5.1.5. Intraoral Stents and Temporary Submandibular Gland (SMG) Transplantation

Two additional non-pharmacological salivary gland-sparing interventions have been utilized, i.e., intraoral stents and temporary submandibular gland transplantation. Intraoral stents are personalized medical devices designed to position and stabilize the oral cavity to prevent unnecessary irradiation of adjacent tissues. These devices are easy to manufacture [193] and have been demonstrated to efficiently reduce irradiation of off-target tissues [194–196]. Salivary glands can be protected from irradiation by temporarily relocating them further away from the field of irradiation in a procedure known as temporary SMG transplantation. This surgical alternative has been shown to be safe and cost effective and involves releasing the SMG from surrounding tissues and temporarily repositioning it in the submental space over the digastric muscle, thereby removing it from the radiation field [197]. Pathak et al. showed that in patients receiving RT, those that underwent temporary SMG transplantation had no significant differences in salivary flow rates before RT compared to those who did not undergo transplantation [168]. After RT, 73% of the group that received the transplantation had a preserved mean salivary flow rate, compared to 27% of the group that did not receive transplantation [198]. Despite its success, due to the risks of co-transplantation of malignant tissues and subsequent relapse or secondary metastases, SMG transplantation is only used in RT for specific types of head and neck cancers.

Recently, novel salivary glands have been identified in humans, dubbed the tubarial glands due to their proximity to the torus tubarius [199], in a retrospective analysis of PET/CT scans of 100 prostate or para-urethral gland cancer patients using radiolabeled ligands that bind prostate-specific membrane antigen (PSMA), which is highly expressed in all major and minor salivary glands [199,200]. The tubarial glands were described as predominantly mucous gland tissue with multiple draining ducts located in the dorsolateral pharyngeal wall. The sparing techniques we describe in this review have not taken into consideration these glands and none of the current targeted techniques avoid these structures that lie posterior to the nasopharynx [199]. The effect of RT dose on tubarial glands was further investigated with the incidence of xerostomia and dysphagia found to be correlated in 723 HNC

patients at both 12- and 24-months after initial physician-rated xerostomia. This exciting discovery raises the question of whether modifying radiation fields to spare the tubarial glands will prevent RT-induced xerostomia. As of yet, these glands have not been identified in any preclinical animal models and it is noteworthy that mice lack the torus tubarius [201]. However, if similar glands are present in animal models, we anticipate that future studies will examine possible RT field modifications to optimize radioprotective therapies that preserve glandular function.

Radiation treatment plans for HNC are not one size fits all and depend on many factors, such as cancer type, location, stage and the patient's overall health. Comparisons of multiple types of radiotherapy plans for HNC have been performed and researchers found that there are benefits to certain planning methods, depending on the type and stage of HNC [202]. Furthermore, while there have been substantial improvements in RT techniques in recent years to reduce exposure to organs at risk, patients still exhibit side effects, such as hyposalivation and xerostomia, which can lead to multiple complications, as discussed earlier [1]. Further evaluation of mechanisms of radiation damage to salivary glands to develop novel radioprotective and/or regenerative approaches is, therefore, necessary to improve the quality of life for HNC survivors.
