rev Cancer. 2004;4:277-284.
The initiation stage of tissue injury occurs rapidly following the administration
of CT or RT, resulting in DNA damage in basal epithelial cells (Figure 2). The CT and RT used
in conditioning regimens cause breaks to occur in DNA strands within target cells in the mucosal
epithelium and in the underlying submucosa. DNA strand breaks interfere with normal cellular
functioning.1 The CT or RT used in the conditioning regimens also generates reactive oxygen
species (ROS), which can directly damage cells, tissues, and blood vessels.2 ROS are also crucial
mediators of downstream biological events that occur in the development and progression of oral
mucositis. At this stage, the mucosa appears normal; however, a cascade of events is
initiated in the submucosa that ultimately results in mucosal destruction.1
During this second phase of oral mucositis, multiple events are known
to occur simultaneously. CT, RT, and ROS cause DNA damage and subsequent
apoptosis (cell death) in the epithelium of the mucosa (Figure 2). CT, RT,
and ROS also activate various transcription factors, leading to increased
production of inflammatory cytokines such as tumor necrosis factor-alpha
(TNF-α) and interleukin 1-beta (IL-1β), and apoptosis.1,2
During the third phase of oral mucositis, the inflammatory cytokines
produced during the second phase of oral mucositis, such as TNF-α and IL-1β,
stimulate cells in the submucosa through positive feedback loops that amplify
the original signals triggered by the CT- and RT-induced damage.
These cytokines cause further tissue damage, amplifying signaling
cascades and the injury process.1,2
The ulcerative phase of oral mucositis is the most significant to both patient
and caregiver. Loss of mucosal integrity produces extremely painful lesions.
Breaks in the mucosal epithelium may provide portals of entry for bacteria,
viruses, and fungi. Bacterial cell wall products induce immune cells
to produce cytokines, leading to further inflammation and apoptosis.2
In the final stage of oral mucositis, signals from the submucosa are
thought to initiate healing of the epithelium. The proliferation, differentiation,
and migration of epithelial cells restore the integrity of
the mucosa until it appears normal.1,2
Risk factors that impact the development, severity, and duration of oral
mucositis may be patient-related and therapy-related. Patient-related risk factors
include age, nutritional status, type of malignancy, pretreatment oral condition,
oral care during treatment, and pretreatment neutrophil count.6
| 1 |
Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4:277-284. |
| 2 |
Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100 (suppl 9):1995-2025. |
| 3 |
Data on file. |
| 4 |
Sonis ST. Oral complications. In: Holland JF, Frei E III, Bast RC Jr, eds. Cancer Medicine. 5th ed. Philadelphia, Pa: BC Decker Inc; 2000:2371-2379. |
| 5 |
Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol. 1998;34:39-43. |
| 6 |
Pico JL, Avila-Garavito A, Naccache P. Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist. 1998;3:446-451. |
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IMPORTANT PRODUCT SAFETY INFORMATION
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