Phenomenologic model describing flow reduction for parotid gland irradiation with intensity-modulated radiotherapy: Evidence of significant recovery effect

Abstract

Objective To develop a model describing the relationship between the parotid gland radiation dose and salivary flow reduction. Salivary function was described by the "relative flow reduction" (RFR)—a continuous variable in contrast to the traditional binary response used in normal tissue complication probability estimations. Methods and materials Twenty-three patients with squamous cell carcinoma of the head and neck who were treated with intensity-modulated radiotherapy (RT) were the subject of this study. Of these patients, 19 had sufficiently long follow-up to be eligible for analysis. All were treated with curative intent, most (14 of 19) in the postoperative setting. The planning objectives were to deliver a mean dose of 50, 60, or 70 Gy, respectively, to low-risk microscopic, high-risk microscopic, and gross disease areas, while maintaining a mean dose of ≤20 Gy to the spared portion of one or both parotid glands. The mean dose to all parotid glands (right and left) was 30.2 Gy. All submandibular glands received >50 Gy when not surgically removed. Whole-mouth saliva collections, including both stimulated and unstimulated saliva flow, were obtained before treatment and at regular intervals after RT. These measurements were converted to the RFR by comparing the posttreatment and pretreatment flow rates. Any follow-up flow rates greater than baseline were scored as 0 relative reduction. We used Lyman's model to relate the equivalent uniform dose to RFR at various points for each patient. The equivalent uniform dose was calculated using the linear quadratic model, with an assumed α/β ratio of 3 Gy for the parotid gland. Measurements were modeled 1–3 months after RT (early) and >6 months after RT (late), and using the best and worst measurements, regardless of when measured. Results Fitting the Lyman model to RFR data of unstimulated flow revealed a statistically significant dose–complication relationship. We observed a stepwise reduction in flow, with the threshold dose D₅₀ at 2 Gy per fraction (D₅₀) increasing from 12.4 Gy (early) to 43.9 Gy (late). For the worst and best flow measurements, the corresponding D₅₀ (2 Gy/fr) was 13.0 Gy and 40.1 Gy, respectively. For most stimulated flow measurements, a weak relationship was found between the RFR and equivalent uniform dose. In those cases, the model did not yield a statistically significant description of the data. However, in the case of late measurements, the relationship was statistically significant and similar to that seen in the unstimulated cases, with a D₅₀ (2 Gy/fr) of 47.5 Gy. Conclusion We observed a strong relationship between the generalized mean parotid gland dose and RFR. The threshold dose increased markedly between the early and late measurements, indicating a statistically significant recovery effect in this tissue. Compared with unstimulated flow, the RFR for stimulated flow was not described as well by the model, because the effect of the stimulant was not included in the model.