Dose-Effect Relationships for the Submandibular Salivary Glands and Implications for Their Sparing by Intensity Modulated Radiotherapy

Purpose

Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose–response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT).

Methods and Materials

A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs.

Results

Stimulated SMG flow rates decreased exponentially by (1.2%)^Gy as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses ≤39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)^Gy as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving ≤39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2–3 Gy.

Conclusions

SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

Introduction

After conventional radiotherapy (RT) of head-and-neck (HN) cancer, permanent xerostomia has been the most prevalent late sequela, cited by patients as a major cause of reduced quality of life (QOL) (1). In recent years, many studies used intensity-modulated radiotherapy (IMRT) to reduce xerostomia by partially sparing the parotid salivary glands (2). These studies demonstrated higher parotid and whole-mouth saliva flows compared with conventional RT. Moreover, saliva production from the spared glands increased significantly over time, unlike conventional RT (3). It had been predicted that parallel improvements in the symptoms of xerostomia would follow. However, this issue was found to be much more complex and uncertain.

Xerostomia is primarily a QOL issue, and similar to other QOL items, patient-reported scores are likely to be more valid and reliable than observer-rated ones such as the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer or Common Toxicity Criteria scores 4, 5. Several studies showed significant correlations between patient-reported xerostomia scores and salivary output 4, 6, 7, 8, 9, whereas others did not 10, 11. Even in the studies that demonstrated statistically significant correlations, the correlation coefficients were modest and a substantial variability in the QOL scores could not be explained by the salivary flow rates alone. Two recent randomized studies comparing IMRT to conventional RT for nasopharyngeal cancer demonstrated the dichotomy between the preserved parotid saliva and xerostomia symptoms: Kam et al. found that salivary flows, but not patient-reported xerostomia scores, were significantly better following IMRT compared with conventional RT (12), and Pow et al. reported substantially higher salivary flow rates in the IMRT group; however, the improvement in symptoms, although statistically significant, was modest (6).

The likely explanation for the discrepancy between the preserved parotid salivary output and patient-reported xerostomia is that sparing of the parotid glands alone is not sufficient to prevent symptoms of dry mouth. This explanation is based on both the important role of the submandibular glands (SMGs) in secreting saliva in the non-stimulated state (13), and, perhaps most importantly, on the relative lack of mucins in the parotid saliva. Mucins serve as mucosal lubricants and selective permeability barrier of the mucosal membranes and their presence helps maintain these tissues in hydrated state and contribute to patient's subjective sense of hydration (14). Mucin-secreting glands include the SMGs and the minor salivary glands (15). The important role of the mucin-producing glands has been demonstrated in studies that correlated RT doses to these glands and patient-reported xerostomia 3, 16, 17, and in studies that transferred surgically the contralateral SMG to the nonirradiated submental space, resulting in a significant improvement of both SMG salivary flow rates and patient-reported dry mouth symptoms (18).

An increasing body of data has been published in recent years about dose–response relationships for the parotid glands, but no such data exist for the SMGs. An understanding of these relationships is an initial step in the efforts to spare effectively the mucin-producing glands and further improve the modest gains in xerostomia achieved to date by the sparing of the parotid glands alone. We have prospectively measured selective SMG salivary output at the same time points at which we measured parotid gland output, in patients participating in our xerostomia and dysphagia-reducing studies 3, 19. This article reports the dose–response relationships for the SMGs based on these measurements. In addition, we have examined the potential implications of these data on the sparing of the SMGs by IMRT.