Understanding mechanisms yields novel approaches to reduce radiotherapy-related xerostomia

First, we would like to thank Dr. Eisbruch for his interest in and balanced discussion of our paper (1). The main finding was that stem cells that were previously identified to be responsible for the regeneration of salivary glands after a radiation insult (2), are predominantly localized in the major ducts of the gland. Moreover, we showed that sparing of that region leads to function loss proportional to the irradiated volume, which is consistent to the classically hypothesized parallel organization of the gland. However, if this region is irradiated, this results in global degeneration (1,3). Such response is more representative of an organ with serial organization. Though this may seem to contradict the commonly-reported association with mean dose to the parotid, it should be realized that in most data different dose metrics characterizing the dose to the parotid gland are strongly correlated. In our paper this can be recognized from the small difference in correlation coefficients between outcome and either dose to the stem cell or dose to the total gland. As such, solely modelling of retrospective clinical data is a weak test of the role of hypothesized organ structures in the response of the parotid gland. Therefore, in our study this hypothesis relies on a number of more specific radiobiological studies in mice, rats and patients. In addition, we fully agree with Dr. Eisbruch that prospective testing of the hypothesis that the stem cell region plays a crucial role in the response of the gland to non-uniform irradiation requires prospective testing. To this end we already initiated a prospective double-blind randomized controlled trial comparing parotid sparing IMRT to stem cell sparing IMRT (https://clinicaltrials.gov/ct2/show/NCT01955239). Combining both arms of the trial will yield data in which the correlation between dose to the whole gland and dose to its stem cell region is reduced, providing better insight in the question which dose metric is most critical for the response of the gland. At the time of writing this correspondence patient accrual is nearly complete (95 of the planned 102 patients.)