Purpose: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). Methods and Materials: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose–volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to ≤25% pre-RT flow at 12 months. Results: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD 50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. Conclusions: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of ≤26 Gy should be a planning goal if substantial sparing of the gland function is desired.

Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer

Purpose: We investigated the factors that affect salivary function after head-and-neck radiotherapy (RT), including parotid gland dose-volume effects, potential compensation by less-irradiated gland tissue, and functional recovery over time. Methods and Materials: Sixty-five patients with head-and-neck tumors were enrolled in a prospective salivary function study. RT was delivered using intensity-modulated RT ( n = 45), forward-planning three-dimensional conformal RT ( n = 14), or three-dimensional conformal RT with an intensity-modulated RT boost ( n = 6). Whole salivary flow was measured before therapy and at 6 months ( n = 61) and 12 months ( n = 31) after RT. A wide variety of dose-volume models to predict post-RT salivary function were tested. Xerostomia was defined according to the subjective, objective, management, analytic (SOMA) criteria as occurring when posttreatment salivary function was Results: A significant correlation was observed between the relative quality-of-life scores and relative stimulated saliva values at 6 months after RT (Spearman's correlation coefficient [R s ] = 0.46, p (−A × mean gland dose), with A equal to 0.054/Gy (68% confidence interval 0.052–0.059), provided a good representation of the data and was incorporated into our multimetric analysis. Using that model, we estimated that a mean parotid dose of 25.8 Gy, on average, was likely to reduce a single parotid gland's flow to 25% of its pretreatment value, regardless of the treatment delivery method. Significant correlations were observed between a logistic multivariate model (incorporating the mean dose-exponential equation, gender, and Karnofsky performance status) and stimulated saliva flow at 6 months (R s = 0.73), stimulated saliva flow at 12 months (R s = 0.54), and quality-of-life score at 6 months (R s = 0.35) after RT. Conclusion: Stimulated parotid salivary gland dose-volume models strongly correlated with both stimulated salivary function and quality-of-life scores at 6 months after RT. The mean stimulated saliva flow rates improved from 6 to 12 months after RT. Salivary function, in each gland, appeared to be lost exponentially at a rate of approximately 5%/1 Gy of mean dose. Additional research is necessary to distinguish among the models for use in treatment planning. The incidence of xerostomia was significantly decreased when the mean dose of at least one parotid gland was kept to

Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.

Parotid gland function during and following radiotherapy of malignancies in the head and neck. A consecutive study of salivary flow and patient discomfort.

Radiation therapy for cancer of the head and neck region often causes salivary gland dysfunction and xerostomia. Several reports suggest that the submandibular/sublingual (SM/SL) glands may be less radiosensitive than the parotid. The purpose of this study was to evaluate differential radiation effects on the major salivary glands. Fifty patients with radiation-induced xerostomia were evaluated (33 males, 17 females; mean age 52.7). The average total tumor dose was 6034 cGy. Major salivary gland function was compared with that of 50 non-irradiated controls. Salivary flow rates included unstimulated and stimulated flows of both the parotid and SM/SL glands. Sialochemical analyses included total protein, lysozyme, lactoferrin, sodium, chloride, and potassium. All four measures of salivary flow were significantly reduced in patients as compared to controls (p = .0001). Like the parotid, submandibular/sublingual gland dysfunction appears to be radiation dose- and field-dependent. Patients in the lowest radiation dose quartile ( or = 6800 cGy; p = .025). Glands that were partially irradiated were more likely to have some residual function than fully irradiated glands (p = .003). Lactoferrin content was increased in parotid saliva of radiation patients (p = .0001). Chloride content was significantly increased also (p = .0001). The SM/SL glands are clearly dysfunctional in post-irradiation xerostomia patients compared to controls, in terms of both flow rates and sialochemistry.

Major salivary gland function in patients with radiation- induced xerostomia: flow rates and sialochemistry

Background. Xerostomia can have a significant impact on the quality of life of patients treated by radiation therapy (RT) for cancer in the head and neck. The first aim of the study was to evaluate the degree of xerostomia in 39 long-term survivors treated between 1965-1995 by conventional two-dimensional radiation therapy and currently without evidence of disease. The second aim was to develop a concise instrument to evaluate the subjective aspects of xerostomia. Methods. A newly developed questionnaire and a visual analog scale (VAS) were used in analyzing the degree of dry mouth and xerostomia-related problems. The radiation dose received by the major salivary glands was estimated by analyzing two-dimensional simulation films. Results. Sixty-four percent of the patients experienced a moderate to severe degree of xerostomia. In the multivariate analysis, three questions regarding dry mouth, eating, and speech were particularly discriminatory for establishing the degree of xerostomia as expressed by the VAS score. Conclusions. In this survey, 64% of the long-term survivors, after treatment by conventional two-dimensional radiation therapy for a malignancy in the head and neck region, still experienced a moderate to severe degree of permanent xerostomia. A simplified instrument to evaluate xerostomia subjectively can consist of the VAS score and three graded questions.

Patients with head and neck cancer cured by radiation therapy: A survey of the dry mouth syndrome in long-term survivors

Sequential changes in flow rate of whole saliva are detailed in 13 patients. Samples were collected without exogneous stimulation during a course of fractionated radiotherapy involving major portions of the salivary glands. Flow rate decreased markedly during the initial 3 treatment days and gradually thereafter until a minimal flow rate was reached. Early in the treatment, variable degrees of recovery were seen on Mondays following a weekend (Friday-Sunday) without treatment. After a minimal flow rate was reached, no such recovery was observed. Radiation needed to produce minimal flow varied from 450 to 4,050 rad. Patients with higher initial flow rates required higher dosages to reach the minimum. No return of secretory function was noted after extended periods of time.

WB Wescott

Papers

Alterations in whole saliva flow rate induced by fractionated radiotherapy