Clinical management of salivary gland hypofunction and xerostomia in head-and-neck cancer patients: successes and barriers

Abstract

The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy.

Fig. 1

Based on the slow turnover rates of their cells, salivary glands are expected to be late responding, but the changes in quantity and composition of saliva already occur shortly after radiotherapy (red circle). This resembles an immediacy of a radiation response (short latent interval) that is normally observed for cells with a higher labelling index (such as intestine). However, when one looks at the actual kill of acinar cells, the curve behaves just like any other late responding tissue (gray circle) (adapted from Stewart and van de Kogel, 2002).

Fig. 2

Flow rate of 2% citric acid-stimulated parotid (single gland) and bilateral submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (RT) [Conventional RT; both parotid, submandibular and sublingual glands located in the treatment portal, 2 Gy per day, 5 days per week, total dose 60–70 Gy. Parotid-sparing 3-dimensional (3D)/intensity-modulated RT (IMRT); bilateral (the majority) and unilateral RT (scattered radiation to contralateral gland). For parotid IMRT data: 1.8–2.0 Gy per fraction, prescribed dose to primary target 64 Gy (range 57.6–72 Gy) and for SM/SL IMRT data: 2 Gy per day, 70 Gy to gross disease planning target volume]. Initial flow rates are set to 100% (modified after Burlage et al. for conventional RT, Eisbruch et al. for parotid glands IMRT, and Murdoch-Kinch et al. for SM/SL glands IMRT).

Fig. 3

Fig. 3a Effect of AdhAQP1 on net fluid movement across SMIE cell monolayers. Data shown are the mean ± SEM of experiments originally reported in He et al. SMIE cell monolayers were either transduced at a multiplicity of infection of 5 with AdhAQP1 or AdCMVhGH (control vector, encoding human growth hormone), and 24 hours later transepithelial fluid movement was measured for 60 min. Fig. 3b Parotid salivary output after delivery of an adenoviral vector containing a water channel or control. The flow rate prior to irradiation was set at 100% and the salivary flow rates obatained at times thereafter are represented as a percentage of this initial value. The arrow indicates the time point when the adenoviral vectors were administered. AdhAQP1 is the vector encoding the water channel transgene hAQP1. AdCMVluc is a control vector (modified after Shan et al., 2005⁷⁴).

Fig. 3

Fig. 3a Effect of AdhAQP1 on net fluid movement across SMIE cell monolayers. Data shown are the mean ± SEM of experiments originally reported in He et al. SMIE cell monolayers were either transduced at a multiplicity of infection of 5 with AdhAQP1 or AdCMVhGH (control vector, encoding human growth hormone), and 24 hours later transepithelial fluid movement was measured for 60 min. Fig. 3b Parotid salivary output after delivery of an adenoviral vector containing a water channel or control. The flow rate prior to irradiation was set at 100% and the salivary flow rates obatained at times thereafter are represented as a percentage of this initial value. The arrow indicates the time point when the adenoviral vectors were administered. AdhAQP1 is the vector encoding the water channel transgene hAQP1. AdCMVluc is a control vector (modified after Shan et al., 2005⁷⁴).

Fig. 4

Restored organ function by transplanted progenitor/stem cells. Cells of day 3 old salispheres cultured from dispersed submandibular gland cells were intra-glandularly injected 30 days post-irradiation. Injection of 300–1000 c-Kit⁺ cells (green bars) restored gland function up to 120 days post-irradiation, whereas 10,000–90,000 c-Kit⁻ only temporarily, and to a much lesser extent, restored function (up to 90 days) indicating that they may also contain some progenitor cells. All (red) all cells of the salispheres; (n.d. not determined).