Table 1 Proven and suspected risk factors for the development of mucositis Risk factors for the development of mucositis Oral mucositis and its treatments Patient-related risk factors Age: Children and over 50 years old Female sex Denutrition Tumor location (eg, oral cavity, throat) Drug-induced xerostomia Pre-existing mouth damage Periodontal status Tobacco and alcohol consumption Genetic predisposition Treatment-related risk factors Chemotherapy: Type of drug Dose and intensity Induced neutropenia Radiotherapy: Fractioning Location Combined with chemotherapy Bone marrow transplantation Finally, it should be noted that there are huge discrepancies in the way the severity of mucositis is described. Different scales exist; the most commonly used are the National Cancer Institute – Common Toxicity Criteria and the scale developed by the World Health Organization (Sonis et al 2004). These scales are graded from 0 to 4, and they are highly reproducible and easy to use, combining evaluation of objective functions and symptomatic variables. Grades III and IV are the most debilitating states because patients are no longer able to eat or require parenteral or enteral support. Other scales have been developed, but they are essentially used for research purposes. All of these methods of evaluation have been extensively reviewed by Sonis et al (2004) and Peterson and Cariello (2004). Recently, interesting pathologic evaluations also have been described. These evaluations result in, for example, estimates of the cell viability after mouthwashes using trypan blue coloration (Wynenga et al 1999), measurement of neutrophil levels in mouthwashes (Graham et al 1992), or assessment of epithelial cell morphology, and differentiation/ maturation (Wynenga et al 1997). The use of these in vitro pathological tests must be encouraged because they can reduce the bias of subjective methodology. Physiopathology Clinically, oral mucositis appears about 7 to 10 days after the start of chemotherapy. Recovery occurs between days 14 to 21 (Saadeh 2005). However, mucositis complicating radiotherapy usually develops later, and it has a more chronic course (Sonis et al 2004). It starts at a cumulative dose of 15 Grays (Gy) and peaks at 30Gy. Despite this difference in timing of occurrence, physiopathologic mechanisms underlying the Therapeutics and Clinical Risk Management 2006:2(2) development of oral mucositis are probably identical, and these mechanisms have recently been thoroughly explored. It has become clear now that oral mucositis is not only the direct consequence of a direct physical or chemical epithelial damage but also the result of a cascade of events involving the entire mucosa (Sonis 2004). Recently, Sonis and co-workers (2004) proposed an interesting model that describes the different biological events occurring during mucositis. In this model, five different but interdependent phases have been identified, as described below and depicted in a flow chart in Figure 1. Initiation Initiation is the first phase. Immediately after exposure to radiotherapy or chemotherapy, there is DNA and non-DNA damage. This damage is observed in mucosa and submucosa, but only a small proportion of cells die quickly (Sonis 2004). However, this initial insult triggers a cascade of biological events. Generation of oxidative stress and reactive oxygen species is thought to be the origin of injuries to mucosal cells, tissues, and blood vessels. Message generation Message generation is the second phase. During this period, there is an upregulation of transcription factors, such as nuclear factor-κB (NF-κB), and genes coding for proinflammatory cytokines (eg, tumor necrosis factor [TNF-α], and interleukins [ILs] IL-1, IL2, and IL-6) and adhesion molecules. In addition, enzymes such as neutral and acidic sphingomyelinases and ceramide synthase are activated. This activation results in apoptosis of submucosal endothelial cells and fibroblasts. Fibroblast destruction leads to generation of fibronectin, which 161