International Journal of Radiation Oncology*Biology*Physics
Critical ReviewClinical Management of Salivary Gland Hypofunction and Xerostomia in Head-and-Neck Cancer Patients: Successes and Barriers
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
References (73)
- et al.
Parotid and submandibular/sublingual flow during high dose radiotherapy
Radiother Oncol
(2001) - et al.
Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer
Int J Radiat Oncol Biol Phys
(2007) - et al.
Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer
Int J Radiat Oncol Biol Phys
(2001) Salivary flow patterns and the health of hard and soft oral tissues
J Am Dent Assoc
(2008)- et al.
The intra-oral distribution of unstimulated and chewing-gum-stimulated parotid saliva
Arch Oral Biol
(1997) - et al.
Comparison of radiosensitivity of rat parotid and submandibular glands after different radiation schedules
Radiother Oncol
(2002) - et al.
On the mechanism of salivary gland radiosensitivity
Int J Radiat Oncol Biol Phys
(2005) - et al.
Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis
Int J Radiat Oncol Biol Phys
(2009) - et al.
Salivary flow rates in patients with head and neck cancer 0.5 to 25 years after radiotherapy
Oral Surg Oral Med Oral Pathol
(1990) - et al.
Dose, volume and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer
Int J Radiat Oncol Biol Phys
(1999)
Dose-effect relationship for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy
Int J Radiat Oncol Biol Phys
Quantitative dose-volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region
Int J Radiat Oncol Biol Phys
Modeling of salivary production recovery after radiotherapy using mixed models: Determination of optimal dose constraint for IMRT planning and construction of convenient tools to predict salivary function
Int J Radiat Oncol Biol Phys
Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: Results of a nonrandomized prospective study using a standardized follow-up program
Int J Radiat Oncol Biol Phys
Intensity modulated photon and proton therapy for the treatment of head and neck tumors
Radiother Oncol
Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: Planning comparison and NTCP evaluation
Int J Radiat Oncol Biol Phys
A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours
Radiother Oncol
Intensity modulation in radiotherapy: Photons versus protons in the paranasal sinus
Radiother Oncol
Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and-neck cancer: 2 year follow-up of a prospective, randomized, phase III trial
Int J Radiat Oncol Biol Phys
Protection of salivary function by concomitant pilocarpine during radiotherapy: A double-blind, randomized, placebo-controlled study
Int J Radiat Oncol Biol Phys
A Phase II trial of subcutaneous amifostine and radiation therapy in patients with head-and-neck cancer
Int J Radiat Oncol Biol Phys
Botulinum toxin prevents radiotherapy-induced salivary gland damage
Oral Oncol
Optimum dose range for the amelioration of long term radiation-induced hyposalivation using prophylactic pilocarpine treatment
Radiother Oncol
Enhanced proliferation of acinar and progenitor cells by prophylactic pilocarpine treatment underlies the observed amelioration of radiation injury to parotid glands
Radiother Oncol
Radiation-induced hyposalivation and its treatment with oral pilocarpine
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
Synergistic effect of sialogogues in management of xerostomia after radiation therapy
Oral Surg Oral Med Oral Pathol
Acupuncture for pilocarpine-resistant xerostomia following radiotherapy for head and neck malignancies
Int J Radiat Oncol Biol Phys
A phase I-IIstudy in the use of acupuncture-like transcutaneous nerve stimulation in the treatment of radiation-induced xerostomia in head-and-neck cancer patients treated with radical radiotherapy
Int J Radiat Oncol Biol Phys
The effects of mucin-containing artificial saliva on severe xerostomia
Int J Oral Surg
A clinical comparison between commercially available mucin- and CMC-containing saliva substitutes
Int J Oral Surg
Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands
Mol Ther
Oral sequelae of head and neck radiotherapy
Crit Rev Oral Biol Med
Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy
J Clin Oncol
Xerostomia and hypofunction of the salivary glands in cancer therapy
Support Care Cancer
A systematic review of salivary gland hypofunction and xerostomia induced bycancer therapies: Management strategies and economic impact
Support Care Cancer
Cited by (0)
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.