Radiation-induced oral mucositis (RIOM) (Figures 1, 4 and 5C) is one of the major ionizing radiation toxicities and normal tissue injuries that result from radiotherapy (1). RIOM was first termed in 1980 as a side effect of radiotherapy (RT) in cancer patients (2). RIOM is a normal tissue injury lasting between 7 and 98 days, which starts as an acute inflammation of oral mucosa, tongue, and pharynx after RT exposure (1, 3). This coincides with recruitment of various inflammatory cells and release of inflammatory cytokines, chemotactic mediators, and growth factors. RIOM can progress to an acute life-threatening stage as a result of severe physical obstruction of food and water intake with subsequent weight loss and septic complication due to lost protective epithelial and basement membrane barriers. This leads to limitations of local tumor control due to cancer treatment interruption and alterations in radiation dose fractionation (4–7). Studies suggested the stages of progression of RIOM as initial hyperemia and erythema during the preulcer phase, during which there is a release of various pro-inflammatory cytokines from epithelial, vascular, and connective tissue cells at the site of tissue injury. This is followed by the epithelial phase with various degrees of desquamation and basement membrane damage with loss of the protective barrier, which ends with the physical appearance of the ulceration. The postulcerative phase varies depending on the extent of the tissue toxicity. A secondary infection with Gram-negative bacteria or yeast may occur, with microcoagulation of the vasculature that worsens the inflammation by the local ischemia with more necrotic tissue yield. The final stage will be the healing phase and fibrosis (2, 8, 9).

Radiation-induced oral mucositis occurs in up to 80% of head and neck cancer irradiated patients and reaches up to 100% in patients with altered fractionation head and neck cancer. RIOM of grade 3 and 4 have been recorded in 56% of head and neck cancer patients treated with radiotherapy (1, 12).

Many risk factors have been identified for RIOM. These risk factors include concomitant chemotherapy (CT), bad oral hygiene, below average nutritional stratus, lack of antibiotic use at early stage mucositis, and smoking (13).

Table 1 shows the significant predictors for the prevalence of severe RIOM and the symptoms of RIOM in a longitudinal study of patients with oral cavity cancer among head and neck cancer outpatients of a radiation department at a major medical center in Taiwan (14). This study used the Generalized Estimating Equations to analyze the predictive factors of prevalence of severe RIOM and RIOM-related symptoms. They found that the significant predictors for the prevalence of severe RIOM included type of treatment [RT vs. concomitant chemoradiotherapy (CCRT)], cumulative radiation dose, smoking, and body mass index (BMI). Patients who received CCRT (Coef. 0.145, p < 0.05), who have a higher cumulative radiation dose (Coef. 0.000, p < 0.01), who are smokers (Coef. 0.090, p < 0.01), and who have lower BMI (Coef. 0.005, p < 0.05) were at high risk to develop severe RIOM. RIOM-related symptoms were also predicted by type of treatment (RT vs. CCRT) (Coef. 1.618, p < 0.05), cumulative radiation dose (Coef. 0.003, p < 0.05), and smoking (Coef. 1.759, p < 0.001). These significant predictors are implemented by radiation oncologists to minimize and/or prevent the RIOM. June Eilers and Rita Million have summarized the patient-linked factors leading to increased risk for RIOM (Table 2) (15). They found that very young age, female gender, poor oral health and hygiene, decreased saliva secretion, low BMI, poor renal function with elevated serum creatinine level, smoking, and history of RIOM are risk factors predicting the development of RIOM in head and neck cancer patients (15).

Radiation-induced oral mucositis side effects and sequels include oral pain in 69% of patients, dysphagia in 56% of patients, opioid use in 53% of patients, weight loss of 3–7 kg, feeding tube insertion and hospitalization (ICU admission) in 15% of patients, and modification or interruption of treatment in 11–16% of patients (1, 12, 16).

In the United States, RIOM may add up to 1,700.00–6,000.00 USD per patient depending on the inflammatory grade of the injury (12). RIOM treatment adds an economic cost that was estimated to increase up to 17,000.00 USD per patient treated for head and neck cancers (16).

Radiation-induced oral mucositis injury challenges radiation oncologists from many aspects, such as radiation dose limitations, changes in dose fractionation protocol, and dramatic negative effects on patients’ quality of life (1). The major clinical consequences of RIOM include hospital admission or extended hospitalization for total parenteral nutrition, intravenous (IV) analgesia, and IV antibiotics. Sixty-two percent of patients require hospitalization, and 70% of patients with grade 3–4 oral mucositis (OM) require feeding tube insertion. Reduction or cessation of cancer treatment occurs in 35% of patients due to the developed dose-limiting toxicity (17).

The pathophysiology of RIOM is not fully understood. Recent studies proposed that the pathogenesis of RIOM is composed of four phases: an initial inflammatory/vascular phase, an epithelial phase, a (pseudomembranous) ulcerative/bacteriological phase, and a healing phase (2, 5).

At the inflammatory phase, the RT-induced tissue injury results in the release of inflammatory cytokines; e.g., interleukin (IL)-1β, prostaglandins (PGs), and tumor necrosis factor-α (TNF-α) from the resident cells such as epithelial, endovascular, and connective tissue. These mediators might increase the damage by increasing the vascular permeability, leading to more infiltration and recruitment of inflammatory cells. Stem cells travel to the site of the tissue injury with other innate immunity components, e.g., MPO-positive leukocytes, macrophages, and neutrophils (18). On the other hand, there are some anti-inflammatory cytokines, such as IL-10 and IL-11, that work to minimize the injury (18).

The epithelial phase is initiated within a week by the apoptotic and cytotoxic effects of RT on the proliferating basal cells. This is why the recovery period is dependent on the rate of epithelial turnover, which could be enhanced by growth factors like epidermal growth factor and keratinocyte growth factor (KGF) (19).

After a week, the epithelial breakdown ends with the beginning of the ulceration. This occurs, when epithelial loss leads to disrupted basement membrane, formation of ulcer pseudomembrane, and inflammatory exudate. The ulceration stage is very painful, since the protective barrier that covers the nerve endings at the lamina propria is lost (19). The resulting microcoagulation and neutropenic state facilitate the Gram-negative bacteria and yeast colonization with the production of secondary infection. Bacterial exotoxins aggravate the inflammatory reaction by inducing mononuclear burst with the release of more IL-1β, TNF-α, and nitric oxide (8, 9, 16, 20).

Signaling pathways suggested to be involved in RIOM pathobiology include nitrogen metabolism, Toll-like receptor signaling, nuclear factor-κB (NF-κB) signaling, B-cell receptor signaling, P13K/AKT signaling, cell cycle: G2/M DNA damage checkpoint receptor, p38 mitogen-activated protein kinase (MAPK) signaling, Wnt/B-catenin signaling, glutamate receptor signaling, integrin signaling, vascular endothelial growth factor signaling, IL-6 signaling, death receptor signaling, and SAPK/JNK signaling (Table 3) (10, 19).

In 2004, Sonis suggested five stages (phases) of OM injury induced by radiotherapy (RT) and/or CT: initiation, signaling, amplification, ulceration, and healing (Figure 1) (16).

In 2009, Redding summarized Sonis’ RIOM pathobiology phases (Figure 2). The initiation phase with RT and/or CT injury results in direct and lethal DNA damage with the release of reactive oxygen species (ROS) from epithelial and vascular endothelial cells, fibroblasts, and tissue macrophages. This is followed by amplification of this signal (11). During the primary damage response, the DNA damage and ROS act through three major pathways: (1) fibronectin breakdown, which stimulates the macrophages leading to activation of the matrix metalloproteinases (MMPs), (2) nuclear factor-κB (NF-κB) activation, which stimulates the gene expression and the release of pro-inflammatory cytokines, e.g., TNF-α, IL-1β, and IL-6, and (3) ceramide pathway through sphingomyelinase and ceramide synthase. The end result will be more tissue injury and stimulated apoptosis (11). 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. The basement membrane protective barrier is lost during the ulceration phase. This leads to Gram-negative and yeast secondary infection potential, which adds more pro-inflammatory reactions and complicates the already existing inflammation. The healing phase starts by matrix signaling to basal epithelial cells to migrate, proliferate, and differentiate (11). Signal amplification during RIOM or CT-induced OM is a main step in this treatment-induced injury, according to Sonis et al. (17). RT and/or CT activate the transcription factor NF-κB in epithelial, endothelial, and mesenchymal cells and macrophages, resulting in upregulation of genes and production of pro-inflammatory cytokines: tumor necrosis factor-α (TNF-α) and IL-1β, which amplify the primary signal and activate NF-κB. This leads to transcription of genes responsible for MAPK, cyclooxegenase-2 (COX-2), and tyrosine kinase signaling molecules. These signaling pathways activate MMPs 1 and 3 in the epithelial and lamina propria cells, which collectively cause tissue injury (10) (Figure 3).

There has been more than one grading scale for RIOM. Table 4 shows the comparison of different RIOM scoring scales (14, 21–23).

World Health Organization Oral Toxicity Scale measures the anatomical, symptomatic, and functional elements of OM (Figure 4). The Radiation Therapy Oncology Group (RTOG) determined the acute radiation morbidity scoring criteria for mucous membranes. Finally, the Western Consortium for Cancer Nursing Research describes only the anatomical changes associated with OM (24).

Radiation Therapy Oncology Group developed the Acute Radiation Morbidity Scoring Criteria for the evaluation of RT effects (another criterion was generated for late effects of RT) (25). The National Cancer Institute (NCI) Common Toxicity Criteria (NCI-CTC) scores CT-related side effects. The RTOG was gathered with the NCI-CTC to produce version 2.0, which has been used in all NCI clinical trials since March 1998 (Table 5) (2, 25, 26).

The OM Index (OMI) scores the severity of OM by the erythema, ulceration, atrophy, and edema (a scale of 0–3 was designated for each element: 0 = none and 3 = severe). The OMI is considered internally consistent with high test–retest and interscorer reliability, and it shows solid validity (27).

The OM Assessment Scale (OMAS) is a highly reproducible scoring scale for RIOM, responsive over time, and accurate in detecting OM-associated elements (25). OMAS records the objective assessment of OM depending on the scoring of the presence and size of the ulceration or pseudomembrane (score 0–3: 0 = no lesion; 1 = lesion of <1 cm²; 2 = lesion of 1–3 cm²; 3 = lesion >3 cm²) and erythema (score 0–2: 0 = none; 1 = not severe; 2 = severe) on the upper and lower lips, right and left cheeks, right and left ventral and lateral tongue, floor of the mouth, soft palate, and hard palate (23, 28).

All these scoring scales are validated and are required in assessing RIOM and the therapeutic benefits of any new treatment of RIOM.

Radiation-induced oral mucositis can develop within or after 2 weeks from the beginning of RT. Oral assessment guide could be a useful tool for detection of early OM (Table 6) (20). Apart from the early clinical signs and symptoms, CBC with differential is considered the baseline to help radiation oncologists to determine the most susceptible time for developing OM or oral infection. Radiation oncologists can start the RT provided that there is no evidence of any periodontal disease. If at any point RIOM develops, oral lesion culture and antimicrobial therapy are recommended as soon as possible (29). Since renal diseases are considered contributing factors for OM (15), chemistry levels should be regularly monitored by the treating physician (29).

Because similar conditions can coexist in immunocompromised patients including cancer patients receiving RT and/or CT, differential diagnosis for RIOM is critical. Table 7 shows possible similar conditions (Figure 5) (20, 31).

The general long-term prognosis is reasonably good since most lesions resolve within 2–4 weeks after stopping the RT or CT. Although RIOM is considered a self-limited injury in some patients, it could be a lethal injury in moderately to severely ill patients, which could lead to ICU admission with obligatory cessation of RT. Patient losses are a common event under these circumstances (32).

Maintaining good oral care is the main preventive measure for RIOM to minimize the risk for candidiasis or secondary bacterial infection, especially in hyperfractionated radiotherapy, combined CCRT regimens, or RT combined with a targeted agent due to increased mucositis severity (3). We will summarize the most recent agents and measures to prevent RIOM.

No single agent has been approved by the US-FDA for the treatment of RIOM. Symptoms reduction and complications prevention of RIOM, including nutritional support, pain control, prophylaxis, and/or treatment of secondary infections, are considered the main cornerstone in the management of RIOM (34–36). Agents that were investigated and/or applied in RIOM treatment are discussed in the context of recently updated evidence-based preclinical and clinical studies.

Bone marrow-derived mesenchymal stromal cells (bmMSCs) therapy have been applied in fractionated radiation-induced OM where the administration of a systemic single dose of six million MSCs resulted in a significant decrease in ED₅₀ (the RT dose that produces ulcer in 50% of irradiated mice) (239). The first MSCs therapy for RIOM was done in 2014 by Schmidt et al. (239). They concluded that transplantation of BM or bmMSCs could modulate RIOM in fractionated RT, depending on the time of transplantation (239). Nevertheless, in another study, the authors concluded that bmMSCs transplantation had no therapeutic benefits on RIOM in single-dose RT when compared to the therapeutic effect of mobilization of endogenous BM stem cells (240). More studies are needed in this field building on the initial studies, which showed significant and clinically relevant therapeutic gain of MSCs therapy for RIOM (Table 10).

Despite its high incidence, RIOM is a self-limited radiotherapy-induced normal tissue injury. It is a dose-limiting toxicity in most cases of head and neck cancer patients. However, in moderately to severely sick patients, it could be a lethal injury. Many preclinical and clinical studies have been conducted for the prevention and treatment of RIOM. Currently, there are numerous prevention and treatment strategies for RIOM. However, there is no single agent or management regimen that has been agreed upon between caregivers that significantly improves RIOM to a clinically relevant and satisfactory standard. Nevertheless, the current guidelines recommend good oral care, IMRT, radiation shields, palifermin, amifostine, and cryotherapy for RIOM prevention. RIOM treatment focuses on palliative measures and symptoms relief; e.g., pain management, nutritional support, good oral hygiene, and reduced oral microbial load. Interestingly, mesenchymal stromal cells therapy for RIOM shows promise for potential therapeutic and clinically relevant benefits. However, more studies are still needed to confirm such therapeutic potential.

OM: conception and design, collection and/or assembly of data, review writing, and final approval of the review. NE: conception, design, and final approval of the review. TM: conception and design, financial support, and final approval of the review.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.