Cancer is the leading cause of death in the world, responsible for 16% of all deaths worldwide in 2016, projecting an increase of 13.1 million by 2030.

Antineoplastic treatments such as radiotherapy (RT), chemotherapy (CT) or radio-chemotherapy (RTCT) have the mechanism of action of inhibiting the deregulation of these physiological processes, so it is common to observe tissue damage, which under physiological conditions has a high rate of cell replication such as the oral and gastrointestinal mucosa (Alonso Castell et al., 2001).

These secondary reactions are manifested acutely or late. Acute reactions occur during treatment and will have their remission weeks or months after its completion, while late reactions can occur months and years after completion of antineoplastic treatment (Bascones et al., 2013).

Within the acute complications at the oral level, oral mucositis (OM), a term introduced in the late 1980’s to describe the inflammation of the oral mucosa, as the main acute manifestation of toxicity related to CT treatments (Chemotherapy), RT (Radiotherapy) and RT-QT (Bascones et al.; Chaveli & Bagán, 2016).


  •  Affects approximately 40% of patients receiving chemotherapy at standard doses and 76% or more at high doses.
  • 59% of patients treated with mTOR* experience mucositis.
*The mammalian target of rapamycin (mTOR), is a protein that helps control several cell functions, including cell division and survival, and binds to rapamycin and other drugs. mTOR may be more active in some types of cancer cells than it is in normal cells. Blocking mTOR may cause the cancer cells to die. It is a type of serine/threonine protein kinase.


The pathogenesis of mucositis is multifaceted and involves not only the epithelium, but also the cells and tissues within the submucosa. Signaling from damaged endothelium, fibroblasts and infiltrating leukocyte cells contributes to apoptosis, loss of renewal, atrophy and ulceration. (Chaveli-López, 2014; Villa and Sonis, 2015).

The initiation of mucositis is triggered by oxidative stress and the generation of reactive oxygen species (ROS), direct DNA and non-DNA damage, and activation of the innate immune response. These events follow the release of endogenous damage-associated molecular pattern molecules from injured cells of the basal epithelial layers, submucosa, and endothelium. Based on the trajectory of gene activation and pathway analysis, it is clear that the initiating biological cascade happens within seconds of the stimulating insult.

Following initiation, ROS and the innate immune response further damage cell membranes, stimulate macrophages and activate several transcription factors of which nuclear factor NF-κB plays a prominent role. Once activated, NF-κB-mediated gene expression results in a surge of many pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β and cyclooxygenase-2 (COX-2). The up-regulation of other genes causes the expression of adhesion molecules and angiogenesis (Sonis, 2002; Rm et al., 2007).

More in depth, TNF-α up-regulation may activate caspase pathways and generate a feedback on NF-κB to amplify its response and initiate mitogen-activated protein kinase (MAPK) pathway, leading to activation of c-Jun N-terminal kinase (JNK) signaling; fibronectin breakdown leads to macrophage activation. NF-κB independent pathways such as ceramide pathway may also play a role, resulting in apoptosis of submucosal and basal epithelial cells leading to mucosal ulceration (ulcerative phase) and atrophic changes. Recent studies confirmed the involvement of deregulated expression of metalloproteinases (MMPs) in the pathobiology of mucositis (Al-Dasooqi et al., 2010).

The first three phases rapidly lead to apoptosis of epithelial stem cells. In the case of stratified epithelium (i.e., the upper aerodigestive tract and rectal mucosa), loss of renewal leads to atrophy and then ulceration. From the clinical point of view, the overlying mucosa appears initially normal despite the biological havoc taking placing beneath it. In the case of bolus CT, the time between initial basal cell injury and clinical notable mucosal changes (erythema and thinning) takes about 4 days with ulceration occurring shortly thereafter. In contrast, the consequences of cellular damage in the intestinal villi are almost immediate with clinical evidence of enteritis becoming apparent within 24–48 h of CT.

Bacterial colonization of non-intestinal lesions lags slightly behind ulcer development. However, at that time, a large increase in the bacterial load is seen. In the case of patients receiving CT, this occurs at the time that the patient is least capable of dealing with potential infection as it roughly inversely parallels the course of the leukopenia. Ulcer colonization also results in the release of bacterial cell wall products and cytokine production. Healing generally occurs spontaneously and is characterized by epithelial proliferation, migration, and differentiation stimulated by the extracellular matrix (Blijlevens and Sonis, 2007; Al-Ansari et al., 2015). After the healing phase, the oral mucosa returns normal, although the patient have an increased risk of future episodes of mucositis due to residual angiogenesis.