Prediction of Radiation-Induced Parotid Gland-Related Xerostomia in Patients With Head and Neck Cancer: Regeneration-Weighted Dose

Despite improvements to treatment, patients with head and neck cancer (HNC) still experience radiation-induced xerostomia due to salivary gland damage. The stem cells of the parotid gland (PG), concentrated in the gland's main ducts (stem cell rich [SCR] region), play a critical role in the PG's response to radiation. Treatment optimization requires a dose metric that properly accounts for the relative contributions of dose to this SCR region and the PG's remainder (non-SCR region) to the risk of xerostomia in normal tissue complication probability (NTCP) models for xerostomia.Treatment and toxicity data of 1013 prospectively followed patients with HNC treated with definitive radiation therapy (RT) were used. The regeneration-weighted dose, enabling accounting for the hypothesized different effects of dose to the SCR and non-SCR region on the risk of xerostomia, was defined as Dreg PG = Dmean SCR region + r × Dmean non-SCR region, where Dreg is the regeneration-weighted dose, Dmean is the mean dose, and r is the weighting factor. Considering the different volumes of these regions, r > 3.6 in Dreg PG demonstrates an enhanced effect of the SCR region. The most predictive value of r was estimated in 102 patients of a previously published trial testing stem cell sparing RT. For each endpoint, Dreg PG, dose to other organs, and clinical factors were used to develop NTCP models using multivariable logistic regression analysis in 663 patients. The models were validated in 350 patients.Dose to the contralateral PG was associated with daytime, eating-related, and physician-rated grade ≥2 xerostomia. Consequently, r was estimated and found to be smaller than 3.6 for most PG function-related endpoints. Therefore, the contribution of Dmean SCR region to the risk of xerostomia was larger than predicted by Dmean PG. Other frequently selected predictors were pretreatment xerostomia and Dmean oral cavity. The validation showed good discrimination and calibration.Tools for clinical implementation of stem cell sparing RT were developed: regeneration-weighted dose to the parotid gland that accounted for regional differences in radiosensitivity within the gland and NTCP models that included this new dose metric and other prognostic factors.