Radiation-induced Xerostomia is Related to Stem Cell Dose-dependent Reduction of Saliva Production.

Purpose: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (D) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and D is explained by a dose-dependent reduction of saliva production.

Methods And Materials: In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOW) and submandibular/sublingual (FLOW) glands, and patient-reported daytime (XER) and nighttime (XER) xerostomia were prospectively measured before, at 6 months, and 12 months after RT. Using linear mixed effect models, the relationship of the mean dose to the parotid glands (D), D, non-SCR parotid gland tissue (D), submandibular glands (D), and oral cavity (D) with salivary flow and xerostomia was analyzed while correcting for known confounders.

Results: D proved to be responsible for the effect of D on FLOW (P ≤ .03), while D did not affect FLOW (P ≥ .11). To illustrate, increasing D by 10 Gy at a fixed D reduced FLOW by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOW was observed (0.00 mL/min [4%]). As expected, D was significantly associated with FLOW (P < .001). For example, increasing D by 10 Gy reduced FLOW by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. D and D were associated with higher XER scores (P ≤ .05), while D increased XER scores (P = .01). For example, an increase of 10 Gy in D raised XER scores by 2.13 points (5%) after RT, while an additional 10 Gy in D increased XER scores by 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions; ie, FLOW only influenced XER (P < .001, 10.92 points lower XER per 1 mL/min saliva), while FLOW affected XER and XER (P ≤ .004, 6.69 and 5.74 points lower XER and XER, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, D only increased XER scores via reducing FLOW, whereas the effects of D on XER and D on XER were independent of salivary flow.

Conclusions: Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.