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

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Abstract

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 TD50 (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.

Introduction

The parotid salivary glands produce the majority (60–65%) of the oral salivary output (1). Their secretion is controlled by the autonomous nervous system and is stimulated by the sensations of taste, smell, or chewing, as well as by psychological factors. These stimuli result in increased saliva production during chewing and swallowing food. The salivary glands are highly sensitive to radiation: saliva flows are reduced significantly following 10–15 Gy delivered to most of the gland 2, 3, 4. While recovery of function is possible over time following radiation doses up to 40–50 Gy, higher doses to most of the glands cause irreversible hypofunction and permanent xerostomia, which is the most common side effect and cause of reduced quality of life following irradiation (RT) of head and neck cancer (1). Dose–response relationships and the effects of the irradiated gland volumes on function have been described in past studies 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. However, the accuracy of these studies was limited by several factors. In some studies whole oral saliva output was measured, rather than the saliva secreted by the parotid glands alone (5, 9–12, 14, 15). In all the studies, the dose to the gland and the irradiated gland volumes were estimated from the simulation films, estimations which are fraught with uncertainties. Also, the use of standard RT techniques (usually lateral opposed fields) limited the range of RT doses and irradiated gland volumes, thus diminishing the ability to assess dose/volume/effect relationships over a wide range of doses and irradiated volumes.

In recent years we have used computed tomography (CT)-based RT methods to treat head and neck cancer while sparing major salivary glands. These studies included conformal techniques in unilateral neck irradiation for cases where the contralateral neck was not at risk for metastases (2), conformal RT to treat the neck bilaterally while partly sparing parotid gland tissue using beam’s-eye-view techniques (16), and, more recently, intensity-modulated RT techniques for bilateral neck RT sparing parotid tissue (17). These studies aimed at reducing the dose to the parotid glands throughout the course of irradiation and resulted in heterogeneous dose distributions in the parotid glands. The planning CT scans provided details of the three-dimensional dose distributions in each gland which were displayed in the form of dose–volume histograms (DVHs). Saliva flow rate measurements taken selectively from each parotid gland before and periodically after RT, in conjunction with the corresponding gland DVH, provided an opportunity to assess dose/volume/function relationships more accurately than had previously been possible. In addition to assessing these relationships, we sought to determine for future treatment planning purposes which doses and irradiated gland volumes would allow significant function preservation following RT. To this end, the data were fit using models designed to interpolate dose–volume data and estimate the amount of saliva that may be preserved in future patients.

Section snippets

Methods and materials

The study population consisted of patients with head and neck cancer treated with primary or postoperative irradiation at the University of Michigan between March 1994 and August 1997. CT-based 3-dimensional treatment planning was performed according to previously published methods for patients requiring bilateral (16, 17) or unilateral (18) neck RT. The primary tumor, postoperative surgical resection bed, lymph node metastases, and each lymph node chain at risk of subclinical metastases were

Patient characteristics

The study included 88 patients (Table 1). Thirty-seven patients were treated unilaterally. They had early tonsillar or oral cavity (buccal mucosa, alveolar ridge, or retromolar trigone) cancer or tumors originating in the salivary glands, skin, maxillary sinuses, or glomus. Fifty-one patients with Stage III or IV oral, oropharyngeal, hypopharyngeal, advanced laryngeal tumors or neck metastases of unknown primary were irradiated comprehensively to both neck sides. The median prescribed dose to

Discussion

Our data suggest mean dose thresholds for both unstimulated (24 Gy) and stimulated (26 Gy) parotid saliva flow rates. Glands receiving a mean doses below the threshold retained a substantial fraction of their pre-RT salivary output whereas glands receiving higher doses demonstrated very little or nonmeasurable saliva. Furthermore, glands receiving doses below the threshold demonstrated functional recovery over time, whereas most glands receiving higher doses did not recover. Taking into account

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    Supported by NIH Grant R03-CA78165.

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