**1. Introduction**

Advances in radiotherapy (RT) for cancer have aimed at minimizing damage to surrounding tissues through modified treatment regimens, technological improvements affording more precise RT delivery and novel radiation sources. These efforts notwithstanding, damage to surrounding tissues such as salivary glands following RT for head and neck cancer (HNC) remains a significant problem. Despite being a highly differentiated, slowly proliferating tissue, salivary glands are surprisingly sensitive to RT [1], a phenomenon attributed to disruption of the plasma membrane on secretory salivary acinar cells and apoptosis [2–9]. RT-induced salivary gland dysfunction results in hyposalivation (i.e., measured reduction in saliva production), xerostomia (i.e., the sensation of oral dryness), mucositis, nutritional deficiencies, oral infections and functional changes, such as difficulties with mastication, dysphagia (i.e., problems with swallowing) and loss of taste, which can significantly reduce the quality of life for afflicted patients [10,11]. It is estimated that >80% of HNC patients exhibit xerostomia and salivary gland hypofunction following RT [12]. Depending on the RT dose, delivery method and salivary gland-sparing techniques employed, chronic xerostomia affects 64–91% of RT patients with HNC [12–14]. There are limited treatment options for RT-induced hyposalivation. The muscarinic receptor agonists pilocarpine and cevimeline that induce saliva secretion from residual acinar cells [15] and artificial saliva provide only temporary symptom relief, which comes at a substantial long-term financial cost [12]. Amifostine is the only FDA-approved radioprotective

therapeutic aimed at preventing damage to normal tissues, including salivary glands [16]. However, due to toxicity and potential tumor-protective effects, amifostine is not widely used [17]. Thus, development of innovative approaches to restore or retain salivary function in HNC patients receiving RT is essential [9]. The lack of treatment options to prevent dysfunction or recover function in irradiated salivary glands is compounded by a limited understanding of the underlying mechanisms and the range of variable responses to different RT regimens. In the present review, we explore the mechanisms underlying short- and long-term RT-induced salivary gland dysfunction as well as current and promising future therapeutics.
