Oral Mucositis: Chemotherapy-Associated Toxicity

Oral mucositis (OM) occurs as a result of chemotherapy or radiation therapy (RT) and causes inflammatory and/or ulcerative lesions of the oral mucosa.¹ OM is distinct from stomatitis, which is a more general inflammatory condition of the oral mucosa, typically caused by targeted therapies. The major risk factor for the development of OM is the dose and schedule of chemotherapy — most commonly taxanes, alkylating agents, antimetabolites, and anthracyclines — and RT. However, other risk factors may include low body mass index, young age, female gender, renal impairment, tobacco smoking, and cumulative radiation dose.^2,3

OM is estimated to occur in 20% to 40% of patients receiving conventional chemotherapy and up to 80% of patients receiving high-dose chemotherapy.³ Nearly all patients receiving fractionated radiation for head and neck cancers experience OM, with 56% to 85% of patients experiencing grade 3 to 4 OM.^1,4 Among pediatric patients treated with chemotherapy, one study demonstrated that 56% of children experienced any grade OM, and 39% and 8.3% experienced grade 2 or grade 4 OM, respectively.⁵

Presentation

OM initially presents as erythema and soreness, followed by painful ulcerations.^1,3,6 These symptoms follow the pathophysiology, which has been described to include 5 phases: initiation, upregulation and activation of second messengers, signal amplification, ulceration, and healing.⁶ OM is believed to be initiated by reactive oxygen species that cause DNA and non-DNA damage and the corresponding immune response. As a result of this process, cells of the basal epithelial layers, submucosa, and endothelium sustain injury. Cell membranes receive further injury with the continued innate immune response and ongoing ROS exposure, resulting in the release of proinflammatory cytokines and upregulation of genes associated with adhesion and angiogenesis. These processes lead to apoptosis of the epithelial stem cells, and the loss of the ability for cell renewal results in atrophy and, ultimately, ulceration.

The timing of mucosal changes associated with OM differ according to the type of treatment (ie, chemotherapy vs radiation) and the dose (Table 1).⁶ For example, bolus chemotherapy typically results in a shorter time to erythema and ulceration. The initial signs of OM can occur shortly after chemotherapy administration, with a peak in symptoms between 7 and 14 days after treatment. Symptoms typically resolve 14 to 21 days after treatment. The onset of symptoms for radiation-induced OM occur 2 to 3 weeks after the first treatment and continue during radiation therapy. OM typically resolves within 2 to 4 weeks after the last radiation dose.

Table 1. Approximate Timing of Oral Mucositis Following Chemotherapy or Radiation Therapy⁶

	Chemotherapy	Radiation
Onset of signs	Shortly after administration	2-3 weeks after treatment
Peak	7-14 days	Continuous throughout treatment
Resolution	14-21 days	2-4 weeks after last dose

Complications and Quality of Life

OM has a profound effect on quality of life (QoL) because it is typically very painful and can be highly debilitating. OM results in pain (69%), opioid use (53%), dysphagia (56%), weight loss requiring feeding tube placement and hospitalization (15%), and modification of treatment (11%-16%).⁴ One study demonstrated that patients with OM were significantly more likely to experience severe pain (54%) and weight loss of more than 5% (60%) compared with patients without OM (6%; P < .01 and 17%; P < .001, respectively).⁷

Severe OM that results in swallowing impairment and/or pain that prevents oral intake results in weight loss, anorexia, malnutrition, anemia, and fatigue and frequently requires chemotherapy or radiation treatment modification, interruption, or discontinuation.⁶ In addition, ulceration may be followed by microorganism infection that can become disseminated, particularly among patients with severe neutropenia.

In addition to, and likely because of, pain and impairment, OM is also associated with poorer QoL outcomes. Several studies demonstrated that patients with OM have substantially worse scores for functional, emotional, and social domains that correspond to increasing severity or worsening of symptoms of OM.^8-10