Radiation-induced xerostomia is related to stem cell dose-dependent reduction of saliva production

BACKGROUND AND PURPOSE: 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.

MATERIAL/METHODS: In 570 head and neck cancer patients treated with definitive radiation therapy (RT), flow from the parotid (FLOW PAR) and submandibular/sublingual glands (FLOW SMSL) and patient-reported daytime (XER DAY) and nighttime xerostomia (XER NIGHT) were prospectively measured before, and at 6 and 12 months after RT. Using linear mixed effect models, the relations of 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 were analyzed while correcting for known confounders.

RESULTS: D mean,SCR proved to be responsible for the effect of D mean,par on FLOW PAR (p≤0.03), while D mean,non-SCR did not affect FLOW PAR (p≥0.11). To illustrate, increasing D mean,SCR by 10 Gy at fixed D mean,non-SCR, reduced FLOW PAR by 0.02 (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<0.001). For example, increasing D mean,sub by 10 Gy, reduced FLOW SMSL with 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≤0.05), while D mean,sub increased XER NIGHT scores (p=0.01). For example, an increase of 10 Gy in D mean,SCR raised XER DAY scores with 2.13 (5%) points after RT, while an additional 10 Gy in D mean,subs increased XER NIGHT scores with 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, i.e., FLOW PAR only influenced XER DAY (p<0.001, 10.92 points lower XER DAY per 1 ml/min saliva), while FLOW SMSL affected XER DAY and XER NIGHT (p≤0.004, 6.69 and 5.74 points lower XER DAY and XER NIGHT, respectively, per 1 ml/min saliva). Therefore, the observed relations 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 of D mean,sub on XER NIGHT were independent of salivary flow.

CONCLUSION: 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.