**2. Clinical Presentation**

Fractionated radiotherapy is the most common treatment regimen for head and neck squamous cell carcinoma (HNSCC), which consists of daily radiotherapy, usually 2 gray (Gy) per fraction, five days per week, to a total dose of 70 Gy to the tumor [18]. For HNC patients receiving radiotherapy, acute hyposalivation occurs within the first week after RT with a 50–60% loss of saliva flow [19]. In addition to patient-reported xerostomia, which is scored using quality of life (QoL) questionnaires, RT-induced salivary gland dysfunction is verified by an objective measure of salivary gland flow rates or scintigraphic assessment of gland function [20–22]. Rapid RT dose-dependent loss of secretory function seems to result from a marked loss of salivary acinar epithelial cells [23,24], a finding that has been supported in animal studies [3–7]. During the first three weeks after RT, nearly all patients present with mucositis due to significant inflammatory damage to the mucosal surfaces [25]. Interestingly, the incidence of mucositis is highest following fractionated radiation treatment regimens [26]. While these lesions usually resolve within a few weeks, they are reportedly painful and can be so severe as to disrupt HNC treatment regimens [11]. In addition to decreased volume, changes in saliva quality (e.g., pH, protein composition, consistency) affect the buffering capacity and digestive functions of saliva, as well as the composition of oral microbiota [27–30].

Chronic hyposalivation, usually lasting at least 6 months, is commonly experienced by HNC patients undergoing RT [12–14,19,31]. Chronic salivary gland dysfunction is attributed in part due to failure to regenerate functional acini and the development of glandular fibrosis [32–36], although the degree of acute dysfunction is predictive of long-term complications [37,38]. Chronic xerostomia is responsible for a host of complications, including functional impairments in speaking, swallowing and eating [37], poor oral clearance and altered saliva quality that lead to increased incidence of oral bacterial, yeast and fungal infections, dental caries, periodontitis [39,40], digestive disorders and nutritional deficiencies [19], which significantly reduce the quality of life of afflicted patients [20]. Thus management of chronic xerostomia is critical. Unfortunately, current management strategies are inadequate, relying on transient symptom relief afforded by artificial saliva products [41,42] or sialagogues that promote saliva production from residual acinar cells, as discussed in the therapeutics section of the present review [15]. However, there are some promising strategies for RT-induced salivary gland dysfunction, such as recently evaluated oral probiotic lozenges [30]. We will discuss novel therapies being investigated for radioprotection or salivary gland regeneration at the end of this review.
