Xerostomia induced by radiotherapy: an overview of the physiopathology, clinical evidence, and management of the oral damage

Figures & data

Table 1 World incidence, mortality, and 5-year prevalence of head and neck cancer

Cancer	Incidence			Mortality			5-year prevalence
	Number	%	ASR (W)	Number	%	ASR (W)	Number	%	Proportion
Lip, oral cavity	300,373	2.1	4.0	145,328	1.8	1.9	702,149	2.2	13.5
Nasopharynx	86,691	0.6	1.2	50,828	0.6	0.7	228,698	0.7	4.4
Other pharynx	142,387	1.0	1.9	96,090	1.2	1.3	309,991	1.0	6.0
Esophagus	455,784	3.2	5.9	400,156	4.9	5.0	464,063	1.4	8.9
Larynx	156,877	1.1	2.1	83,376	1.0	1.1	441,675	1.4	8.5
Thyroid	298,102	2.1	4.0	39,769	0.5	0.5	1,206,075	3.7	23.2

Notes: % = risk of getting or dying from the disease before age 75.

Abbreviation: ASR, age-standardized rate.

Table 2 European Union incidence, mortality, and 5-year prevalence of head and neck cancer

Cancer	Incidence			Mortality			5-year prevalence
	Number	%	ASR (W)	Number	%	ASR (W)	Number	%	Proportion
Lip, oral cavity	43,847	1.6	4.9	14,467	1.1	1.5	121,633	1.7	28.4
Nasopharynx	3,267	0.1	0.4	1,494	0.1	0.2	9,283	0.1	2.2
Other pharynx	26,585	1.0	3.2	12,583	1.0	1.4	67,590	0.9	15.8
Esophagus	34,777	1.3	3.4	29,845	2.3	2.8	38,086	0.5	8.9
Larynx	28,336	1.1	3.1	12,248	1.0	1.2	94,193	1.3	22.0
Thyroid	37,440	1.4	5.4	3,637	0.3	0.3	149,044	2.1	34.8

Note: % = risk of getting or dying from the disease before age 75.

Abbreviation: ASR, age-standardized rate.

Table 3 Papers excluded

Reference	Year	Authors	Journal	Reason
^Citation19	1991	Vissink et al	J Oral Pathol Med	Animal study
^Citation70	1998	Davies	Br Med J	Editorial
^Citation46	1998	Spielman	J Dent Res	Animal study
^Citation51	2000	Kuntz et al	Int J Pharm Compound	Opinion paper
^Citation3	2005	Waltimo et al	Schweiz Monatsschr Zahnmed	Article in German

Table 4 Reviews included

Reference	Year	Authors	Journal	Aim	Number of papers reviewed	Qualities and relevance of studies included score
^Citation23	1977	Dreizen et al	Postgrad Med	Narrative – To evaluate the main injury of the surrounding tissues during radiotherapy for oral cancer that can have devastating physical and psychological consequences for the patients	13	++
^Citation45	1994	Atkinson and Wu	J Am Dent Assoc	Narrative – To evaluate the three most common known causes (medication, radiotherapy, and Sjögren’s syndrome) of salivary gland dysfunction and their clinical management	62	+++
^Citation17	1996	Scully and Epstein	Eur J Cancer B Oral Oncol	Narrative – To discuss the etiopathogenesis and current means available for preventing, ameliorating, and treating radiotherapy complications, as well as indicating research directions	282	+++
^Citation1	1998	Bivona	N Y State Dent J	Narrative – To evaluate generally physiopathological features and clinical management of Sjögren’s syndrome	16	++
^Citation61	2000	Dyke	Int J Pharm Compound	Narrative – To evaluate physiopathological features and clinical management of Sjögren’s syndrome	19	+
^Citation18	2000	Sreebny	Int Dent J	Systematic – This paper reviews the role of saliva, the prevalence of oral dryness, and consequent importance of salivary flow as well as the relationship between xerostomia and salivary gland hypofunction among the causes of oral dryness. Other aspects: association between saliva and Sjögren’s syndrome and esophageal function; use of saliva as diagnostic tool	134	+++
^Citation47	2002	Pedersen et al	Oral Dis	Narrative – This paper reviews the role of human saliva and its compositional elements in relation to the gastrointestinal functions of taste, mastication, bolus formation, enzymatic digestion, and swallowing	161	+
^Citation2	2003	Cassolato and Turnbull	Gerodontology	Narrative – To outline for clinicians the common etiologies, clinical identification, and routine therapeutic modalities available for individuals with xerostomia	86	+++
^Citation12	2004	Porter et al	Oral Surg Oral Med Ora Pathol Oral Radiol Endod	Narrative – To create an update of the etiology and management of xerostomia	229	+++
^Citation14	2008	Argiris et al	Lancet	Narrative – To review the epidemiology, molecular pathogenesis, diagnosis and staging, and the latest multimodal management of squamous cell carcinoma of the HNC	153	+++
^Citation63	2008	Sagar	Curr Treat Options Oncol	Narrative – To describe the effectiveness of acupuncture to control the symptoms of cancer patients, with an evidence-based approach	59	++
^Citation55	2010	Ramos-Casals et al	JAMA	Systematic – To summarize evidence on primary Sjögren’s syndrome drug therapy from randomized controlled trials	74	+
^Citation10	2010	Jensen et al	Support Care Cancer	Systematic – To assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations	154	+++
^Citation10	2010	Jensen et al	Support Care Cancer	Systematic – To assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies	203	+++
^Citation66	2010	O’Sullivan and Higginson	Acupunct Med	Systematic – To systematically review evidence on clinical effectiveness and safety of acupuncture in irradiation-induced xerostomia in patients with HNC	51	+++
^Citation41	2013	Radvansky et al	Am J Health Syst Pharm	Narrative – To evaluate current strategies for preventing and managing radiation-induced dermatitis, mucositis, and xerostomia, with an emphasis on pharmacologic interventions	52	++
^Citation67	2013	Zhuang et al	Integr Cancer Ther	Systematic – To evaluate the preventive and therapeutic effect of acupuncture for radiation-induced xerostomia among patients with HNC	46	+++

Notes: +++, high level; ++, medium level; +, low level.

Abbreviation: HNC, head and neck cancer.

Table 5 Clinical trial papers included

Reference	Year	Authors	Journal	Aim	Number of patients	Results	Qualities and relevance of studies included score
^Citation35	1974	Brown et al	J Dent Res	To assess the effects of radiation-induced xerostomia on the human oral microflora	30	Cariogenic microorganisms gain prominence at the expense of non-cariogenic microorganisms in concert with saliva shutdown	+++
^Citation49	1974	Chen and Webster	Cancer	One hundred and one cases of head and neck cancer were subjected to oral culture for Candida albicans before, during, and l month after radiotherapy	101	Thirty percent of the patients had a positive culture before radiotherapy. During the course of radiotherapy, almost half of the negative patients turned positive. The severity of the acute radiation reaction of the oropharyngeal mucosa was not related to the apparent presence or absence of C. albicans. Amphotericin B (1 cm^3 [100 mg] four times daily) converted about one-third of the positive patients to negative	++
^Citation24	1975	Ben-Aryeh et al	Int J Oral Surg	Flow rate, pH, electrolytes, protein, and phosphate evaluation of whole saliva in 15 healthy individuals and 15 patients with malignant tumors in the head and neck region before and during irradiation therapy	30	The most significant finding was the increased sodium content. Irradiation reduces the reabsorption ability of the tubuli, causing the sodium content of the saliva to increase	++
^Citation25	1976	Dreizen et al	Cancer	Saliva and serum electrolyte concentrations were monitored in 30 patients given a course of xerostomia-producing cancer radiotherapy	30	The xerostomic saliva was more concentrated and had a greater salinity than the pretreatment saliva in each instance. In contrast, none of the serum electrolytes measured was significantly altered by the subtotal salivary shutdown	++
^Citation28	1981	Abelson and Mandel	J Dent Res	To evaluate the impact of the saliva on plaque in vivo, following exposure to a sucrose substrate, in ten caries-resistant and ten caries-susceptible subjects under varying conditions of salivary access	20	The study results indicate that saliva plays a major role in mediating plaque pH and qualitatively reflects caries status	+
^Citation36	1981	Keene et al	Caries Res	To evaluate the prevalence of Streptococcus mutans in both preradiation and irradiation patients	39	S. mutans were detected in 82% of the irradiated patients and 100% of the preradiotherapy patients. In the irradiated group without current caries, S. mutans prevalence was inversely related to the number of elapsed years postradiotherapy	+++
^Citation34	1981	Izutsu et al	Oral Surg Oral Med Oral Pathol	Albumin concentrations were measured in whole and parotid saliva samples collected from patients who were undergoing various cancer treatment protocols and had a high incidence of stomatitis	7	The salivary albumin increases always preceded and often occurred in the absence of stomatitis, suggesting that the whole saliva albumin level may be a useful measure and predictor of this condition	++
^Citation26	1981	Marks et al	Int J Radiat Oncol Biol Phys	To establish a dose–response curve for the human parotid, selective measurements of right and left parotid salivary flow were done for 15 age-matched control patients whose parotids were not irradiated, 17 patients who had both parotids irradiated, and 12 whose parotids were irradiated by unilateral electron beam technique	46	In this study there clearly exists a dose–response correlation for the late effects of radiation on parotid salivary flow. Indeed, parotid salivary flow progressively decreased with increasing doses of radiation. A change in the pH of saliva that, especially at high doses, becomes acidic was found	+++
^Citation33	1986	Makkonen et al	Oral Surg Oral Med Oral Pathol	To analyze the radiation-induced changes in the flow rate and protein composition of stimulated whole saliva in eleven patients treated for malignant conditions of the head and neck	11	It is concluded that the observed qualitative changes in whole saliva components are net effects caused by the cancer itself, radiotherapy given, systemic diseases, or medications, as well as mucosal inflammations	+++
^Citation11	1987	Fox et al	J Am Dent Assoc	Describes the responses to a questionnaire of oral findings and QOL in patients with reduced saliva flow. Moreover, an objective measurement of the major saliva output unstimulated and stimulated	100	In this study there exists a correlation between clinical symptoms and low-rate salivary flow. The questionnaire clearly helps to identify xerostomic patients and allows appropriate management to begin	++
^Citation37	1988	Hase and Birkhed	Arch Oral Biol	The aim was to study the effect of different salivary secretion rates on glucose clearance in saliva and on pH change in dental plaque in man, in normal and hyposalivation conditions		The pH changes in dental plaque after the mouth rinse with glucose at extremely low secretion rate were significantly more pronounced than the normal flow rate. Thus, the salivary secretion rate affects both the glucose clearance in saliva and the pH changes in dental plaque in man	+
^Citation16	1991	Maciejewski et al	Radiother Oncol	To evaluate the effects and efficacy of the application of 2% silver-nitrate solution for several days before radiotherapy in 16 patients treated for squamous cell carcinoma of the oral cavity or oropharynx	16	The application of solutions and astringents is effective in modifying the development of acute side effects of radiotherapy and to decrease signs, symptoms, and suffering by modulating the biological status of critical normal tissue before the onset of radiotherapy. Unfortunately, their application before radiotherapy has not given significant results in order to promote reparative processes	+++
^Citation29	1993	Lingström and Birkhed	Acta Odontol Scand	To evaluate plaque pH and oral retention after consumption of starchy snack products at normal and low salivary secretion rate	10	All products resulted in greater pH falls and remained at a low level for a longer period during low secretion rate. There were no differences in concentration of carbohydrates in saliva after consumption of starchy snack products. Low secretion rate increased the oral retention for all products	++
^Citation32	1993	Valdez et al	Cancer	To evaluate whether the sialogogue pilocarpine given during radiotherapy may reduce the severity of xerostomia and salivary dysfunction. The patients, requiring head, neck, or mantle radiotherapy, took either 5 mg of pilocarpine or placebo four times daily for 3 months, beginning the day before radiotherapy. Subjective complaints and salivary functions were assessed	10	The stimulation with pilocarpine may reduce the severity of salivary dysfunction and associated oral symptoms during radiotherapy	++
^Citation60	1997	Bagheri et al	Eur J Clin Pharmacol	To compare the effects of yohimbine, an alpha-2 adrenoceptor antagonist, and anethole trithione, a reference drug in the treatment of dry mouth, in patients treated with psychotropic drugs (tricyclic antidepressants or neuroleptics) and suffering from xerostomia	10	The study results show that under experimental conditions, yohimbine, but not anethole trithione, stimulates salivary secretion after a 5-day treatment in patients receiving antidepressants or neuroleptics and suffering from dry mouth	+
^Citation48	1997	Ramirez-Amador et al	Oral Med Oral Pathol Oral Radiol Endod	To quantitate oral Candida colonization, assessing symptoms, and response to antifungal management, especially Candida, and evaluate the influence of smoking and dentures	46	When salivary glands are included in the field of radiation, xerostomia occurs causing progressive increases in oral Candida colonization. Because 17.4% developed clinical candidiasis during radiotherapy and the question of fungal resistance remains speculative, a recommendation for the prophylactic use of antifungal medication is unresolved	+++
^Citation31	1998	Almståhl and Wikström	J Dent Res	To evaluate the effect of hyposalivation on the oral microflora	38	The results indicated that a low salivary secretion rate mainly promotes a flora associated with the development of caries	+++
^Citation38	1998	Ravald and List	Swed Dent J	The investigation is designed to study caries and periodontal conditions in a selected group of patients with primary Sjögren’s syndrome. Clinical examination includes registrations of dental caries, restorations, and periodontal condition	21	The patients with primary Sjögren’s syndrome face a high risk of developing both coronal and root caries due to xerostomia. The periodontal conditions are similar to those found in patient groups in general dentistry	++
^Citation13	1999	De-Graeff et al	Oral Oncol	To describe prospectively the QOL and mood in patients with oral or oropharyngeal cancer treated with surgery radiotherapy	75	After treatment, a gradual improvement in emotional functioning occurred. Surgical treatment for oral or oropharyngeal cancer results in significant deterioration of physical functioning and symptoms during the first year, especially when combined with radiotherapy	+++
^Citation59	1999	Hamada et al	Am J Med Sci	To evaluate the efficacy of AT, a cholagogue, for xerostomia signs management	49	The results indicate that AT sufficiently stimulates salivation and improves xerostomia	+++
^Citation39	2001	Almståhl et al	Oral Microbiol Immunol	To compare lactoferrin, amylase, and MUC5B concentrations in stimulated whole saliva collected from subjects with radiation-induced hyposalivation, subjects with primary Sjögren’s syndrome, and subjects with hyposalivation of unknown origin or due to medicines. In addition, the data in relation to the presence of selected microbial species that have been associated with oral disorders were analyzed	75	The saliva composition in subjects with hyposalivation of unknown origin or due to medicines was close to that in the healthy controls. All three hyposalivation groups tended to display a decrease in the concentrations of MUC5B and amylase. None of the microbial species analyzed correlated with concentration of MUC5B in saliva	+++
^Citation20	2001	Burlage et al	Radiother Oncol	It was studied whether differences in acute radiosensitivity exist between parotid and submandibular/sublingual glands	18	The results revealed that salivary flow rates decreased dramatically during the first 2 weeks of radiotherapy. Neither recovery nor significant differences were observed between the production of saliva from the parotid and submandibular/sublingual glands during the 13-week observation period	+++
^Citation21	2001	Epstein et al	Head Neck	To assess the QOL, oral function, and oral symptoms in a cohort of patients during and after radiotherapy, by QLQ-C30, with an added oral symptom and function	20	The EORTC QLQ-C30 questionnaire with the oral assessment addendum provides a measure of the QOL and oral function in head and neck cancer patients and may provide useful outcome measures for assessment of oral care prevention and management strategies in these patient populations	++
^Citation9	2001	Moore et al	Oral Surg Oral Med Oral Pathol Oral Radiol Endod	The study evaluates the prevalence of dry-mouth symptoms (xerostomia), the prevalence of hyposalivation in this population, and the possible interrelationships between salivary dysfunction and diabetic complications	676	Subjects with type 1 diabetes who had developed neuropathy more often reported symptoms of dry mouth as well as symptoms of decreased salivary flow rates	+
^Citation42	2002	Wijers et al	Head Neck	The first aim of the study was to evaluate the degree of xerostomia in 39 long-term survivors* treated between 1965 and 1995 by conventional 2D radiotherapy and currently without evidence of disease. The second aim was to develop a concise instrument to evaluate the subjective aspects of xerostomia	39	In this survey, 64% of the long-term survivors*, after treatment by conventional 2D radiotherapy for a malignancy in the head and neck region, still experienced a moderate-to-severe degree of permanent xerostomia	++
^Citation56	2004	Hendrickson et al	J Emerg Med	A report of a case of unintentional overdose of oral pilocarpine tablets that resulted in bradycardia, mild hypotension, and muscarinic symptoms in a patient with Sjögren’s syndrome	1		++
^Citation53	2004	Koseki et al	Oral Dis	To investigate oral symptoms and clinical parameters in dry eye patients	224	The sensation of a dry mouth and changes in oral soft tissues, dental caries, and oral Candida frequently occurred in dry eye patients	++
^Citation30	2006	Eliasson et al	Eur J Oral Sci	To investigate the secretion rate from palatal, buccal, and labial glands, and to analyze the IgA concentrations in relation to age, sex, circulatory disease, diabetes, medication, smoking, and pregnancy	142	The results did not suggest any effect of aging on the secretion capacity of minor salivary glands, but the IgA concentration seemed to increase with age. Women had lower buccal and labial saliva secretion rates, and lower levels of IgA in buccal saliva, than men. For whole saliva, resting, but not stimulated, saliva secretion rates were reduced with age, and the secretion rate of stimulated whole saliva was lower in women than in men	+
^Citation57	2007	Chambers et al	Int J Radiat Oncol Biol Phys	To assess the safety of long-term cevimeline treatment of radiation-induced xerostomia in patients with head and neck cancer; and to assess the efficacy of cevimeline in these patients	255	Cevimeline 45 mg three times daily was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head and neck region	+++
^Citation57	2007	Chambers et al	Int J Radiat Oncol Biol Phys	To study the efficacy and safety of cevimeline in two double-blind trials enrolling patients with head and neck cancer in whom xerostomia developed after radiotherapy	500	Cevimeline was well tolerated by patients with xerostomia after radiotherapy for head and neck cancer, and oral administration of 30–45 mg of cevimeline three times daily increased unstimulated salivary flow	+++
^Citation4	2009	Brand et al	Br Dent J	To assess the severity of xerostomia in HSCT patients and to investigate the association of xerostomia with other chronic oral complications	89	HSCT patients have more severe xerostomia, which is associated with other oral complaints	+
^Citation8	2009	Busato et al	Oral Surg Oral Med Oral Pathol Oral Radiol Endod	To evaluate the impact of xerostomia on the QOL of adolescents with DM1	56	Xerostomia is frequent and has a negative impact on QOL of adolescents with DM1	+++
^Citation54	2010	Tomiita et al	Mod Rheumatol	To evaluate the efficacy and safety of orally administered pilocarpine hydrochloride for juvenile-onset Sjögren’s syndrome patients	5	The results of this study suggest that orally administered pilocarpine is safe and effective for treating xerostomia in juvenile-onset Sjögren’s syndrome patients	+
^Citation40	2010	Almståhl et al	Arch Oral Biol	To analyze the frequency of different Lactobacillus spp. in relation to the pH-lowering potential of the plaque	30	There were large intra- and interindividual variations in frequencies of Lactobacillus spp. and Lactobacillus counts, but no specific species could be related to plaque acidogenicity	+++
^Citation52	2010	Almeida and Kowalski	Braz J Otorhinolaryngol	To report on the experience with pilocarpine on the treatment of xerostomia in thyroid cancer patients submitted to adjuvant RIT	84	Pilocarpine seems to relieve xerostomia complaints in thyroid cancer patients because it is able to stimulate salivary flow, but the observed side effects made the patients refuse long-term therapy continuation	+++
^Citation43	2011	Sher et al	Int J Radiat Oncol Biol Phys	A retrospective study of all patients treated at the Dana-Farber Cancer Institute for HNCUP with IMRT between August 2004 and January 2009. The primary endpoint was overall survival; the secondary endpoints were locoregional and distant control, and acute and chronic toxicity	24	In a single-institution series, IMRT-based chemoradiotherapy for HNCUP was associated with superb overall survival and locoregional control. The xerostomia rates were promising, but the aggressive therapy was associated with significant rates of esophageal stenosis	++
^Citation7	2011	Villa et al	J Am Dent Assoc	To estimate the prevalence of the subjective perception of dry mouth in dental patients in Italy, to relate these estimates to the patients’ ages and sexes, and to determine whether xerogenic medications taken by these patients were associated with complaints of xerostomia	1,201	The authors found that medication use and age were highly significant risk factors for dental patients reporting xerostomia	++
^Citation6	2011	Villa and Abati	Aust Dent J	To examine the symptoms and risk factors associated with self-reported xerostomia	601	Participants reported having dry mouth in 19.6% of cases. Older individuals were significantly more likely to report dry mouth, and the prevalence of xerostomia increased with advancing age. The prevalence of xerostomia in patients taking one or more drugs was significantly higher compared to medication-free patients, and increased with increasing numbers of medications used. Finally, individuals with a nervous or mental disorder, or who wore removable dentures, were five times more likely to develop xerostomia than patients without mental disorder or dentures	++
^Citation44	2012	Schoenfeld et al	Int J Radiat Oncol Biol Phys	To analyze the recent single-institution experience of patients with salivary gland tumors who had undergone adjuvant IMRT, with or without concurrent chemotherapy	35	Treatment of salivary gland malignancies with postoperative IMRT was well tolerated with a high rate of local control. Chemoradiotherapy resulted in excellent local control in a subgroup of patients with adverse prognostic factors and might be warranted in select patients	++

Notes: +++, high level; ++, medium level; +, low level.

* The cohort of patients who had been free of disease for 5 years or longer.

Abbreviations: EC, ethylenedicysteine; ECD, N,N′-1,2-ethylenediylbis-l-cysteinediethylester; AT, anethole trithione; QLQ, Quality of Life Questionnaire; IgA, immunoglobulin A; HSCT, hematopoietic stem cell transplantation; QOL, quality of life; DM1, type 1 diabetes mellitus; RIT, radioactive iodine therapy; HNCUP, head and neck squamous cell carcinoma; IMRT, intensity-modulated radiotherapy; 2D, two-dimensional; EORTC, European Organization for Research and Treatment of Cancer; QLQ-C30, Quality of Life Questionnaire.

Figure 1 Search flowchart.

Table 6 Reviews included related to physiopathological and clinical consequences in cancer therapy

Reference	Year	Authors	Journal	Aim	Number of papers reviewed	Qualities and relevance of studies included score
Physiopathological consequences
^Citation17	1996	Scully and Epstein	Eur J Cancer B Oral Oncol	Narrative – To discuss the etiopathogenesis and current means available for preventing, ameliorating, and treating these complications, as well as indicating research directions	282	+++
^Citation18	2000	Sreebny	Int Dent J	Systematic – This paper reviews the role of saliva, the prevalence of oral dryness, and consequent importance of salivary flow as well as the relationship between xerostomia and salivary gland hypofunction among the causes of oral dryness. Other aspects: associations between saliva and Sjögren’s syndrome and esophageal function; use of saliva as diagnostic tool	134	+++
Radiation-induced changes of saliva
^Citation23	1977	Dreizen et al	Postgrad Med	Narrative – To evaluate the main injury to surrounding tissues during radiotherapy for oral cancer that can have devastating physical and psychological consequences for the patients	13	++
Radiotherapy clinical consequences
^Citation45	1994	Atkinson and Wu	J Am Dent Assoc	Narrative – To evaluate the three most common known causes (medication, radiotherapy, and Sjögren’s syndrome) of salivary gland dysfunction and their clinical management	62	+++
^Citation47	2002	Pedersen et al	Oral Dis	Narrative – This paper reviews the role of human saliva and its compositional elements in relation to the gastrointestinal functions of taste, mastication, bolus formation, enzymatic digestion, and swallowing	161	+
^Citation41	2013	Radvansky et al	Am J Health Syst Pharm	Narrative – To evaluate current strategies for preventing and managing radiation-induced dermatitis, mucositis, and xerostomia, with an emphasis on pharmacologic interventions	52	++

Notes: +++, high level; ++, medium level; +, low level.

Figure 2 Viscous appearance of the saliva in a radiotherapeutic patient.

Figure 3 Dry and sticky appearance of oral mucosa in a radiotherapeutic patient.

Figure 4 Cheilitis and cracked lips, and teeth cervical caries in a radiotherapeutic patient.

VissinkAKalicharanDS-GravenmadeEJAcute irradiation effects on morphology and function of rat submandibular glandsJ Oral Pathol Med1991204494561804990

 PubMed Web of Science ®Google Scholar

DaviesAClinically proved treatments for xerostomia were ignoredBMJ199831612479583935

 PubMedGoogle Scholar

SpielmanAIGustducin and its role in tasteJ Dent Res1998775395449539456

 PubMed Web of Science ®Google Scholar

KuntzRAllenMOsburnJXerostomiaInt J Pharm Compd2000411761177

 Google Scholar

WaltimoTChristenSMeurmanJHFilippiADental care of patients with leukemiaSchweiz Monatsschr Zahnmed200511530831515901038

 PubMedGoogle Scholar

DreizenSADalyTEDraneJBBrownLROral complications of cancer radiotherapyPostgrad Med1977618592834698

 PubMed Web of Science ®Google Scholar

AtkinsonJCWuAJSalivary gland dysfunction: causes, symptoms, treatmentJ Am Dent Assoc19941254094168176076

 PubMed Web of Science ®Google Scholar

ScullyCEpsteinJBOral health care for the cancer patientEur J Cancer B Oral Oncol1996322812928944831

 PubMedGoogle Scholar

BivonaPLXerostomia. A common problem among the elderlyN Y State Dent J19986446529707984

 PubMedGoogle Scholar

DykeSClinical management and review of Sjögren’s syndromeInt J Pharm Compd2000433834123981695

 PubMedGoogle Scholar

SreebnyLMSaliva in health and disease: an appraisal and updateInt Dent J20005014016110967766

 PubMed Web of Science ®Google Scholar

PedersenAMBardowAJensenSBNauntofteBSaliva and gastrointestinal functions of taste, mastication, swallowing and digestionOral Dis2002811712912108756

 PubMed Web of Science ®Google Scholar

CassolatoSFTurnbullRSXerostomia: clinical aspects and treatmentGerodontology200320647714697016

 PubMedGoogle Scholar

PorterSRScullyCHegartyAMAn update of the etiology and management of xerostomiaOral Surg Oral Med Oral Pathol Oral Radiol Endod200497284614716254

 PubMed Web of Science ®Google Scholar

ArgirisAKaramouzisMVRabenDFerrisRLHead and neck cancerLancet20083711695170918486742

 PubMed Web of Science ®Google Scholar

SagarSMAcupuncture as an evidence-based option for symptom control in cancer patientsCurr Treat Options Oncol2008911712618688727

 PubMed Web of Science ®Google Scholar

Ramos-CasalsMTzioufasAGStoneJHSisóABoschXTreatment of primary Sjögren syndrome: a systematic reviewJAMA2010304445246020664046

 PubMed Web of Science ®Google Scholar

JensenSBPedersenAMVissinkASalivary Gland Hypofunction/Xerostomia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of lifeSupport Care Cancer2010181039106020237805

 PubMed Web of Science ®Google Scholar

O’SullivanEMHigginsonIJClinical effectiveness and safety of acupuncture in the treatment of irradiation-induced xerostomia in patients with head and neck cancer: a systematic reviewAcupunct Med20102819119921062848

 PubMed Web of Science ®Google Scholar

RadvanskyLJPaceMBSiddiquiAPrevention and management of radiation-induced dermatitis, mucositis, and xerostomiaAm J Health Syst Pharm2013701025103223719879

 PubMed Web of Science ®Google Scholar

ZhuangLYangZZengXThe preventive and therapeutic effect of acupuncture for radiation-induced xerostomia in patients with head and neck cancer: a systematic reviewIntegr Cancer Ther20131219720522791311

 PubMed Web of Science ®Google Scholar

BrownLRDreizenSHandlerSJohnstonDAEffect of radiation-induced xerostomia on human oral microfloraJ Dent Res19745447407501099136

 PubMed Web of Science ®Google Scholar

ChenTYWebsterJHOral monilia study on patients with head and neck cancer during radiotherapyCancer1974342462494604859

 PubMed Web of Science ®Google Scholar

Ben-AryehHGutmanDSzargelRLauferDEffects of irradiation on saliva in cancer patientsInt J Oral Surg197514205210811576

 PubMedGoogle Scholar

DreizenSBrownLRHandlerSLevyBMRadiation-induced xerostomia in cancer patients. Effect on salivary and serum electrolytesCancer1976382732787352

 PubMed Web of Science ®Google Scholar

AbelsonDCMandelIDThe effect of saliva on plaque pH in vivoJ Dent Res198160163416386943155

 PubMed Web of Science ®Google Scholar

KeeneHJDalyTBrownLRDental caries and Streptococcus mutans prevalence in cancer patients with irradiation-induced xerostomia: 1–13 years after radiotherapyCaries Res1981154164276942926

 PubMed Web of Science ®Google Scholar

IzutsuKTTrueloveELBleyerWAAndersonWMSchubertMMRiceJCWhole saliva albumin as an indicator of stomatitis in cancer therapy patientsCancer1981486145014547023657

 PubMed Web of Science ®Google Scholar

MarksJEDavisCCGottsmanVLPurdyJELeeFThe effects of radiation of parotid salivary functionInt J Radiat Oncol Biol Phys19817101310197298398

 PubMed Web of Science ®Google Scholar

MakkonenTATenovuoJViljaPHeimdahlAChanges in the protein composition of whole saliva during radiotherapy in patients with oral or pharyngeal cancerOral Surg Oral Med Oral Pathol1986622702752427987

 PubMedGoogle Scholar

FoxPCBunchKABaumBJSubjective reports of xerostomia and objective measures of salivary gland performanceJ Am Dent Assoc19871155815843477595

 PubMed Web of Science ®Google Scholar

HaseJCBirkhedDSalivary glucose clearance, dry mouth and pH changes in dental plaque in manArch Oral Biol1988338758803256293

 PubMed Web of Science ®Google Scholar

MaciejewskiBZajuszAPileckiBSalivary Gland Hypofunction/Xerostomia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)Acute mucositis in the stimulated oral mucosa of patients during radiotherapy for head and neck cancerRadiother Oncol1991227111947216

 PubMed Web of Science ®Google Scholar

LingströmPBirkhedDPlaque pH and oral retention after consumption of starchy snack products at normal and low salivary secretion rateActa Odontol Scand1993513793888304015

 PubMed Web of Science ®Google Scholar

ValdezIHWolffAAtkinsonJCMacynskiAAFoxPCUse of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunctionCancer199371184818518448748

 PubMed Web of Science ®Google Scholar

BagheriHSchmittLBerlanMMontastrucJLA comparative study of the effects of yohimbine and anetholtrithione on salivary secretion in depressed patients treated with psychotropic drugsEur J Clin Pharmacol1997523393429272401

 PubMed Web of Science ®Google Scholar

Ramirez-AmadorVSilvermanSJrMayerPTylerMQuiveyJCandidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapyOral Surg Oral Med Oral Pathol Oral Radiol Endod1997841491539269016

 PubMed Web of Science ®Google Scholar

AlmståhlAWikströmMOral microflora in subjects with reduced salivary secretionJ Dent Res1998781410141610439028

 PubMed Web of Science ®Google Scholar

RavaldNListTCaries and periodontal conditions in patients with primary Sjögren’s syndromeSwed Dent J1998223971039768457

 PubMedGoogle Scholar

De GraeffADe LeeuwJRRosWJHordijkGJBlijhamGHWinnubstJAA prospective study on quality of life of patients with cancer of the oral cavity or oropharynx treated with surgery with or without radiotherapyOral Oncol199935273210211307

 PubMed Web of Science ®Google Scholar

HamadaTNakaneTKimuraTTreatment of xerostomia with the bile secretion-stimulant drug anethole trithione: a clinical trialAm J Med Sci199931814615110487404

 PubMed Web of Science ®Google Scholar

AlmståhlAWikströmMGroeninkJLactoferrin, amylase and mucin MUC5B and their relation to the oral microflora in hyposalivation of different originsOral Microbiol Immunol20011634535211737657

 PubMedGoogle Scholar

BurlageFRCoppesRPMeertensHStokmanMAVissinkAParotid and submandibular/sublingual flow during high dose radiotherapyRadiother Oncol20016127127411730996

 PubMed Web of Science ®Google Scholar

EpsteinJBRobertsonMEmertonSPhillipsNStevenson-MoorePQuality of life and oral function in patients treated with radiation therapy for head and neck cancerHead Neck20012338939811295813

 PubMed Web of Science ®Google Scholar

MoorePGuggenheimerJEtzelJKWeyantRJTrevor orchard type 1 diabetes mellitus, xerostomia, and salivary flow ratesOral Surg Oral Med Oral Pathol Oral Radiol Endod20019228129111552145

 PubMed Web of Science ®Google Scholar

WijersOBLevendagPCBraaksmaMMBoonzaaijerMVischLLSchmitzPIPatients with head and neck cancer cured by radiation therapy: a survey of the dry mouth syndrome in long-term survivorsHead Neck20022473774712203798

 PubMed Web of Science ®Google Scholar

HendricksonRGMoroccoAPGreenbergMIPilocarpine toxicity and the treatment of xerostomiaJ Emerg Med200426442943215093850

 PubMed Web of Science ®Google Scholar

KosekiMMakiYMatsukuboTOhashiYTsubotaKSalivary flow and its relationship to oral signs and symptoms in patients with dry eyesOral Dis2004102758014996276

 PubMed Web of Science ®Google Scholar

EliassonLBirkhedDOsterbergTCarlénAMinor salivary gland secretion rates and immunoglobulin A in adults and the elderlyEur J Oral Sci200611449449917184231

 PubMed Web of Science ®Google Scholar

ChambersMSJonesCUBielMAOpen-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomiaInt J Radiat Oncol Biol Phys20076951369137617855005

 PubMed Web of Science ®Google Scholar

BrandHSBotsCPRaber-DurlacherEXerostomia and chronic oral complications among patients treated with haematopoietic stem cell transplantationBr Dent J2009207E1719893563

 PubMed Web of Science ®Google Scholar

BusatoIMIgnácioSABrancherJAGrégioAMMachadoMAAzevedo-AlanisLRImpact of xerostomia on the quality of life of adolescents with type 1 diabetes mellitusOral Surg Oral Med Oral Pathol Oral Radiol Endod200910837638219716505

 PubMed Web of Science ®Google Scholar

TomiitaMTakeiSKuwadaNEfficacy and safety of orally administered pilocarpine hydrochloride for patients with juvenile-onset Sjögren’s syndromeMod Rheumatol201020548649020517630

 PubMed Web of Science ®Google Scholar

AlmståhlACarlénAEliassonLLingströmPLactobacillus species in supragingival plaque in subjects with hyposalivationArch Oral Biol20105525525920149344

 PubMed Web of Science ®Google Scholar

AlmeidaJPKowalskiLPPilocarpine used to treat xerostomia in patients submitted to radioactive iodine therapy: a pilot studyBraz J Otorhinolaryngol201076565966220963353

 PubMed Web of Science ®Google Scholar

SherDJBalboniTAHaddadRIEfficacy and toxicity of chemoradiotherapy using intensity-modulated radiotherapy for unknown primary of head and neckInt J Radiat Oncol Biol Phys2011801405141121177045

 PubMed Web of Science ®Google Scholar

VillaAPolimeniAStrohmengerLCicciùDGherloneEAbatiSDental patients’ self-reports of xerostomia and associated risk factorsJ Am Dent Assoc201114281181621719803

 PubMed Web of Science ®Google Scholar

VillaAAbatiSRisk factors and symptoms associated with xerostomia: a cross-sectional studyAust Dent J20115629029521884145

 PubMed Web of Science ®Google Scholar

SchoenfeldJDSherDJNorrisCMJrSalivary gland tumors treated with adjuvant intensity-modulated radiotherapy with or without concurrent chemotherapyInt J Radiat Oncol Biol Phys20128230831421075557

 PubMed Web of Science ®Google Scholar