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Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients

Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients Abstract Background The most manifest long-term consequences of radiation therapy in the head and neck cancer patient are salivary gland hypofunction and a sensation of oral dryness (xerostomia). Methods This critical review addresses the consequences of radiation injury to salivary gland tissue, the clinical management of salivary gland hypofunction and xerostomia, and current and potential strategies to prevent or reduce radiation injury to salivary gland tissue or restore the function of radiation-injured salivary gland tissue. Results Salivary gland hypofunction and xerostomia have severe implications for oral functioning, maintenance of oral and general health, and quality of life. Significant progress has been made to spare salivary gland function chiefly due to advances in radiation techniques. Other strategies have also been developed, e.g., radioprotectors, identification and preservation/expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, and application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. Conclusion Many advances to manage salivary gland hypofunction and xerostomia induced by radiation therapy still only offer partial protection since they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects. Intensity-modulated radiation therapy (IMRT), and its next step, proton therapy, have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients. Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for regaining function and/or regeneration of radiation-damaged salivary gland tissue. It is well documented that head and neck radiotherapy, in addition to its antitumor effects, inevitably induces severe adverse effects to normal oral tissues surrounding the tumor tissue. Adverse effects include mucositis, pain, salivary gland hypofunction (objectively decreased saliva secretion), and xerostomia (subjective feeling of dry mouth), fungal infection, taste disturbances and muscular fibrosis. Depending on the cumulative radiation dose to the gland tissue, permanent salivary gland hypofunction may occur, impeding oral functioning, compromising oral and general health, and diminishing the quality of life following radiation therapy in head and neck cancer patients (1–4). In addition, the head and neck cancer patient may also experience a heavy economic burden due to the extensive need for oral preventive measures and dental treatment after radiation therapy. It should be noted that salivary gland hypofunction and xerostomia may also be sequelae of other radiation regimes, although to a much lesser extent, that is, radioiodine treatment of thyroid cancer and preconditioning total body irradiation in hematopoietic stem cell transplantation for the treatment of hematologic malignancies (4–6). The National Institutes of Health (NIH) Consensus Conference In 1989, the NIH sponsored the first Development Consensus Conference on Oral Complications of Cancer Therapies (7). No well-defined treatment strategies to prevent or minimize xerostomia were available at that time. A general consensus from this conference was the need to establish baseline data for salivary gland hypofunction and xerostomia, to which all subsequent examinations could be compared, and to identify risk factors for the development of oral complications. With regard to management strategies, the consensus was that volumetric assessment of resting and stimulated whole saliva should be performed before cancer therapy to identify these risk factors. In addition, recommendations for management of chronic xerostomia were given, including regular use of topical fluorides, attention to oral hygiene, and use of sialagogues. Even more importantly, the 1989 NIH conference identified directions for future research applicable to salivary gland hypofunction and xerostomia, that is, 1) to devise accurate, quantifiable, reproducible criteria for assessing and classifying oral complications of cancer therapy; 2) to determine incidence and prevalence of oral complications related to different types of cancer therapies and related risk factors; 3) to study the mechanisms of cancer treatment injury to the hard and soft oral tissues at the molecular and cellular level and to determine how these affect the oral environment; 4) to develop radioprotective and chemoprotective agents; and 5) to develop more effective sialagogues and saliva substitutes and to evaluate their effectiveness in preventing the complications of xerostomia. As two decades had passed since the abovementioned conference, in 2009 the NIH held a second conference to update the community regarding current strategies and future research directions related to oral complications of emerging cancer therapies. Part of this conference was to critically review the long-term consequences of head neck radiotherapy for salivary gland hypofunction and xerostomia. The consensus reported in this paper is a compilation of recommendations from the 2009 conference, updated to 2019, and more recent systematic reviews of the literature providing prevalence, impact on quality of life, and management strategies of salivary gland hypofunction and xerostomia induced by cancer therapies (4, 8–13). Three key research questions were addressed: Can radiation injury of salivary gland tissue be prevented? If radiation injury of salivary gland tissue has occurred, what is then the most effective method to alleviate the resulting problems? Can radiation damage of salivary gland tissue be restored? Pathobiology: Current Paradigm and New Frontiers Saliva plays an essential role in maintenance of tooth integrity, in the protection of mucosal surfaces, and in dilution and mechanical cleansing of food detritus. Radiation-induced salivary gland hypofunction can have a profound impact on oral functions and tissues, resulting in persistent xerostomia, dry and fragile oral mucosa, oral mucosal discomfort and pain, and hampered speech. Saliva also has a crucial role in the upper gastrointestinal functions including taste perception, formation and translocation of a food bolus, facilitation of mastication, swallowing, and speech, as well as lubrication of oropharyngeal and esophageal mucosa (14–16). Finally, saliva provides antimicrobial activity to prevent oral infections, such as candidiasis, and patients with salivary gland hypofunction are prone to carious destruction of teeth or tooth loss, resulting in increased risk of osteoradionecrosis of the jaw (14, 17–19). As a consequence of the adverse effects directly related to salivary gland hypofunction, the quality of life following radiation therapy for the head and neck cancer patient may severely deteriorate, characterized by restriction of daily activities, a poorer general health, social disabilities, and malnutrition (1–4, 13, 20). The impact of the adverse effects of radiation-induced hyposalivation on quality of life is lifelong. In radiation treatment for head and neck cancer, the major and minor salivary glands are often included within the radiation portal because of the site and extension of primary tumors and the path of lymphatic spread, which is in close proximity to the salivary glands (17, 21, 22). Tumor cells are actively dividing and, consequently, their DNA is highly sensitive to radiation damage, rendering cells incapable of proper cell division, and resulting in cell death or senescence of cells that attempt to divide. In contrast, salivary glands are highly specialized organs comprised of well-differentiated cells that have a relatively low mitotic index. Differentiated salivary acinar cells have a mean life span of more than 3 months, however, the origin of replacement and regeneration of acinar cells remains unclear. It has been proposed that differentiated salivary acinar cells may be able to divide in response to damage through a process known as “self-duplication”, a slowly cycling stem cell population, or that multiple cell types might have regenerative potential for restoring salivary gland function (23–27). Based on the slow turnover rate of their cells, the salivary glands are expected to be relatively radioresistant. However, changes in the amount and composition of saliva that occur early after irradiation suggest that the salivary gland is actually an acutely responding tissue (12, 28–30). Radiation exposure of salivary glands located within the treatment portal results in a dramatic loss of gland function within the first week of treatment with a continuous decrease in salivary flow rate throughout the course of therapy to barely measurable flow rates (Figure 1). Following high-dose radiotherapy [the critical dose limit for parotid and submandibular salivary gland tissue is just less than 40 Gy (31, 32), and most radiation regimens exceed this limit], a second phase of functional deterioration in secretion may be noted up to several months after completion of radiation therapy and is concomitant with progressive, irreversible changes of the salivary gland tissue with no significant recovery in gland function (4, 28, 33). Irradiation leads to the loss of saliva-producing acinar cells and impairment of duct function, although morphologically the duct tissue mostly remains intact (23, 24). However, it is not clear whether acute salivary gland hypofunction is caused by the direct effects of radiation on the secretory acini and ductal cells, or if it is secondary to injury of the vascular structures, which results in increased capillary permeability, loss of the capillary bed and fibrosis of arteries and veins, interstitial edema, and inflammatory infiltration (34, 35). Figure 1. View largeDownload slide Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy. Tx treatment, RT radiotherapy, Mo. months, Yrs. years, Unstim. unstimulated, Stim. stimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010.Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy (RT). Stim. = stimulated; Unstim. = unstimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010. Figure 1. View largeDownload slide Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy. Tx treatment, RT radiotherapy, Mo. months, Yrs. years, Unstim. unstimulated, Stim. stimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010.Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy (RT). Stim. = stimulated; Unstim. = unstimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010. Several mechanisms have been suggested for explaining the high radiation sensitivity of salivary gland cells. The acute functional impairment may be selective radiation damage to the plasma membrane of the secretory cells resulting in disruption of muscarinic receptor-stimulated water secretion. It has also been suggested that the acute dysfunction of the salivary glands may be caused by radiation-induced apoptosis of the serous acinar cells, because genetically engineered mouse models with alterations in key components of the apoptotic pathway do not exhibit salivary gland hypofunction following radiation (36–38). Although saliva flow rate is significantly reduced and water secretion is selectively hampered, some studies have shown no reduction in number of acinar cells early after radiotherapy (39–41). Therefore, the role of apoptotic cell death and its subsequent downstream signaling effects in acute salivary gland dysfunction after radiation therapy is still under debate (12, 24, 42). The severity of glandular damage and potential for recovery is dependent on the irradiated gland volume, the cumulative radiation dose, and the ability of surviving cells to repopulate (24). The later salivary gland damage is currently suggested to be due to radiation-induced loss of acinar cells, together with impaired parasympathetic innervation and injury to vascular structures (35, 43–45). Thus, the remaining intact salivary gland stem cells and/or progenitor cells could determine the regenerative capacity of the salivary gland after radiation therapy. It has been shown in humans that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicts the function of the salivary glands postradiotherapy (46). A low dose to a region postulated to be rich in salivary stem cells can even result in a hyper-radiosensitivity, which is followed by relative radioresistance at higher radiation doses (47). Both observations might have implications for radiotherapy treatment planning (47). As discussed above, the irradiated patient is predisposed to a variety of morbidities that develop either directly or as an indirect result of decreased salivary flow rate (insufficient oral clearance and lubrication) and negative salivary compositional changes (reduced buffer capacity, pH, immunoglobulin, and antimicrobial proteins) (16, 17, 48). Clinical Management: Successes and Barriers Prevention of Radiation Injury to Salivary Gland Tissue Radiation Techniques Intensity-modulated radiation therapy (IMRT) is an improvement over traditional radiotherapy that allows more accurate delivery of specific radiation dosage and dose distribution to the tumor, enabling better sparing of surrounding normal tissues (eg, major salivary glands) and has the potential to minimize the severity of salivary gland hypofunction and xerostomia (12, 49–51). After an initial decrease in saliva secretion 1–3 months after IMRT, salivary secretion from spared salivary glands (ie, those parts of the salivary glands that have been irradiated with a cumulative dose below the threshold dose for irreversible damage; see below) has the potential to gradually recover over time (1–2 years) (Figure 2) (4). Figure 2. View largeDownload slide Flow rate of 2% citric acid-stimulated parotid (single gland) and bilateral submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (RT) (Conventional RT; both parotid, submandibular and sublingual glands located in the treatment portal, 2 Gy per day, 5 days per week, total dose 60–70 Gy. Parotid-sparing three-dimensional/intensity-modulated RT [IMRT]; bilateral [the majority] and unilateral RT [scattered radiation to contralateral gland]. For parotid IMRT data: 1.8–2.0 Gy per fraction, prescribed dose to primary target 64 Gy [range = 57.6–72 Gy], and for SM/SL IMRT data: 2 Gy per day, 70 Gy to gross disease planning target volume). Initial flow rates are set to 100% [modified after Burlage et al. (28) for conventional RT, Eisbruch et al. (52) for parotid glands IMRT, and Murdoch-Kinch et al. (31) for SM/SL glands IMRT]. Modified with permission from Elsevier (9). Figure 2. View largeDownload slide Flow rate of 2% citric acid-stimulated parotid (single gland) and bilateral submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (RT) (Conventional RT; both parotid, submandibular and sublingual glands located in the treatment portal, 2 Gy per day, 5 days per week, total dose 60–70 Gy. Parotid-sparing three-dimensional/intensity-modulated RT [IMRT]; bilateral [the majority] and unilateral RT [scattered radiation to contralateral gland]. For parotid IMRT data: 1.8–2.0 Gy per fraction, prescribed dose to primary target 64 Gy [range = 57.6–72 Gy], and for SM/SL IMRT data: 2 Gy per day, 70 Gy to gross disease planning target volume). Initial flow rates are set to 100% [modified after Burlage et al. (28) for conventional RT, Eisbruch et al. (52) for parotid glands IMRT, and Murdoch-Kinch et al. (31) for SM/SL glands IMRT]. Modified with permission from Elsevier (9). In contrast, a fractionated schedule of conventional radiotherapy results in major parts of the salivary glands being irradiated with cumulative doses above the threshold and consequently no recovery after radiotherapy (Figure 2) (4). As such, the benefits from IMRT on salivary gland function, xerostomia, and xerostomia-related quality of life are most pronounced late (≥6 months) after radiotherapy (4, 53, 54). A cumulative mean dose to the parotid gland around 39 Gy has been found to cause a clinically and statistically significant reduction in parotid flow rate (32), and a comparable cumulative mean dose of 39 Gy has been found to result in a clinically and statistically significant reduction in flow rate for the submandibular and sublingual glands (31). These calculations have been made with the assumption that the cumulative radiation dose on the gland can be averaged and disregards the possibility of regional differences in sensitivity, in particular, the areas within a salivary gland where the stem cells potentially reside (55). The regional differences identified by van Luijk and colleagues (46) suggest a need for reassessment of the 39 Gy limit to determine whether a significant loss of salivary gland function will occur or not. Nevertheless, incomplete improvement in xerostomia by sparing of the parotid gland via IMRT emphasizes the need to enhance protection of the submandibular glands, because these glands, together with the sublingual and minor salivary glands, are the greatest contributors to whole saliva during rest (4). Further improvement of salivary gland tissue sparing could be achieved by new radiation techniques using protons. The physical and radiobiological properties of protons allow a superior dose distribution because of a more targeted location of the maximum deposited energy dose (12, 51, 56). In contrast, current photon (x-ray) radiotherapy deposits the largest amount of energy dose to the first point of entry into the biological matter, where after the energy deposited, decreases slowly resulting in a large affected area. Comparative studies have shown a potential benefit of protons compared to photons as a result of minimizing the dose to normal tissues (57, 58), particularly in the treatment of tumors localized in the pharynx (59, 60), the paranasal sinuses (61, 62), and in head and neck cancer patients treated with bilateral neck irradiation (58, 63–65). Radioprotectors Amifostine. Amifostine (Table 1), a radical scavenger, accumulates with high concentrations in the salivary glands. It provides direct radioprotection when systemically administered during radiotherapy (73–75). Amifostine has been reported to reduce xerostomia during and post radiotherapy, although the benefit may be clinically minor (11, 76, 77). Many studies showed a beneficial effect of the use of amifostine on xerostomia, although most studies failed to show that amifostine treatment resulted in preserved salivary flow rate in response to radiotherapy (11, 73, 78, 79). Furthermore, when administered intravenously, amifostine is accompanied by severe adverse effects (eg, hypotension, nausea, vomiting, allergic reaction). However, when administered subcutaneously, amifostine appears to be better tolerated (80). Recently, in an animal model, it was shown that localized administration of amifostine to the salivary glands by retroductal delivery might result in better preservation of salivary gland function than with systemic administration of this drug thereby reducing hypotension (81). While there is no overall difference in nausea and/or vomiting or patient compliance with subcutaneous compared to intravenous administration, a lower prevalence of grade 1–2 hypotension and higher rates of skin rash and pain at injection sites with subcutaneous administration have been reported (82). Although better tolerated, in the latter study the incidence of grade 2 or greater xerostomia was significantly higher for patients who received amifostine via subcutaneous administration. Finally, there is still concern that amifostine might have an undesirable effect of tumor protection, raising questions about the appropriateness of amifostine in cancer patients (75, 83). However, a meta-analysis of updated survival data and a median follow-up of 5.2 years from individual patients treated with radiotherapy or chemoradiotherapy did not show a detectable impact on overall survival with the use of concurrent amifostine (84). Table 1. Management guidelines to reduce radiation-induced xerostomia and their level of evidence* Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C * For guideline details, see systematic review by Jensen et al. (8) and the additional systematic reviews on each individual topic. † Quality of recommendations according to the American Society of Clinical Oncology clinical practice guidelines (71, 72). Level of evidence: I = meta-analysis of multiple well-designed studies, high-powered randomized trials; II = at least one well-designed experimental trial, low-powered randomized trials; III = well-designed, quasi-experimental studies (eg, nonrandomized, controlled, single-group, pre–post, cohort); IV = well-designed, nonexperimental studies (eg, comparative and correlational descriptive and case studies); V = case reports and clinical examples. Grade of recommendation: A = evidence of type I or consistent findings of multiple types II, III, or IV; B = evidence of types II, III, or IV with generally consistent findings; C = evidence of types II, III, or IV, but generally inconsistent findings; D = little or no systematic empirical evidence. Guideline classification: recommendation = reserved for guidelines based on levels I or II evidence; suggestion = guideline based on levels III, IV, V evidence, implies panel consensus on the interpretation of the evidence; no guideline possible = used with insufficient evidence to base a guideline because 1) little or no evidence on the practice in question or 2) the panel lacks consensus on the interpretation of existing evidence. View Large Table 1. Management guidelines to reduce radiation-induced xerostomia and their level of evidence* Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C * For guideline details, see systematic review by Jensen et al. (8) and the additional systematic reviews on each individual topic. † Quality of recommendations according to the American Society of Clinical Oncology clinical practice guidelines (71, 72). Level of evidence: I = meta-analysis of multiple well-designed studies, high-powered randomized trials; II = at least one well-designed experimental trial, low-powered randomized trials; III = well-designed, quasi-experimental studies (eg, nonrandomized, controlled, single-group, pre–post, cohort); IV = well-designed, nonexperimental studies (eg, comparative and correlational descriptive and case studies); V = case reports and clinical examples. Grade of recommendation: A = evidence of type I or consistent findings of multiple types II, III, or IV; B = evidence of types II, III, or IV with generally consistent findings; C = evidence of types II, III, or IV, but generally inconsistent findings; D = little or no systematic empirical evidence. Guideline classification: recommendation = reserved for guidelines based on levels I or II evidence; suggestion = guideline based on levels III, IV, V evidence, implies panel consensus on the interpretation of the evidence; no guideline possible = used with insufficient evidence to base a guideline because 1) little or no evidence on the practice in question or 2) the panel lacks consensus on the interpretation of existing evidence. View Large Pilocarpine administered before and during radiation therapy (Table 1). Oral pilocarpine administered before and during radiotherapy reduced salivary gland hypofunction and xerostomia without concomitant tumor protection in some studies (85–87), whereas others did not observe statistically significant differences in xerostomia between patients treated with either placebo or oral pilocarpine during radiotherapy (87–93). In line, no statistically significant differences were found with regard to submandibular/sublingual flow rates between patients who had received oral pilocarpine during radiotherapy and a placebo group (87). However, the results of the latter study also showed that the beneficial effect of pilocarpine depended on the radiation dose distribution to the parotid glands and indicated that when the mean cumulative parotid dose exceeds 40 Gy, pilocarpine might spare parotid flow rate and reduce xerostomia; this protection was statistically significant after 12 months (87). However, it has to be emphasized that the latter study was not designed and powered to investigate the beneficial effect of pilocarpine in subsets of patients. The possible protective effect of pilocarpine on salivary gland function has been explained by pilocarpine causing depletion of secretory granules in serous cells, thereby reducing the extent of radiation-induced salivary gland damage (94). Others suggest that pilocarpine has stimulatory actions on minor salivary glands outside the radiation field (85, 95). When pilocarpine was administered before irradiation in rats, it was shown that amelioration of early loss of salivary gland function after radiation was partial because of compensatory mechanisms through increased proliferation of undamaged cells (96, 97). Other preventive agents. Tempol, a stable nitroxide, has been shown to act as a radioprotector in vivo and in vitro and is likely to act by several mechanisms including oxidizing transition metals, mimicking superoxide dismutase activity, and scavenging free radicals (98). In mice, it was shown that tempol can protect salivary glands against radiation damage without protecting tumor tissue (99–102). Furthermore, this protective action was observed both when tempol was administered systemically and as topical oral formulas (100). These various studies support further development and consideration of tempol for human clinical trials as a selective protector against radiation-induced salivary gland damage. These studies are important because it is likely that tempol will be accompanied by fewer side effects than amifostine. Other potential preventive agents that have been studied in animal models include administration of insulin growth factor-1 (IGF-1); keratinocyte growth factor (KGF); adenoviral vector-mediated transfer of complementary DNAs encoding the angiogenic proteins, basic fibroblast growth factor (bFGF) (103); tyrosine kinase inhibitors (104,105); and vascular endothelial growth factor. Intravenous injection of IGF-1 aims to suppress apoptosis because it has been suggested that radiation-induced salivary gland dysfunction in mice results from p53-dependent apoptosis (34,36). In addition to effects on the apoptotic response, IGF-1 has been shown to regulate the cell cycle arrest and DNA repair responses following radiation (106,107). IGF-1-mediated cell cycle arrest uncovered differential phosphorylation of molecules (cdk1) involved in the G2/M phase checkpoint. Utilization of a commercially available cyclin-dependent kinase inhibitor (Roscovitine) resulted in cell cycle arrest and preserved salivary gland function following radiation that was similar to pretreatment with IGF-1 (108). IGF-1 promotion of efficient DNA repair following radiation of this model was mediated in a Sirtuin-1-dependent manner. Subcutaneous administration of KGF in mice was shown to reduce radiation-induced hyposalivation (109). When applied before radiation, KGF induced salivary gland stem/progenitor cell proliferation, resulting in enhanced survival of stem/progenitor cells and acinar cells after radiation. When administered after radiation, KGF seemed to act through accelerated expansion of the pool of progenitor/stem cells that had survived the irradiation treatment (109). Local administration of adenovirus vectors encoding bFGF and vascular endothelial growth factor before irradiation in mice was shown to reduce loss in microvessel density in the submandibular glands and to diminish the decrease in salivary flow rate after radiation (35). Also, percutaneous administration of human recombinant bFGF to the submandibular gland has shown to prevent salivary gland dysfunction after irradiation by inhibition of radiation-induced apoptosis and a paracrine effect in secretory salivary gland tissue (110). Concurrent transient activation of the Wnt/ß-catenin pathway during radiation therapy has also been proposed to prevent radiation-induced salivary gland dysfunction (111), although it is a concern that Wnt/ß-catenin signaling may lead to radioresistance of cancer stem cells (112). Radioresistance of cancer cells is a concern of many of the substances tested to prevent radiation damage as well. It has been reported that preradiation intraglandular administration of botulinum toxin into rat submandibular glands may reduce radiation injury at a glandular level (113). Also, bethanechol was more effective than a placebo in preventing radiation damage to salivary gland tissue (114,115). Novel strategies for radioprotection of the salivary gland that are in preclinical development have focused on inhibition of the pre-apoptotic signaling molecule, protein kinase C delta (PKCdelta) (104). Inhibition of PKCdelta using small interfering RNA (siRNA) targeted to the submandibular gland protects salivary gland function in irradiated mice (38). Based on their ability to inhibit PKCdelta activation, Wie and colleagues (104) have pursued the use of tyrosine kinase inhibitors such as dasatinib and imatinib for radioprotection. Oral delivery of dasatinib or imatinib prior to or immediately after irradiation dramatically suppressed irradiation-induced cell death and preserved salivary gland function in mice. Remarkably, when mice are dosed with tyrosine kinase inhibitors every week after irradiation, salivary gland function was preserved for at least 5 months after irradiation (105). This long-term protection was associated with regeneration of the parotid gland (105). Aldehyde dehydrogenase 3A1 is highly expressed in mouse salivary stem/progenitor cells. Saiki et al. (116) looked for a method to reduce aldehyde accumulation in salivary stem/progenitor cells. D-limonene, a food-flavoring agent, can activate aldehyde dehydrogenase 3A1 and thus reduce aldehyde accumulation in salivary glands and improve salivary gland structure and function in vivo after irradiation. These authors also showed in a phase 0 study in patients with salivary gland tumors that d-limonene is effectively delivered to human salivary glands when given orally. As such, d-limonene may be a good candidate to protect salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for preventing radiation-induced xerostomia. Surgical Transfer of the Submandibular Gland A preventive strategy to reduce radiation-induced salivary gland hypofunction and xerostomia in select patient populations is the surgical transfer of one submandibular gland to the submental space not included in the radiation portal (Table 1) (117–119). A prospective feasibility study with modification of the submandibular gland transfer procedure (ie, the submandibular gland contralateral to the cancer is transferred to the parotid region) has been performed in patients with oral cancer where transfer to the submental space is contraindicated and showed that it was feasible without interfering with the radiation therapy (120). Surgical transfer of one submandibular gland to the submental space has been shown to be superior to the administration of oral pilocarpine in the management of radiation-induced xerostomia (121,122). A pilot study of two-stage autologous transplantation of one submandibular gland to the forearm during radiation therapy and reimplantation of the gland to the floor of the mouth 2–3 months after radiation therapy has also indicated the potential to reduce radiation-induced salivary gland hypofunction and xerostomia (123,124). Clinical Management of Radiation-Induced Salivary Gland Hypofunction and Xerostomia Management of salivary gland hypofunction and xerostomia induced by radiotherapy is primarily palliative by stimulation of residual secretory capacity of the salivary glands or by applied artificial lubrication when saliva secretion cannot be stimulated (Table 1). Pharmacological Sialagogues Randomized, placebo-controlled trials have suggested that approximately 50% of postradiotherapy patients experience improvement of xerostomia from administration of oral pilocarpine. The maximum effect is obtained with continuous treatment for more than 8 weeks with doses higher than 2.5 mg three times a day (125–128). Oral pilocarpine administered after radiation therapy likewise increases whole salivary and parotid flow rates (125–127) and mucous palatal secretion (129). However, in a number of studies, the improvement of xerostomia did not correlate with the increase in salivary secretion (11, 95, 125, 130). This might be attributed to stimulation of the mucous minor salivary glands because they have been shown to have a greater preserved functional capacity and ability to recover after radiation therapy than serous parotid glands (129). The minor salivary glands play a significant role in lubricating the oral mucosa, but contribute by only 10% to the total volume of saliva. Preferential preservation of secretion of the minor glands after radiotherapy vs the major salivary glands is easily overlooked when collecting whole saliva. Mild to moderate side effects are common in relation to administration of pilocarpine, and at a standard dose of 5 mg three times daily these may include sweating, headache, urinary frequency, vasodilatation, dizziness, dyspepsia, lacrimation, and nausea (125, 126, 131, 132). The side effects of pilocarpine are of clinical relevance as the functional gain disappears if the treatment is stopped and the patients therefore need to be treated lifelong (125, 126). Other drugs that have been reported to be of significance in the treatment of radiation-induced salivary gland hypofunction and xerostomia include cevimeline (133) and bethanechol (115, 134). The effect of all these drugs is, however, rather minimal in many patients (10, 11, 67). Acupuncture Stimulation of residual salivary functional capacity by acupuncture may increase whole salivary flow rates and alleviate xerostomia after radiotherapy (135–138). The effects of acupuncture treatment on unstimulated and stimulated whole salivary flow rates and xerostomia have been reported to last up to 6 months, and with additional acupuncture therapy the effect could be sustained for up to 3 years (135). Also, neuronal activity has been associated with acupuncture, which was absent during sham acupuncture stimulation (139). Recently, it was shown that the effect of acupuncture was comparable to that of postradiotherapy administration of pilocarpine (140). However, a recent review indicated that there are considerable heterogeneities in acupuncture treatment protocols for radiation-induced xerostomia, which make it difficult to assess its efficacy and to compare treatments (10, 141, 142). A Cochrane review concluded that, although there was evidence for acupuncture to induce a small increase in saliva production, there is insufficient evidence for any of these therapies to significantly improve xerostomia (70). Gustatory and Masticatory Stimulation Gustatory and masticatory effects on salivary gland hypofunction and xerostomia following radiotherapy have been sporadically addressed. Small studies of sucking on acidic candy and salivary-stimulating lozenges have shown an increase in whole saliva secretion and improvement of oral dryness, respectively (143, 144), whereas an oral antimicrobial lozenge administered to reduce mucositis did not influence xerostomia during radiotherapy (145). Extra-oral Electrostimulation Transcutaneous electrical nerve stimulation (TENS) delivered using an extra-oral device placed externally on the skin overlying the parotid glands during and after radiation therapy has shown the potential to increase whole saliva flow rate (146, 147). Intra-oral Electrostimulation Intra-oral electrical stimulation devices have been designed that deliver a low-intensity electrical current to the oral mucosa to stimulate the afferent neurons of the salivary reflex and efferent neurons (eg, the lingual nerve) as a nonpharmacological approach with no reported adverse effects. Such devices have been tested in the palliation of xerostomia including irradiated head and neck cancer patients, and although the results are promising, further studies are needed (70, 148–150). Hyperbaric Oxygen Alleviation of xerostomia and slightly increased unstimulated and stimulated whole saliva flow rates have been reported in response to hyperbaric oxygen treatment indicating that hyperbaric oxygen may have a beneficial effect on radiation-induced salivary gland damage (151, 152). However, this approach needs further research to investigate the potential biological effects, clinical significance, and the longevity of efficacy (153, 154). Oral Mucosal Lubricants/Saliva Substitutes Oral mucosal lubricants/saliva substitutes are mainly useful in patients who do not respond to pharmacological, gustatory, or masticatory stimulation. Various saliva substitutes with constituents resembling the physical properties of glycoproteins and antibacterial components of saliva have been developed and are commercially available in the form of moisturizing gels, mouthwashes, or sprays. These formulas may be based on, for example, animal mucin, carboxymethylcellulose (CMC), hydroxypropylmethylcellulose, hydroxyethylcellulose, polyglycerylmethacrylate, polyethylene oxide, xanthan gum, linseed extract, rape seed oil, and aloe vera. Mucin-containing saliva substitutes are usually preferred over CMC-containing and placebo substitutes (2, 155–158). Furthermore, CMC gel has been found to be slightly inferior to polyglycerylmethacrylate gel (159, 160), polyethylene oxide (161), and linseed fluid (162) in reducing xerostomia, whereas CMC spray was found to be equally effective to mucin (extracted from pig stomach) spray, aloe vera gel, and rape seed oil spray (163). Also a combination of saliva substitutes might be helpful (164). However, the various saliva substitutes have generally been sporadically tested, often for a short period of use and in small numbers of patients. The major disadvantage of saliva substitutes is the short duration of relief they provide and thus patients may instead prefer frequent use of water (161, 165). Finally, it has been shown that patients have to be encouraged to try various saliva substitutes as one substitute might be of most benefit to one patient and another type of substitute to another patient (166, 167). The recommendations given below can be used as a guideline for proper selection and use of a saliva substitute: If severe xerostomia, the application of a saliva substitute with gel-like properties may provide relief during the night and when daily activities are at a low level. During daytime, a saliva substitute with less viscous properties resembling natural saliva based on, for instance, polyacrylic acid, xanthan gum, mucin, betaine, allantoin, and aloe vera, may provide relief (168). If moderate xerostomia, saliva substitutes with a rather low viscoelasticity, such as substitutes based on CMC, hydroxypropylmethylcellulose, mucin, or low concentrations of xanthan gum and polyacrylic acid, are indicated, supplemented by a gel to provide relief during night or other periods of severe oral dryness (168). At slight xerostomia, little alleviation is to be expected from the use of saliva substitutes (168). Potential Restoration of Salivary Gland Function following Radiation Injury Currently, there is no clinical treatment option for restoration of salivary gland function lost due to irradiation. However, promising approaches, such as gene therapy, stem cell transfer, and pharmacologic agents, are aimed at regaining function after radiotherapy. Gene Therapy Few acinar cells survive radiation, leaving the salivary gland tissue with little residual capacity for primary fluid secretion; however, salivary duct cells are much less affected after irradiation. Intact salivary duct cells are considered relatively water-impermeable because they lack water channels in the plasma membranes. The therapeutic rationale of gene therapy for functional recovery of radiation-induced damaged salivary gland tissue is based on a possible insertion of a pathway for water transport in the surviving ductal cell membranes to elicit water secretion (169). The water channel protein, human aquaporin-1 (hAQP1), can facilitate rapid movement of water in response to an osmotic gradient and is expressed all around a cell’s plasma membrane, which ensures that there is a facilitated pathway for water to move from the basal side of the cell, adjacent to the bloodstream, into the duct cell, and thereafter into the lumen. Importantly, expression of hAQP1 protein in cell types in which it is not normally found can lead to dramatic increases in osmotically obliged water movement (169, 170). In vivo studies in animal models have used a recombinant serotype 5 adenoviral vector-encoding hAQP1, AdhAQP1, which is delivered to salivary glands via intraductal cannulation through the orifice of the main excretory duct. These studies have shown salivary flow rates in the AdhAQP1-dosed rat approaching those of sham-irradiated rats treated with the control virus (ie, near normal) (169). Similarly, after an initial decrease of saliva secretion to less than 20% of baseline in the miniature pig post-irradiation, administration of AdhAQP1 resulted in a transient (∼2–4 weeks) dose-dependent increase in parotid salivary flow rate to about 80% of preradiation levels (171). Because the hAQP1 transgene in the latter study was expressed only in parotid duct cells, the implication is that the increased salivary secretion observed was due to enhanced water permeability in the normally water-impermeable duct cells (171). A serotype 2 adeno-associated viral vector administered in the miniature pig has been demonstrated to mediate extended gene transfer to the parotid glands (peak salivary flow rates between weeks 6–10) (172). Recently, it was shown that administration of a neurturin-expressing adenovirus before irradiation even might prevent irradiation-induced salivary gland hypofunction after radiotherapy (173). A phase I study has been completed in which the efficacy and safety of gene transfer in 11 humans with parotid gland hypofunction was tested (174, 175). All patients tolerated vector (AdHAQP1) delivery and study procedures well. No serious adverse events or dose-limiting toxicities occurred. An objective positive response was observed in six participants; none of these participants had received the highest dose. Five of them also experienced subjective improvement in xerostomia. Four of five nonresponders did not perceive amelioration or worsening of their oral dryness. AdhAQP1 uses the human cytomegalovirus promoter (176). As participant peak responses were at times much longer (7–42 days) than expected, it was assumed that human cytomegalovirus promoter may not be methylated in human salivary gland cells to the extent previously observed in rodent salivary gland cells. Thus, hAQP1 was probably not methylated in transduced human salivary gland cells of responding participants, resulting in an unexpectedly longer functional expression of hAQP1. Late effects of AdhAQP1 administration have been evaluated in five participants who were identified as responding positively to the gene transfer out of 11 participants in a previous phase I study on efficacy and safety (175, 177). All participants had marked increases in parotid flow rate 3–4.7 years after treatment and with improved symptoms for approximately 2–3 years (177). However, it is yet unknown how long the increase in salivary flow rate can last in humans. Stem Cell Therapy Lack of replacement of differentiated functional cells in salivary glands after radiotherapy may be due to the unresponsiveness of endogenous progenitor and/or stem cells in the gland tissue, hence, handicapping the capacity for natural regeneration (24, 109, 178). These stem cells are proposed to be localized in the parotid gland region excretory ducts, an area that, when irradiated, results in the loss of saliva secretion (46). Stem cell transfer could be able to restore tissue homeostasis after irradiation by increasing the regenerative potential of salivary glands (179). Furthermore, the salivary duct compartment, which remains relatively intact after irradiation, could serve as a natural engraftment place for the transplanted cells. Along this line, a population of c-Kit+ cells with the capability to regenerate and partially restore function to radiation-induced damaged salivary glands of rodents has been cultured. In vitro, salispheres can be grown from these c-Kit+ stem cells, and cells from these salispheres were shown also to express many other stem cell markers [eg, Sca-1, c-Kit, Musashi-1, CD49f, and CD133 (180, 181)] and were able to differentiate into all salivary gland lineages (181). Moreover, these cells were able to self-renew in vitro for many generations (>48 weeks) and in vivo (44, 180, 182). After stem cell enrichment by flow cytometric selection using c-Kit as a single marker, c-Kit+ cells were able to regenerate and significantly improve submandibular gland function. As few as 100 c-Kit+ cells obtained from irradiated primary recipients were shown to improve salivary gland function and restore morphology in irradiated secondary recipients 3 months after transplantation (44). Also, salispheres cultured from human parotid and submandibular glands have been shown to contain c-Kit+ cells with self-renewal and differentiation capacities in vitro (44, 183, 184). Clinical trials to assess whether salivary gland stem cell transplantation is feasible in humans are in progress, and phase I–II trials are commencing testing stem cells harvested from different tissues (eg, salivary gland stem cells and adipose-derived mesenchymal stem cells) (185–187). Pharmacological Approaches to Restoration Pharmacological methods based on improving salivary gland output following radiation are largely in the preclinical stage. Morgan-Bathke et al. (188) reported that utilization of the rapalogue CCI-779 following radiation led to increased salivary function and decreased compensatory proliferation in a mouse model (188). CCI-779 (temsirolimus) is an allosteric inhibitor of the mammalian target of rapamycin complex 1 resulting in the inability of mTOR to bind to FKBP12, thereby inhibiting downstream signaling. Depending on cellular context, treatment with CCI-779 induces autophagy, inhibits protein synthesis, promotes immunosuppression, and/or inhibits cell-cycle progression (189). A clinical trial to evaluate the restorative effects of rapalogues is currently being designed. Reactivation of development pathways has also been proposed as a potential mechanism to reverse radiation-induced salivary gland hypofunction. Hill et al. (190) used a monoclonal antibody against the ectodysplasin receptor to activate this critical developmental pathway in adult mice that had been treated with radiation 4 days prior. Treatment with monoclonal antibody against the ectodysplasin receptor completely restored salivary flow rates and amylase secretion to unirradiated levels within 30 days of radiotherapy (190). Strategies to Promote Development and Funding for New Research Since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies, significant progress has been made in our ability to spare salivary gland function chiefly because of advances in radiation techniques, including the optimizing of 3-D treatment planning, conformal radiation techniques, and IMRT. Other strategies have also been developed, for example, radioprotectors such as tempol and identification and preservation and/or expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, as well as the application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. IMRT, and its next step, proton therapy, still have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients. Nonetheless, many of these advances still only offer partial protection against salivary gland damage because of the fact that they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects, emphasizing the need for therapies aimed at regaining function and/or regeneration of radiation-damaged salivary gland tissue. Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for functional recovery and regeneration of salivary gland function after radiotherapy. Although for some studies, such as those aimed at selecting the most effective method to alleviate the problems of radiation damage to salivary glands, a sufficiently large patient cohort often can be selected within the researcher’s own institution, a multidisciplinary and often multi-institutional approach is needed for studies aimed at either the prevention of radiation injury to salivary gland tissue or the restoration of radiation-damaged salivary gland tissue. The development and testing of strategies for gene transfer and stem cell research to restore radiation-induced functional loss of the salivary glands may also require collaboration of researchers from diverse research backgrounds. Furthermore, a lot of work, including transfer of a preclinical protocol to good medical practice, has to be done to bring gene transfer and stem cell therapy from a laboratory bench to the clinic (174). Such research efforts are very costly and need the involvement of researchers that have access to national and international scientific societies (eg, European Organisation for Research and Treatment of Cancer Head and Neck Cancer Group, European Society for Therapeutic Radiation Oncology, International Society for Stem Cell Research, Stem Cells in Development and Disease, and Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology). Such researchers have access to a network that will allow them to successfully compete for multinational translational grants from, for instance, the NIH and the European Framework Programs. Moreover, the interest of governmental, public, and private funding organizations and among researchers with an interest in healthy aging is growing, and research aimed at prevention and reduction of the morbidity of cancer treatment well fits within these programs. Funding Funding for writing this consensus report has been made available from the authors’ institutions. Notes Affiliations of authors: Department of Dentistry and Oral Health, Faculty of Health, Aarhus University, Aarhus, Denmark (SBJ); Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center, Groningen, The Netherlands (AV); Department of Nutritional Sciences, University of Arizona, Tucson, AZ (KHL); Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO (MER). The authors declare that they have no conflict of interest. A thankful acknowledgement is made to Bruce J. Baum for helpful comments to the manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Langendijk JA , Doornaert P , Verdonck-de Leeuw IM , Leemans CR , Aaronson NK , Slotman BJ. 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
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10.1093/jncimonographs/lgz016
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Abstract

Abstract Background The most manifest long-term consequences of radiation therapy in the head and neck cancer patient are salivary gland hypofunction and a sensation of oral dryness (xerostomia). Methods This critical review addresses the consequences of radiation injury to salivary gland tissue, the clinical management of salivary gland hypofunction and xerostomia, and current and potential strategies to prevent or reduce radiation injury to salivary gland tissue or restore the function of radiation-injured salivary gland tissue. Results Salivary gland hypofunction and xerostomia have severe implications for oral functioning, maintenance of oral and general health, and quality of life. Significant progress has been made to spare salivary gland function chiefly due to advances in radiation techniques. Other strategies have also been developed, e.g., radioprotectors, identification and preservation/expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, and application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. Conclusion Many advances to manage salivary gland hypofunction and xerostomia induced by radiation therapy still only offer partial protection since they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects. Intensity-modulated radiation therapy (IMRT), and its next step, proton therapy, have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients. Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for regaining function and/or regeneration of radiation-damaged salivary gland tissue. It is well documented that head and neck radiotherapy, in addition to its antitumor effects, inevitably induces severe adverse effects to normal oral tissues surrounding the tumor tissue. Adverse effects include mucositis, pain, salivary gland hypofunction (objectively decreased saliva secretion), and xerostomia (subjective feeling of dry mouth), fungal infection, taste disturbances and muscular fibrosis. Depending on the cumulative radiation dose to the gland tissue, permanent salivary gland hypofunction may occur, impeding oral functioning, compromising oral and general health, and diminishing the quality of life following radiation therapy in head and neck cancer patients (1–4). In addition, the head and neck cancer patient may also experience a heavy economic burden due to the extensive need for oral preventive measures and dental treatment after radiation therapy. It should be noted that salivary gland hypofunction and xerostomia may also be sequelae of other radiation regimes, although to a much lesser extent, that is, radioiodine treatment of thyroid cancer and preconditioning total body irradiation in hematopoietic stem cell transplantation for the treatment of hematologic malignancies (4–6). The National Institutes of Health (NIH) Consensus Conference In 1989, the NIH sponsored the first Development Consensus Conference on Oral Complications of Cancer Therapies (7). No well-defined treatment strategies to prevent or minimize xerostomia were available at that time. A general consensus from this conference was the need to establish baseline data for salivary gland hypofunction and xerostomia, to which all subsequent examinations could be compared, and to identify risk factors for the development of oral complications. With regard to management strategies, the consensus was that volumetric assessment of resting and stimulated whole saliva should be performed before cancer therapy to identify these risk factors. In addition, recommendations for management of chronic xerostomia were given, including regular use of topical fluorides, attention to oral hygiene, and use of sialagogues. Even more importantly, the 1989 NIH conference identified directions for future research applicable to salivary gland hypofunction and xerostomia, that is, 1) to devise accurate, quantifiable, reproducible criteria for assessing and classifying oral complications of cancer therapy; 2) to determine incidence and prevalence of oral complications related to different types of cancer therapies and related risk factors; 3) to study the mechanisms of cancer treatment injury to the hard and soft oral tissues at the molecular and cellular level and to determine how these affect the oral environment; 4) to develop radioprotective and chemoprotective agents; and 5) to develop more effective sialagogues and saliva substitutes and to evaluate their effectiveness in preventing the complications of xerostomia. As two decades had passed since the abovementioned conference, in 2009 the NIH held a second conference to update the community regarding current strategies and future research directions related to oral complications of emerging cancer therapies. Part of this conference was to critically review the long-term consequences of head neck radiotherapy for salivary gland hypofunction and xerostomia. The consensus reported in this paper is a compilation of recommendations from the 2009 conference, updated to 2019, and more recent systematic reviews of the literature providing prevalence, impact on quality of life, and management strategies of salivary gland hypofunction and xerostomia induced by cancer therapies (4, 8–13). Three key research questions were addressed: Can radiation injury of salivary gland tissue be prevented? If radiation injury of salivary gland tissue has occurred, what is then the most effective method to alleviate the resulting problems? Can radiation damage of salivary gland tissue be restored? Pathobiology: Current Paradigm and New Frontiers Saliva plays an essential role in maintenance of tooth integrity, in the protection of mucosal surfaces, and in dilution and mechanical cleansing of food detritus. Radiation-induced salivary gland hypofunction can have a profound impact on oral functions and tissues, resulting in persistent xerostomia, dry and fragile oral mucosa, oral mucosal discomfort and pain, and hampered speech. Saliva also has a crucial role in the upper gastrointestinal functions including taste perception, formation and translocation of a food bolus, facilitation of mastication, swallowing, and speech, as well as lubrication of oropharyngeal and esophageal mucosa (14–16). Finally, saliva provides antimicrobial activity to prevent oral infections, such as candidiasis, and patients with salivary gland hypofunction are prone to carious destruction of teeth or tooth loss, resulting in increased risk of osteoradionecrosis of the jaw (14, 17–19). As a consequence of the adverse effects directly related to salivary gland hypofunction, the quality of life following radiation therapy for the head and neck cancer patient may severely deteriorate, characterized by restriction of daily activities, a poorer general health, social disabilities, and malnutrition (1–4, 13, 20). The impact of the adverse effects of radiation-induced hyposalivation on quality of life is lifelong. In radiation treatment for head and neck cancer, the major and minor salivary glands are often included within the radiation portal because of the site and extension of primary tumors and the path of lymphatic spread, which is in close proximity to the salivary glands (17, 21, 22). Tumor cells are actively dividing and, consequently, their DNA is highly sensitive to radiation damage, rendering cells incapable of proper cell division, and resulting in cell death or senescence of cells that attempt to divide. In contrast, salivary glands are highly specialized organs comprised of well-differentiated cells that have a relatively low mitotic index. Differentiated salivary acinar cells have a mean life span of more than 3 months, however, the origin of replacement and regeneration of acinar cells remains unclear. It has been proposed that differentiated salivary acinar cells may be able to divide in response to damage through a process known as “self-duplication”, a slowly cycling stem cell population, or that multiple cell types might have regenerative potential for restoring salivary gland function (23–27). Based on the slow turnover rate of their cells, the salivary glands are expected to be relatively radioresistant. However, changes in the amount and composition of saliva that occur early after irradiation suggest that the salivary gland is actually an acutely responding tissue (12, 28–30). Radiation exposure of salivary glands located within the treatment portal results in a dramatic loss of gland function within the first week of treatment with a continuous decrease in salivary flow rate throughout the course of therapy to barely measurable flow rates (Figure 1). Following high-dose radiotherapy [the critical dose limit for parotid and submandibular salivary gland tissue is just less than 40 Gy (31, 32), and most radiation regimens exceed this limit], a second phase of functional deterioration in secretion may be noted up to several months after completion of radiation therapy and is concomitant with progressive, irreversible changes of the salivary gland tissue with no significant recovery in gland function (4, 28, 33). Irradiation leads to the loss of saliva-producing acinar cells and impairment of duct function, although morphologically the duct tissue mostly remains intact (23, 24). However, it is not clear whether acute salivary gland hypofunction is caused by the direct effects of radiation on the secretory acini and ductal cells, or if it is secondary to injury of the vascular structures, which results in increased capillary permeability, loss of the capillary bed and fibrosis of arteries and veins, interstitial edema, and inflammatory infiltration (34, 35). Figure 1. View largeDownload slide Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy. Tx treatment, RT radiotherapy, Mo. months, Yrs. years, Unstim. unstimulated, Stim. stimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010.Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy (RT). Stim. = stimulated; Unstim. = unstimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010. Figure 1. View largeDownload slide Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy. Tx treatment, RT radiotherapy, Mo. months, Yrs. years, Unstim. unstimulated, Stim. stimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010.Pooled and weighted data of unstimulated and stimulated whole saliva flow rate changes during and after head and neck radiotherapy (RT). Stim. = stimulated; Unstim. = unstimulated. Modified with permission from Springer Science+Business Media (4): Figure 3, ©Springer-Verlag 2010. Several mechanisms have been suggested for explaining the high radiation sensitivity of salivary gland cells. The acute functional impairment may be selective radiation damage to the plasma membrane of the secretory cells resulting in disruption of muscarinic receptor-stimulated water secretion. It has also been suggested that the acute dysfunction of the salivary glands may be caused by radiation-induced apoptosis of the serous acinar cells, because genetically engineered mouse models with alterations in key components of the apoptotic pathway do not exhibit salivary gland hypofunction following radiation (36–38). Although saliva flow rate is significantly reduced and water secretion is selectively hampered, some studies have shown no reduction in number of acinar cells early after radiotherapy (39–41). Therefore, the role of apoptotic cell death and its subsequent downstream signaling effects in acute salivary gland dysfunction after radiation therapy is still under debate (12, 24, 42). The severity of glandular damage and potential for recovery is dependent on the irradiated gland volume, the cumulative radiation dose, and the ability of surviving cells to repopulate (24). The later salivary gland damage is currently suggested to be due to radiation-induced loss of acinar cells, together with impaired parasympathetic innervation and injury to vascular structures (35, 43–45). Thus, the remaining intact salivary gland stem cells and/or progenitor cells could determine the regenerative capacity of the salivary gland after radiation therapy. It has been shown in humans that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicts the function of the salivary glands postradiotherapy (46). A low dose to a region postulated to be rich in salivary stem cells can even result in a hyper-radiosensitivity, which is followed by relative radioresistance at higher radiation doses (47). Both observations might have implications for radiotherapy treatment planning (47). As discussed above, the irradiated patient is predisposed to a variety of morbidities that develop either directly or as an indirect result of decreased salivary flow rate (insufficient oral clearance and lubrication) and negative salivary compositional changes (reduced buffer capacity, pH, immunoglobulin, and antimicrobial proteins) (16, 17, 48). Clinical Management: Successes and Barriers Prevention of Radiation Injury to Salivary Gland Tissue Radiation Techniques Intensity-modulated radiation therapy (IMRT) is an improvement over traditional radiotherapy that allows more accurate delivery of specific radiation dosage and dose distribution to the tumor, enabling better sparing of surrounding normal tissues (eg, major salivary glands) and has the potential to minimize the severity of salivary gland hypofunction and xerostomia (12, 49–51). After an initial decrease in saliva secretion 1–3 months after IMRT, salivary secretion from spared salivary glands (ie, those parts of the salivary glands that have been irradiated with a cumulative dose below the threshold dose for irreversible damage; see below) has the potential to gradually recover over time (1–2 years) (Figure 2) (4). Figure 2. View largeDownload slide Flow rate of 2% citric acid-stimulated parotid (single gland) and bilateral submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (RT) (Conventional RT; both parotid, submandibular and sublingual glands located in the treatment portal, 2 Gy per day, 5 days per week, total dose 60–70 Gy. Parotid-sparing three-dimensional/intensity-modulated RT [IMRT]; bilateral [the majority] and unilateral RT [scattered radiation to contralateral gland]. For parotid IMRT data: 1.8–2.0 Gy per fraction, prescribed dose to primary target 64 Gy [range = 57.6–72 Gy], and for SM/SL IMRT data: 2 Gy per day, 70 Gy to gross disease planning target volume). Initial flow rates are set to 100% [modified after Burlage et al. (28) for conventional RT, Eisbruch et al. (52) for parotid glands IMRT, and Murdoch-Kinch et al. (31) for SM/SL glands IMRT]. Modified with permission from Elsevier (9). Figure 2. View largeDownload slide Flow rate of 2% citric acid-stimulated parotid (single gland) and bilateral submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (RT) (Conventional RT; both parotid, submandibular and sublingual glands located in the treatment portal, 2 Gy per day, 5 days per week, total dose 60–70 Gy. Parotid-sparing three-dimensional/intensity-modulated RT [IMRT]; bilateral [the majority] and unilateral RT [scattered radiation to contralateral gland]. For parotid IMRT data: 1.8–2.0 Gy per fraction, prescribed dose to primary target 64 Gy [range = 57.6–72 Gy], and for SM/SL IMRT data: 2 Gy per day, 70 Gy to gross disease planning target volume). Initial flow rates are set to 100% [modified after Burlage et al. (28) for conventional RT, Eisbruch et al. (52) for parotid glands IMRT, and Murdoch-Kinch et al. (31) for SM/SL glands IMRT]. Modified with permission from Elsevier (9). In contrast, a fractionated schedule of conventional radiotherapy results in major parts of the salivary glands being irradiated with cumulative doses above the threshold and consequently no recovery after radiotherapy (Figure 2) (4). As such, the benefits from IMRT on salivary gland function, xerostomia, and xerostomia-related quality of life are most pronounced late (≥6 months) after radiotherapy (4, 53, 54). A cumulative mean dose to the parotid gland around 39 Gy has been found to cause a clinically and statistically significant reduction in parotid flow rate (32), and a comparable cumulative mean dose of 39 Gy has been found to result in a clinically and statistically significant reduction in flow rate for the submandibular and sublingual glands (31). These calculations have been made with the assumption that the cumulative radiation dose on the gland can be averaged and disregards the possibility of regional differences in sensitivity, in particular, the areas within a salivary gland where the stem cells potentially reside (55). The regional differences identified by van Luijk and colleagues (46) suggest a need for reassessment of the 39 Gy limit to determine whether a significant loss of salivary gland function will occur or not. Nevertheless, incomplete improvement in xerostomia by sparing of the parotid gland via IMRT emphasizes the need to enhance protection of the submandibular glands, because these glands, together with the sublingual and minor salivary glands, are the greatest contributors to whole saliva during rest (4). Further improvement of salivary gland tissue sparing could be achieved by new radiation techniques using protons. The physical and radiobiological properties of protons allow a superior dose distribution because of a more targeted location of the maximum deposited energy dose (12, 51, 56). In contrast, current photon (x-ray) radiotherapy deposits the largest amount of energy dose to the first point of entry into the biological matter, where after the energy deposited, decreases slowly resulting in a large affected area. Comparative studies have shown a potential benefit of protons compared to photons as a result of minimizing the dose to normal tissues (57, 58), particularly in the treatment of tumors localized in the pharynx (59, 60), the paranasal sinuses (61, 62), and in head and neck cancer patients treated with bilateral neck irradiation (58, 63–65). Radioprotectors Amifostine. Amifostine (Table 1), a radical scavenger, accumulates with high concentrations in the salivary glands. It provides direct radioprotection when systemically administered during radiotherapy (73–75). Amifostine has been reported to reduce xerostomia during and post radiotherapy, although the benefit may be clinically minor (11, 76, 77). Many studies showed a beneficial effect of the use of amifostine on xerostomia, although most studies failed to show that amifostine treatment resulted in preserved salivary flow rate in response to radiotherapy (11, 73, 78, 79). Furthermore, when administered intravenously, amifostine is accompanied by severe adverse effects (eg, hypotension, nausea, vomiting, allergic reaction). However, when administered subcutaneously, amifostine appears to be better tolerated (80). Recently, in an animal model, it was shown that localized administration of amifostine to the salivary glands by retroductal delivery might result in better preservation of salivary gland function than with systemic administration of this drug thereby reducing hypotension (81). While there is no overall difference in nausea and/or vomiting or patient compliance with subcutaneous compared to intravenous administration, a lower prevalence of grade 1–2 hypotension and higher rates of skin rash and pain at injection sites with subcutaneous administration have been reported (82). Although better tolerated, in the latter study the incidence of grade 2 or greater xerostomia was significantly higher for patients who received amifostine via subcutaneous administration. Finally, there is still concern that amifostine might have an undesirable effect of tumor protection, raising questions about the appropriateness of amifostine in cancer patients (75, 83). However, a meta-analysis of updated survival data and a median follow-up of 5.2 years from individual patients treated with radiotherapy or chemoradiotherapy did not show a detectable impact on overall survival with the use of concurrent amifostine (84). Table 1. Management guidelines to reduce radiation-induced xerostomia and their level of evidence* Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C * For guideline details, see systematic review by Jensen et al. (8) and the additional systematic reviews on each individual topic. † Quality of recommendations according to the American Society of Clinical Oncology clinical practice guidelines (71, 72). Level of evidence: I = meta-analysis of multiple well-designed studies, high-powered randomized trials; II = at least one well-designed experimental trial, low-powered randomized trials; III = well-designed, quasi-experimental studies (eg, nonrandomized, controlled, single-group, pre–post, cohort); IV = well-designed, nonexperimental studies (eg, comparative and correlational descriptive and case studies); V = case reports and clinical examples. Grade of recommendation: A = evidence of type I or consistent findings of multiple types II, III, or IV; B = evidence of types II, III, or IV with generally consistent findings; C = evidence of types II, III, or IV, but generally inconsistent findings; D = little or no systematic empirical evidence. Guideline classification: recommendation = reserved for guidelines based on levels I or II evidence; suggestion = guideline based on levels III, IV, V evidence, implies panel consensus on the interpretation of the evidence; no guideline possible = used with insufficient evidence to base a guideline because 1) little or no evidence on the practice in question or 2) the panel lacks consensus on the interpretation of existing evidence. View Large Table 1. Management guidelines to reduce radiation-induced xerostomia and their level of evidence* Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C Treatment approach Guideline Level of evidence, grade of recommendation† Radical scavenger Amifostine (8, 66) Phase III trials have shown that amifostine might reduce xerostomia after radiotherapy. However, no guidelines are possible because of lack of consensus on interpretation of existing evidence. Most studies did not have the statistical power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most studies was at least questionable and the outcomes subject to debate. The majority of the trials lacked a placebo in the control arms. Level II, grade C Muscarinic agonist stimulation During radiotherapy (8) Use of pilocarpine cannot be recommended for improvement of xerostomia because the results of the randomized clinical trials were not univocal. Moreover, improvement of salivary gland hypofunction was limited. The dissimilar results on sparing of the salivary gland function are probably a result of the wide range of cumulative doses applied. The only trial providing an analysis of sparing of parotid gland function related to mean parotid dose indicated significant sparing of parotid gland function and reduced xerostomia for mean parotid doses exceeding 40 Gy (40). Level II, grade C After radiotherapy (8, 11, 67) The use of pilocarpine after radiotherapy can be recommended for improvement of xerostomia. Level II, grade B Mucosal lubricants and saliva substitutes (8, 68) The use of oral mucosal lubricants and saliva substitutes for short-term improvement of xerostomia after radiotherapy can be recommended. Level II, grade B Gustatory and masticatory stimulation (8, 68) No guideline possible because of little evidence on which to base a guideline for patients suffering from xerostomia induced by radiotherapy. Level III, grade D Surgical transfer of submandibular gland (8, 69) The obtained level of gland sparing might be of clinical significance. Level IV, grade B Acupuncture (8, 70) The use of acupuncture to stimulate salivary gland secretion and to alleviate xerostomia can be suggested to the patient. Level II, grade C * For guideline details, see systematic review by Jensen et al. (8) and the additional systematic reviews on each individual topic. † Quality of recommendations according to the American Society of Clinical Oncology clinical practice guidelines (71, 72). Level of evidence: I = meta-analysis of multiple well-designed studies, high-powered randomized trials; II = at least one well-designed experimental trial, low-powered randomized trials; III = well-designed, quasi-experimental studies (eg, nonrandomized, controlled, single-group, pre–post, cohort); IV = well-designed, nonexperimental studies (eg, comparative and correlational descriptive and case studies); V = case reports and clinical examples. Grade of recommendation: A = evidence of type I or consistent findings of multiple types II, III, or IV; B = evidence of types II, III, or IV with generally consistent findings; C = evidence of types II, III, or IV, but generally inconsistent findings; D = little or no systematic empirical evidence. Guideline classification: recommendation = reserved for guidelines based on levels I or II evidence; suggestion = guideline based on levels III, IV, V evidence, implies panel consensus on the interpretation of the evidence; no guideline possible = used with insufficient evidence to base a guideline because 1) little or no evidence on the practice in question or 2) the panel lacks consensus on the interpretation of existing evidence. View Large Pilocarpine administered before and during radiation therapy (Table 1). Oral pilocarpine administered before and during radiotherapy reduced salivary gland hypofunction and xerostomia without concomitant tumor protection in some studies (85–87), whereas others did not observe statistically significant differences in xerostomia between patients treated with either placebo or oral pilocarpine during radiotherapy (87–93). In line, no statistically significant differences were found with regard to submandibular/sublingual flow rates between patients who had received oral pilocarpine during radiotherapy and a placebo group (87). However, the results of the latter study also showed that the beneficial effect of pilocarpine depended on the radiation dose distribution to the parotid glands and indicated that when the mean cumulative parotid dose exceeds 40 Gy, pilocarpine might spare parotid flow rate and reduce xerostomia; this protection was statistically significant after 12 months (87). However, it has to be emphasized that the latter study was not designed and powered to investigate the beneficial effect of pilocarpine in subsets of patients. The possible protective effect of pilocarpine on salivary gland function has been explained by pilocarpine causing depletion of secretory granules in serous cells, thereby reducing the extent of radiation-induced salivary gland damage (94). Others suggest that pilocarpine has stimulatory actions on minor salivary glands outside the radiation field (85, 95). When pilocarpine was administered before irradiation in rats, it was shown that amelioration of early loss of salivary gland function after radiation was partial because of compensatory mechanisms through increased proliferation of undamaged cells (96, 97). Other preventive agents. Tempol, a stable nitroxide, has been shown to act as a radioprotector in vivo and in vitro and is likely to act by several mechanisms including oxidizing transition metals, mimicking superoxide dismutase activity, and scavenging free radicals (98). In mice, it was shown that tempol can protect salivary glands against radiation damage without protecting tumor tissue (99–102). Furthermore, this protective action was observed both when tempol was administered systemically and as topical oral formulas (100). These various studies support further development and consideration of tempol for human clinical trials as a selective protector against radiation-induced salivary gland damage. These studies are important because it is likely that tempol will be accompanied by fewer side effects than amifostine. Other potential preventive agents that have been studied in animal models include administration of insulin growth factor-1 (IGF-1); keratinocyte growth factor (KGF); adenoviral vector-mediated transfer of complementary DNAs encoding the angiogenic proteins, basic fibroblast growth factor (bFGF) (103); tyrosine kinase inhibitors (104,105); and vascular endothelial growth factor. Intravenous injection of IGF-1 aims to suppress apoptosis because it has been suggested that radiation-induced salivary gland dysfunction in mice results from p53-dependent apoptosis (34,36). In addition to effects on the apoptotic response, IGF-1 has been shown to regulate the cell cycle arrest and DNA repair responses following radiation (106,107). IGF-1-mediated cell cycle arrest uncovered differential phosphorylation of molecules (cdk1) involved in the G2/M phase checkpoint. Utilization of a commercially available cyclin-dependent kinase inhibitor (Roscovitine) resulted in cell cycle arrest and preserved salivary gland function following radiation that was similar to pretreatment with IGF-1 (108). IGF-1 promotion of efficient DNA repair following radiation of this model was mediated in a Sirtuin-1-dependent manner. Subcutaneous administration of KGF in mice was shown to reduce radiation-induced hyposalivation (109). When applied before radiation, KGF induced salivary gland stem/progenitor cell proliferation, resulting in enhanced survival of stem/progenitor cells and acinar cells after radiation. When administered after radiation, KGF seemed to act through accelerated expansion of the pool of progenitor/stem cells that had survived the irradiation treatment (109). Local administration of adenovirus vectors encoding bFGF and vascular endothelial growth factor before irradiation in mice was shown to reduce loss in microvessel density in the submandibular glands and to diminish the decrease in salivary flow rate after radiation (35). Also, percutaneous administration of human recombinant bFGF to the submandibular gland has shown to prevent salivary gland dysfunction after irradiation by inhibition of radiation-induced apoptosis and a paracrine effect in secretory salivary gland tissue (110). Concurrent transient activation of the Wnt/ß-catenin pathway during radiation therapy has also been proposed to prevent radiation-induced salivary gland dysfunction (111), although it is a concern that Wnt/ß-catenin signaling may lead to radioresistance of cancer stem cells (112). Radioresistance of cancer cells is a concern of many of the substances tested to prevent radiation damage as well. It has been reported that preradiation intraglandular administration of botulinum toxin into rat submandibular glands may reduce radiation injury at a glandular level (113). Also, bethanechol was more effective than a placebo in preventing radiation damage to salivary gland tissue (114,115). Novel strategies for radioprotection of the salivary gland that are in preclinical development have focused on inhibition of the pre-apoptotic signaling molecule, protein kinase C delta (PKCdelta) (104). Inhibition of PKCdelta using small interfering RNA (siRNA) targeted to the submandibular gland protects salivary gland function in irradiated mice (38). Based on their ability to inhibit PKCdelta activation, Wie and colleagues (104) have pursued the use of tyrosine kinase inhibitors such as dasatinib and imatinib for radioprotection. Oral delivery of dasatinib or imatinib prior to or immediately after irradiation dramatically suppressed irradiation-induced cell death and preserved salivary gland function in mice. Remarkably, when mice are dosed with tyrosine kinase inhibitors every week after irradiation, salivary gland function was preserved for at least 5 months after irradiation (105). This long-term protection was associated with regeneration of the parotid gland (105). Aldehyde dehydrogenase 3A1 is highly expressed in mouse salivary stem/progenitor cells. Saiki et al. (116) looked for a method to reduce aldehyde accumulation in salivary stem/progenitor cells. D-limonene, a food-flavoring agent, can activate aldehyde dehydrogenase 3A1 and thus reduce aldehyde accumulation in salivary glands and improve salivary gland structure and function in vivo after irradiation. These authors also showed in a phase 0 study in patients with salivary gland tumors that d-limonene is effectively delivered to human salivary glands when given orally. As such, d-limonene may be a good candidate to protect salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for preventing radiation-induced xerostomia. Surgical Transfer of the Submandibular Gland A preventive strategy to reduce radiation-induced salivary gland hypofunction and xerostomia in select patient populations is the surgical transfer of one submandibular gland to the submental space not included in the radiation portal (Table 1) (117–119). A prospective feasibility study with modification of the submandibular gland transfer procedure (ie, the submandibular gland contralateral to the cancer is transferred to the parotid region) has been performed in patients with oral cancer where transfer to the submental space is contraindicated and showed that it was feasible without interfering with the radiation therapy (120). Surgical transfer of one submandibular gland to the submental space has been shown to be superior to the administration of oral pilocarpine in the management of radiation-induced xerostomia (121,122). A pilot study of two-stage autologous transplantation of one submandibular gland to the forearm during radiation therapy and reimplantation of the gland to the floor of the mouth 2–3 months after radiation therapy has also indicated the potential to reduce radiation-induced salivary gland hypofunction and xerostomia (123,124). Clinical Management of Radiation-Induced Salivary Gland Hypofunction and Xerostomia Management of salivary gland hypofunction and xerostomia induced by radiotherapy is primarily palliative by stimulation of residual secretory capacity of the salivary glands or by applied artificial lubrication when saliva secretion cannot be stimulated (Table 1). Pharmacological Sialagogues Randomized, placebo-controlled trials have suggested that approximately 50% of postradiotherapy patients experience improvement of xerostomia from administration of oral pilocarpine. The maximum effect is obtained with continuous treatment for more than 8 weeks with doses higher than 2.5 mg three times a day (125–128). Oral pilocarpine administered after radiation therapy likewise increases whole salivary and parotid flow rates (125–127) and mucous palatal secretion (129). However, in a number of studies, the improvement of xerostomia did not correlate with the increase in salivary secretion (11, 95, 125, 130). This might be attributed to stimulation of the mucous minor salivary glands because they have been shown to have a greater preserved functional capacity and ability to recover after radiation therapy than serous parotid glands (129). The minor salivary glands play a significant role in lubricating the oral mucosa, but contribute by only 10% to the total volume of saliva. Preferential preservation of secretion of the minor glands after radiotherapy vs the major salivary glands is easily overlooked when collecting whole saliva. Mild to moderate side effects are common in relation to administration of pilocarpine, and at a standard dose of 5 mg three times daily these may include sweating, headache, urinary frequency, vasodilatation, dizziness, dyspepsia, lacrimation, and nausea (125, 126, 131, 132). The side effects of pilocarpine are of clinical relevance as the functional gain disappears if the treatment is stopped and the patients therefore need to be treated lifelong (125, 126). Other drugs that have been reported to be of significance in the treatment of radiation-induced salivary gland hypofunction and xerostomia include cevimeline (133) and bethanechol (115, 134). The effect of all these drugs is, however, rather minimal in many patients (10, 11, 67). Acupuncture Stimulation of residual salivary functional capacity by acupuncture may increase whole salivary flow rates and alleviate xerostomia after radiotherapy (135–138). The effects of acupuncture treatment on unstimulated and stimulated whole salivary flow rates and xerostomia have been reported to last up to 6 months, and with additional acupuncture therapy the effect could be sustained for up to 3 years (135). Also, neuronal activity has been associated with acupuncture, which was absent during sham acupuncture stimulation (139). Recently, it was shown that the effect of acupuncture was comparable to that of postradiotherapy administration of pilocarpine (140). However, a recent review indicated that there are considerable heterogeneities in acupuncture treatment protocols for radiation-induced xerostomia, which make it difficult to assess its efficacy and to compare treatments (10, 141, 142). A Cochrane review concluded that, although there was evidence for acupuncture to induce a small increase in saliva production, there is insufficient evidence for any of these therapies to significantly improve xerostomia (70). Gustatory and Masticatory Stimulation Gustatory and masticatory effects on salivary gland hypofunction and xerostomia following radiotherapy have been sporadically addressed. Small studies of sucking on acidic candy and salivary-stimulating lozenges have shown an increase in whole saliva secretion and improvement of oral dryness, respectively (143, 144), whereas an oral antimicrobial lozenge administered to reduce mucositis did not influence xerostomia during radiotherapy (145). Extra-oral Electrostimulation Transcutaneous electrical nerve stimulation (TENS) delivered using an extra-oral device placed externally on the skin overlying the parotid glands during and after radiation therapy has shown the potential to increase whole saliva flow rate (146, 147). Intra-oral Electrostimulation Intra-oral electrical stimulation devices have been designed that deliver a low-intensity electrical current to the oral mucosa to stimulate the afferent neurons of the salivary reflex and efferent neurons (eg, the lingual nerve) as a nonpharmacological approach with no reported adverse effects. Such devices have been tested in the palliation of xerostomia including irradiated head and neck cancer patients, and although the results are promising, further studies are needed (70, 148–150). Hyperbaric Oxygen Alleviation of xerostomia and slightly increased unstimulated and stimulated whole saliva flow rates have been reported in response to hyperbaric oxygen treatment indicating that hyperbaric oxygen may have a beneficial effect on radiation-induced salivary gland damage (151, 152). However, this approach needs further research to investigate the potential biological effects, clinical significance, and the longevity of efficacy (153, 154). Oral Mucosal Lubricants/Saliva Substitutes Oral mucosal lubricants/saliva substitutes are mainly useful in patients who do not respond to pharmacological, gustatory, or masticatory stimulation. Various saliva substitutes with constituents resembling the physical properties of glycoproteins and antibacterial components of saliva have been developed and are commercially available in the form of moisturizing gels, mouthwashes, or sprays. These formulas may be based on, for example, animal mucin, carboxymethylcellulose (CMC), hydroxypropylmethylcellulose, hydroxyethylcellulose, polyglycerylmethacrylate, polyethylene oxide, xanthan gum, linseed extract, rape seed oil, and aloe vera. Mucin-containing saliva substitutes are usually preferred over CMC-containing and placebo substitutes (2, 155–158). Furthermore, CMC gel has been found to be slightly inferior to polyglycerylmethacrylate gel (159, 160), polyethylene oxide (161), and linseed fluid (162) in reducing xerostomia, whereas CMC spray was found to be equally effective to mucin (extracted from pig stomach) spray, aloe vera gel, and rape seed oil spray (163). Also a combination of saliva substitutes might be helpful (164). However, the various saliva substitutes have generally been sporadically tested, often for a short period of use and in small numbers of patients. The major disadvantage of saliva substitutes is the short duration of relief they provide and thus patients may instead prefer frequent use of water (161, 165). Finally, it has been shown that patients have to be encouraged to try various saliva substitutes as one substitute might be of most benefit to one patient and another type of substitute to another patient (166, 167). The recommendations given below can be used as a guideline for proper selection and use of a saliva substitute: If severe xerostomia, the application of a saliva substitute with gel-like properties may provide relief during the night and when daily activities are at a low level. During daytime, a saliva substitute with less viscous properties resembling natural saliva based on, for instance, polyacrylic acid, xanthan gum, mucin, betaine, allantoin, and aloe vera, may provide relief (168). If moderate xerostomia, saliva substitutes with a rather low viscoelasticity, such as substitutes based on CMC, hydroxypropylmethylcellulose, mucin, or low concentrations of xanthan gum and polyacrylic acid, are indicated, supplemented by a gel to provide relief during night or other periods of severe oral dryness (168). At slight xerostomia, little alleviation is to be expected from the use of saliva substitutes (168). Potential Restoration of Salivary Gland Function following Radiation Injury Currently, there is no clinical treatment option for restoration of salivary gland function lost due to irradiation. However, promising approaches, such as gene therapy, stem cell transfer, and pharmacologic agents, are aimed at regaining function after radiotherapy. Gene Therapy Few acinar cells survive radiation, leaving the salivary gland tissue with little residual capacity for primary fluid secretion; however, salivary duct cells are much less affected after irradiation. Intact salivary duct cells are considered relatively water-impermeable because they lack water channels in the plasma membranes. The therapeutic rationale of gene therapy for functional recovery of radiation-induced damaged salivary gland tissue is based on a possible insertion of a pathway for water transport in the surviving ductal cell membranes to elicit water secretion (169). The water channel protein, human aquaporin-1 (hAQP1), can facilitate rapid movement of water in response to an osmotic gradient and is expressed all around a cell’s plasma membrane, which ensures that there is a facilitated pathway for water to move from the basal side of the cell, adjacent to the bloodstream, into the duct cell, and thereafter into the lumen. Importantly, expression of hAQP1 protein in cell types in which it is not normally found can lead to dramatic increases in osmotically obliged water movement (169, 170). In vivo studies in animal models have used a recombinant serotype 5 adenoviral vector-encoding hAQP1, AdhAQP1, which is delivered to salivary glands via intraductal cannulation through the orifice of the main excretory duct. These studies have shown salivary flow rates in the AdhAQP1-dosed rat approaching those of sham-irradiated rats treated with the control virus (ie, near normal) (169). Similarly, after an initial decrease of saliva secretion to less than 20% of baseline in the miniature pig post-irradiation, administration of AdhAQP1 resulted in a transient (∼2–4 weeks) dose-dependent increase in parotid salivary flow rate to about 80% of preradiation levels (171). Because the hAQP1 transgene in the latter study was expressed only in parotid duct cells, the implication is that the increased salivary secretion observed was due to enhanced water permeability in the normally water-impermeable duct cells (171). A serotype 2 adeno-associated viral vector administered in the miniature pig has been demonstrated to mediate extended gene transfer to the parotid glands (peak salivary flow rates between weeks 6–10) (172). Recently, it was shown that administration of a neurturin-expressing adenovirus before irradiation even might prevent irradiation-induced salivary gland hypofunction after radiotherapy (173). A phase I study has been completed in which the efficacy and safety of gene transfer in 11 humans with parotid gland hypofunction was tested (174, 175). All patients tolerated vector (AdHAQP1) delivery and study procedures well. No serious adverse events or dose-limiting toxicities occurred. An objective positive response was observed in six participants; none of these participants had received the highest dose. Five of them also experienced subjective improvement in xerostomia. Four of five nonresponders did not perceive amelioration or worsening of their oral dryness. AdhAQP1 uses the human cytomegalovirus promoter (176). As participant peak responses were at times much longer (7–42 days) than expected, it was assumed that human cytomegalovirus promoter may not be methylated in human salivary gland cells to the extent previously observed in rodent salivary gland cells. Thus, hAQP1 was probably not methylated in transduced human salivary gland cells of responding participants, resulting in an unexpectedly longer functional expression of hAQP1. Late effects of AdhAQP1 administration have been evaluated in five participants who were identified as responding positively to the gene transfer out of 11 participants in a previous phase I study on efficacy and safety (175, 177). All participants had marked increases in parotid flow rate 3–4.7 years after treatment and with improved symptoms for approximately 2–3 years (177). However, it is yet unknown how long the increase in salivary flow rate can last in humans. Stem Cell Therapy Lack of replacement of differentiated functional cells in salivary glands after radiotherapy may be due to the unresponsiveness of endogenous progenitor and/or stem cells in the gland tissue, hence, handicapping the capacity for natural regeneration (24, 109, 178). These stem cells are proposed to be localized in the parotid gland region excretory ducts, an area that, when irradiated, results in the loss of saliva secretion (46). Stem cell transfer could be able to restore tissue homeostasis after irradiation by increasing the regenerative potential of salivary glands (179). Furthermore, the salivary duct compartment, which remains relatively intact after irradiation, could serve as a natural engraftment place for the transplanted cells. Along this line, a population of c-Kit+ cells with the capability to regenerate and partially restore function to radiation-induced damaged salivary glands of rodents has been cultured. In vitro, salispheres can be grown from these c-Kit+ stem cells, and cells from these salispheres were shown also to express many other stem cell markers [eg, Sca-1, c-Kit, Musashi-1, CD49f, and CD133 (180, 181)] and were able to differentiate into all salivary gland lineages (181). Moreover, these cells were able to self-renew in vitro for many generations (>48 weeks) and in vivo (44, 180, 182). After stem cell enrichment by flow cytometric selection using c-Kit as a single marker, c-Kit+ cells were able to regenerate and significantly improve submandibular gland function. As few as 100 c-Kit+ cells obtained from irradiated primary recipients were shown to improve salivary gland function and restore morphology in irradiated secondary recipients 3 months after transplantation (44). Also, salispheres cultured from human parotid and submandibular glands have been shown to contain c-Kit+ cells with self-renewal and differentiation capacities in vitro (44, 183, 184). Clinical trials to assess whether salivary gland stem cell transplantation is feasible in humans are in progress, and phase I–II trials are commencing testing stem cells harvested from different tissues (eg, salivary gland stem cells and adipose-derived mesenchymal stem cells) (185–187). Pharmacological Approaches to Restoration Pharmacological methods based on improving salivary gland output following radiation are largely in the preclinical stage. Morgan-Bathke et al. (188) reported that utilization of the rapalogue CCI-779 following radiation led to increased salivary function and decreased compensatory proliferation in a mouse model (188). CCI-779 (temsirolimus) is an allosteric inhibitor of the mammalian target of rapamycin complex 1 resulting in the inability of mTOR to bind to FKBP12, thereby inhibiting downstream signaling. Depending on cellular context, treatment with CCI-779 induces autophagy, inhibits protein synthesis, promotes immunosuppression, and/or inhibits cell-cycle progression (189). A clinical trial to evaluate the restorative effects of rapalogues is currently being designed. Reactivation of development pathways has also been proposed as a potential mechanism to reverse radiation-induced salivary gland hypofunction. Hill et al. (190) used a monoclonal antibody against the ectodysplasin receptor to activate this critical developmental pathway in adult mice that had been treated with radiation 4 days prior. Treatment with monoclonal antibody against the ectodysplasin receptor completely restored salivary flow rates and amylase secretion to unirradiated levels within 30 days of radiotherapy (190). Strategies to Promote Development and Funding for New Research Since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies, significant progress has been made in our ability to spare salivary gland function chiefly because of advances in radiation techniques, including the optimizing of 3-D treatment planning, conformal radiation techniques, and IMRT. Other strategies have also been developed, for example, radioprotectors such as tempol and identification and preservation and/or expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, as well as the application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. IMRT, and its next step, proton therapy, still have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients. Nonetheless, many of these advances still only offer partial protection against salivary gland damage because of the fact that they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects, emphasizing the need for therapies aimed at regaining function and/or regeneration of radiation-damaged salivary gland tissue. Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for functional recovery and regeneration of salivary gland function after radiotherapy. Although for some studies, such as those aimed at selecting the most effective method to alleviate the problems of radiation damage to salivary glands, a sufficiently large patient cohort often can be selected within the researcher’s own institution, a multidisciplinary and often multi-institutional approach is needed for studies aimed at either the prevention of radiation injury to salivary gland tissue or the restoration of radiation-damaged salivary gland tissue. The development and testing of strategies for gene transfer and stem cell research to restore radiation-induced functional loss of the salivary glands may also require collaboration of researchers from diverse research backgrounds. Furthermore, a lot of work, including transfer of a preclinical protocol to good medical practice, has to be done to bring gene transfer and stem cell therapy from a laboratory bench to the clinic (174). Such research efforts are very costly and need the involvement of researchers that have access to national and international scientific societies (eg, European Organisation for Research and Treatment of Cancer Head and Neck Cancer Group, European Society for Therapeutic Radiation Oncology, International Society for Stem Cell Research, Stem Cells in Development and Disease, and Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology). Such researchers have access to a network that will allow them to successfully compete for multinational translational grants from, for instance, the NIH and the European Framework Programs. Moreover, the interest of governmental, public, and private funding organizations and among researchers with an interest in healthy aging is growing, and research aimed at prevention and reduction of the morbidity of cancer treatment well fits within these programs. Funding Funding for writing this consensus report has been made available from the authors’ institutions. Notes Affiliations of authors: Department of Dentistry and Oral Health, Faculty of Health, Aarhus University, Aarhus, Denmark (SBJ); Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center, Groningen, The Netherlands (AV); Department of Nutritional Sciences, University of Arizona, Tucson, AZ (KHL); Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO (MER). The authors declare that they have no conflict of interest. A thankful acknowledgement is made to Bruce J. Baum for helpful comments to the manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Langendijk JA , Doornaert P , Verdonck-de Leeuw IM , Leemans CR , Aaronson NK , Slotman BJ. 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Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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JNCI MonographsOxford University Press

Published: Aug 1, 2019

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