Critical Review
Clinical Management of Salivary Gland Hypofunction and Xerostomia in Head-and-Neck Cancer Patients: Successes and Barriers

Discussed at the Conference on Oral Complications of Emerging Cancer Therapies, April 14–15, 2009, Bethesda, MD.
https://doi.org/10.1016/j.ijrobp.2010.06.052Get rights and content

The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy.

Introduction

Radiotherapy plays a pivotal role in the curative treatment of the majority of patients with head-and-neck cancer, either as single modality or in combination with surgery and/or chemotherapy. Despite the beneficial effects of radiotherapy in locoregional tumor control, the damage inflicted to normal tissues surrounding the tumor may cause severe complications. In particular, coirradiation of the salivary glands during the treatment of head-and-neck cancer results in a progressive loss of gland function (hyposalivation) beginning early in the course of radiotherapy (1).

Quantitative and qualitative salivary changes predispose the irradiated patient to a variety of problems that develop either directly or indirectly as a result of diminished salivary output 2, 3, 4. These include oral dryness, impairment of normal oral functions (speech, chewing, and swallowing) because of insufficient wetting, and decreased lubrication of the mucosal surfaces and of ingested food. Furthermore, the oral mucosa can become dry and atrophic, leading to frequent ulceration and injury. Finally, the shift in oral microflora towards cariogenic bacteria, the reduced salivary flow (oral clearance), and changes in saliva composition (decreased buffer capacity, pH, immunoprotein concentrations) may result in rapidly progressing radiation caries 2, 5.

Although most studies focus on salivary flow, other endpoints related to salivary function, such as patient-rated xerostomia and physician-rated Radiation Therapy Oncology Group–defined xerostomia, are probably of even more clinical relevance 6, 7. Importantly, the subjective symptom of xerostomia may not always correlate with salivary flow rates. For understanding this phenomenon, one should be aware that saliva enters the mouth at several locations and that the different glandular secretions are not well mixed (8). For example, the contribution of parotid saliva to (un)stimulated whole saliva varies from site to site, ranging from being the major contributor to whole saliva collected buccally from the maxillary molars to being almost noncontributing to whole saliva collected in the incisor region (9). The wide variation in local contribution of the various salivary glands to whole saliva is also obvious when assessing mucosal wetness because the thickness of the salivary layer on the oral mucosa is much thinner in the labial and anterior hard palatal region than on the buccal mucosa and anterior tongue (10). These phenomana might explain, at least in part, the differences reported in the literature about level of hyposalivation and sensation of oral dryness.

Radiation-induced DNA damage impairs proper cell division, resulting in cell death or senescence of cells that attempt to divide. On the basis of the slow turnover rates of their cells (60–120 days), the salivary glands would be expected to be late-responding tissue (>60 days) (Fig. 1) (11). However, the changes in quantity and composition of saliva that occur shortly after radiotherapy indicate that these glands respond acutely 1, 12. Radiation injury leads primarily to the loss of saliva-producing acinar cells; however, interestingly, the ducts, although deprived of function, mostly remain intact (13). A human postmortem study suggests that in the lower dose range (<30 Gy, in 2-Gy fractions) damage is reversible to a certain extent, but with cumulative doses (>75 Gy) extensive degeneration of acini is observed along with inflammation and fibrosis in the interstitium (14). The role of apoptotic cell death in early salivary gland dysfunction after radiotherapy remains unclear. Paardenkooper et al.(15) did not observe a dose-related increase in apoptotic cells very early after radiotherapy, whereas Avila et al.(16) found that early radiation-induced salivary gland dysfunction resulted from p53-dependent apoptosis.

Next to the suggestion of massive apoptosis, the leakage of granules and subsequent lysis of acinar cells has been suggested as an alternative explanation for the acute radiation-induced dysfunction of the salivary glands 17, 18. However, several studies show no cell loss during the first days after irradiation, although saliva flow is dramatically reduced and water secretion is selectively hampered 19, 20, 21, 22. One mechanism of action to explain the early effects and the enigmatic high radiosensitivity of salivary cells is selective radiation damage to the plasma membrane of the secretory cells, resulting in disruption of muscarinic receptor-stimulated water secretion. On the basis of their studies in the rat model, Coppes et al.(21) have proposed that radiation-induced loss of salivary gland function occurs over four phases. The first phase (0–10 days) is characterized by a rapid decline in flow rate without changes in amylase secretion or acinar cell number. The second phase (10–60 days) consists of a decrease in amylase secretion paralleled by acinar cell loss. Flow rate, amylase secretion, and acinar cell numbers do not change in the third phase (60–120 days). In the fourth phase (120–240 days) further deterioration of gland function is seen, but is accompanied by an increase in acinar cell number, albeit with poor tissue morphology. Comparable changes have been observed in rat submandibular tissue; however, similar studies are not available in humans 12, 22.

Section snippets

Prevention of Radiation-Induced Injury to the Salivary Gland

In humans, depending on the localization of the radiation portals, a rapid decrease of the salivary flow rate is observed during the first week of radiotherapy, after which there is a continuing gradual decrease to less than 10% of the initial flow rate (Fig. 2) 1, 23, 24. Although in the older literature the submandibular gland was thought to be less radiosensitive than the parotid gland, both glands have been shown to be as sensitive to radiotherapy, at least with respect to their function 1,

Stimulation of residual function

Administration of pilocarpine or pure cholinergic sialogogues to stimulate any residual function of the salivary gland after radiotherapy is worthwhile (Tables 1 and 2); however, the functional gain ceases as soon as the administration of the sialogogue is stopped 49, 50. A more persistent effect can be observed when pilocarpine is administered before radiotherapy and continued during radiotherapy and then stopped (38). Moreover, in a rat study it was shown that amelioration of early loss of

Gene therapy

In the future, gene therapy might provide a therapeutic option for radiation induced-salivary hypofunction in some patients. The gene transfer strategy pioneered by Baum et al.(68) focused on developing a gene transfer event that could elicit fluid secretion from surviving (primarily duct) epithelial cells in an irradiated salivary gland (69). Delporte et al.(69) reasoned that surviving duct cells could serve as water-secreting cells if there was a pathway for water transport inserted in the

Epilogue

Despite advances in our understanding of the cellular and biochemical basis for irradiation-induced loss of salivary gland function, options for the clinical management of irradiation-induced salivary gland hypofunction remain largely limited to palliative therapies. Efforts to protect or diminish irradiation-induced damage, including IMRT and the use of radioprotectors such as Tempol, are progressing; however, there is a need for the concurrent pursuit of therapies aimed at restoration of the

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    Funding for this conference was made possible in part by Award Number R13 DE19330 from the National Institute of Dental and Craniofacial Research. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Partial funding was also provided by the National Cancer Institute, the National Institutes of Health Office of Rare Diseases, The University of Connecticut School of Dental Medicine, Carolinas Medical Center, The Multinational Association of Supportive Care in Cancer, and the International Society of Oral Oncology. This conference was also supported by unrestricted educational grant funds from Endo Pharmaceuticals, Inc. and from EUSA Pharma, and by funds from Biovitrum and Helsinn Healthcare SA.

    Conflict of interest: R.P.C. has received partial research support from AMGEN.

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