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

Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (D_mean,SCR) 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_mean,SCR is explained by a dose-dependent reduction of saliva production.

In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOW_PAR) and submandibular/sublingual (FLOW_SMSL) glands, and patient-reported daytime (XER_DAY) and nighttime (XER_NIGHT) 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_mean,par), D_mean,SCR, non-SCR parotid gland tissue (D_mean,non-SCR), submandibular glands (D_mean,sub), and oral cavity (D_mean,oral) with salivary flow and xerostomia was analyzed while correcting for known confounders.

D_mean,SCR proved to be responsible for the effect of D_mean,par on FLOW_PAR (P ≤ .03), while D_mean,non-SCR did not affect FLOW_PAR (P ≥ .11). To illustrate, increasing D_mean,SCR by 10 Gy at a fixed D_mean,non-SCR reduced FLOW_PAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOW_PAR was observed (0.00 mL/min [4%]). As expected, D_mean,sub was significantly associated with FLOW_SMSL (P < .001). For example, increasing D_mean,sub by 10 Gy reduced FLOW_SMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. D_mean,SCR and D_mean,oral were associated with higher XER_DAY scores (P ≤ .05), while D_mean,sub increased XER_NIGHT scores (P = .01). For example, an increase of 10 Gy in D_mean,SCR raised XER_DAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in D_mean,subs increased XER_NIGHT 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_PAR only influenced XER_DAY (P < .001, 10.92 points lower XER_DAY per 1 mL/min saliva), while FLOW_SMSL affected XER_DAY and XER_NIGHT (P ≤ .004, 6.69 and 5.74 points lower XER_DAY and XER_NIGHT, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, D_mean,SCR only increased XER_DAY scores via reducing FLOW_PAR, whereas the effects of D_mean,oral on XER_DAY and D_mean,sub on XER_NIGHT were independent of salivary flow.

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.