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 (Dmean,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 Dmean,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 (FLOWPAR) and submandibular/sublingual glands (FLOWSMSL) and patient-reported daytime (XERDAY) and nighttime xerostomia (XERNIGHT) 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 (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub) and oral cavity (Dmean,oral) with salivary flow and xerostomia were analyzed while correcting for known confounders. Results Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (p≤0.03), while Dmean,non-SCR did not affect FLOWPAR (p≥0.11). To illustrate, increasing Dmean,SCR by 10 Gy at fixed Dmean,non-SCR, reduced FLOWPAR by 0.02 (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 ml/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (p<0.001). For example, increasing Dmean,sub by 10 Gy, reduced FLOWSMSL with 0.07 ml/min (26%) after RT.Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (p≤0.05), while Dmean,sub increased XERNIGHT scores (p=0.01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores with 2.13 (5%) points after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT 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., FLOWPAR only influenced XERDAY (p<0.001, 10.92 points lower XERDAY per 1 ml/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (p≤0.004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 ml/min saliva). Therefore, the observed relations between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR; whereas the effects of Dmean,oral on XERDAY and of Dmean,sub on XERNIGHT 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.