Radioactive iodine (RAI) therapy is performed to ablate

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1 THYROID Volume 25, Number 7, 2015 ª Mary Ann Liebert, Inc. DOI: /thy Effects of Salivary Secretion Stimulation on the Treatment of Chronic Radioactive Iodine-Induced Sialadenitis Jeong-Seok Choi, 1 Seong Bin Hong, 2 In Young Hyun, 3 Jae-Yol Lim, 1 * and Young-Mo Kim 1 * Background: The aim of this prospective study was to investigate the effect of salivary stimulation therapy using pilocarpine (a cholinergic agent) on chronic radioactive iodine (RAI)-induced sialadenitis. Methods: Sixty-one patients with a diagnosis of chronic RAI-induced sialadenitis after thyroidectomy and RAI therapy were enrolled in this prospective study. Patients received salivary stimulation therapy with pilocarpine (5 mg, 3 times daily) over a 3-month period. Subjective symptom scores were assessed using self-reported questionnaires. Salivary flow rates (SFRs) were measured and salivary gland scintigraphy (SGS) was performed to evaluate objective salivary gland functions. Results: After salivary stimulation therapy, subjective symptom scores were significantly improved ( p = 0.002), but posttreatment unstimulated and stimulated SFRs did not differ significantly from pretreatment values. SGS parameters, that is, uptake ratio (UR), maximum accumulation (MA), T min, and maximum secretion (MS) of parotid and submandibular glands were nonsignificantly different after salivary stimulation therapy. Conclusion: The study shows that salivary stimulation therapy may reduce the subjective symptoms of RAIinduced chronic sialadenitis but does not significantly induce functional restoration. Introduction Radioactive iodine (RAI) therapy is performed to ablate normal and/or cancerous thyroid tissue after total thyroidectomy for well-differentiated thyroid cancer, and chronic sialadenitis is one of the most common long-term complications after RAI therapy with a prevalence of from 11% to 65% (1 4). Although the mechanism of RAI-induced sialadenitis is not well understood, it is generally attributed to direct damage of the epithelium of the intralobular ducts of salivary glands (SGs) (1). In a previous study, we investigated histologic changes in the RAI-exposed SGs of mice and confirmed that RAI causes significant pathologic parenchymal changes, such as atypical ductal configurations, periacinoductal inflammation, and fibrosis (5), and in another more recent study, we found that RAI-damaged ducts present as sialodochitis, a bleached wall, and ductal stenosis, resulting in obstructive sialadenitis (6). At lower therapeutic RAI doses, RAI-induced SG damage leads to acute obstructive salivary symptoms, such as, recurrent swelling and pain during meals, whereas at higher therapeutic RAI doses, it causes chronic hyposalivation and related life-disrupting side effects, such as, speech and swallowing difficulties, taste alterations, oral candidiasis, and dental caries (2,7). Thus, hyposalivation can diminish quality of life in patients with thyroid cancer. Currently, RAI-induced chronic sialadenitis is treated conservatively by ensuring good oral hygiene and using frequent hydration, the use of saliva substitutes, and salivary stimulatory treatments, such as, gland massage, sialogogues, and chewing gum (1,8 12). Pilocarpine is produced by the South American shrub Pilocarpus jaborandi, and is a parasympathomimetic agent that stimulates cholinergic receptors on the surfaces of exocrine glands and decreases the symptoms of xerostomia (13). Pilocarpine is commonly used as a treatment for xerostomia, and was the first medication approved by the Food and Drug Administration (FDA) for the treatment of dry mouth caused by radiotherapy or Sjögren s syndrome. We performed this study to investigate the therapeutic effects of salivary stimulation of medical treatment, including pilocarpine, on chronic sialadenitis following RAI therapy after thyroidectomy. Salivary flow rates (SFRs) were measured, salivary gland scintigraphy (SGS) was performed, and self-assessment symptom questionnaires were administered to patients before and after 3 months of salivary stimulation therapy. 1 Department of Otorhinolaryngology-Head and Neck Surgery, 2 Department of Internal Medicine, 3 Department of Nuclear Medicine, Inha University School of Medicine, Incheon, Republic of Korea. *These authors contributed equally to the study. 839

2 840 CHOI ET AL. Materials and Methods Patient population Patients with a diagnosis of chronic RAI-induced sialadenitis between January 2011 and December 2013 were included in this prospective study. All patients had received RAI ablation therapy after total thyroidectomy for well-differentiated thyroid cancer. Chronic RAI-induced sialadenitis was diagnosed based on symptoms and ultrasonography, computed tomography, sialography, and/or SGS results. Clinical symptoms suggestive of obstructive sialadenitis and objective findings regarding ductal configuration changes with or without glandular atrophy are the most important diagnostic criteria of chronic obstructive sialadenitis, and in the chronic state decreased salivary gland function may be observed. All subjects received pilocarpine orally (5 mg, 3 times per day) for 3 months and conservative management such as sugarfree chewing gum, frequent hydration, and gland massages, the latter of which were self-administered after training. The following candidates were excluded from the study: those who had undergone external radiotherapy of the head and neck and/or previous or concurrent chemotherapy; those with a SG tumor and/or another SG diseases, such as Sjögren s syndrome at initial presentation; and those in whom pilocarpine was contraindicated, such as those with a severe cardiovascular disease, chronic obstructive pulmonary disease, or glaucoma. In addition, we excluded those taking cardiac medication, such as, beta-adrenergic antagonists, or other medications known to influence SG function, and pregnant women. Clinical data, such as sex, age, treatment modalities, pathologic diagnosis, time to the development of sialadenitis after RAI treatment, RAI dosage, and thyroid hormone levels were also documented. Patients answered 21 questions related to salivary dysfunction prestimulation and poststimulation therapy. SGS was performed pretreatment and posttreatment and SFRs were measured. The study was approved by our Institutional Review Board. Symptom questionnaires A detailed questionnaire was used to assess subjective symptoms. This questionnaire was composed of 21 questions that addressed the symptoms of obstructive sialadenitis and chronic sialadenitis (6). Patients were asked to score each question from 1 to 5, where a higher score corresponded to an increased level of complaint (Table 1). Salivary flow rates Unstimulated and stimulated saliva samples were collected from all 61 patients by the same experienced clinician between 8:00 and 12:00 am to account for diurnal variations in salivary excretion. Patients were prohibited from eating, drinking, or smoking for 2 hours before saliva collection. To collect saliva samples, patients were asked to sit in a comfortable chair, given a preweighed plastic tube, and asked to collect unstimulated over 5 minutes. Ascorbic acid (500 mg, a sialagogue) was then given over 4 minutes to stimulate SGs, and saliva was collected in the same manner. After collection, saliva samples were weighed and SFRs (ml/min) were calculated by dividing volumes of saliva collected by the collection period (5 minutes) (6,14). The weight of each saliva Table 1. Details of the Xerostomia Questionnaire Regarding General Conditions Related to Obstructive Sialadenitis and Hyposalivation Xerostomia Questionnaire My chin and cheek often swells* Pain in my chin and cheek often develops* I have trouble swallowing solid food I wake up while sleep for a cup of water I feel dryness in my mouth while eating I have dryness in my mouth now I need a sip of water to swallow solid food I usually drink water to reduce dryness I have trouble eating dry food I eat sweets to reduce dryness I feel dryness in my mouth while speaking I feel dryness in my mouth while chewing I have pain or burning sense in my tongue I have bad breath I usually have ulcers around my lips I have throat discomfort I often experience hoarseness I have trouble with taste My lip often runs dry My nasal cavity often runs dry I visited dentist for oral carries or gingivitis sample (in grams) was equated to volume (ml) because the specific gravity of saliva is 1.0 (15). Salivary gland scintigraphy SGS was performed as previously described (6) to assess SG function. Briefly, SGS was conducted 30 minutes after injecting 370 MBq 99m Tc-pertechnate intravenously; patients were prohibited from eating, drinking, smoking, or gargling for at least 2 hours beforehand. Saliva excretion was stimulated after giving patients a 500 mg ascorbic acid tablet 20 minutes after injecting 99m Tc-pertechnate. Time-activity curves for glandular activity, as represented by the uptake and secretion of 99m Tc-pertechnate were obtained (16). The following parameters were used to evaluate salivary functions; uptake ratio (UR, defined as gland-to-background ratio at maximum count), maximum accumulation ( MA, calculated by dividing [maximum count - height of the initial shoulder on the time-activity plot] by the maximum count), T min (time from stimulation to minimum count) and maximum secretion ( MS, calculated by dividing [the maximum count - the minimum count after stimulation] by the maximum count) (6,16). Statistical analysis The sentences marked with asterisk are questions related to obstructive symptoms. Data analysis was performed using the Graph Pad Prism 5 package (GraphPad Software Inc., La Jolla, CA). The significances of differences between experiments were evaluated using the paired t-test. p Values of < 0.05 were considered significant. Results are expressed as means standard deviations (SDs).

3 SALIVARY STIMULATION AND THE TREATMENT OF SIALADENITIS 841 Results Patient characteristics Sixty-one patents who met our inclusion criteria were enrolled in this prospective study: 50 females and 11 males; overall mean age, 50.7 years (range, years). The mean RAI dosage administered was 163 mci (range, mci), mean time to symptom onset was 10.1 months (range, 1 36 months) after completing RAI therapy, and mean follow-up was 13.3 months (range, 7 32 months). No adverse effects related to pilocarpine administration were encountered. Patient demographics and clinical TNM stages are summarized in Table 2. Changes in subjective symptoms All patients completed the symptom questionnaire and showed high scores for all symptoms, that is, severe mouth dryness and difficulty chewing, swallowing, and speaking. Mean pretreatment and posttreatment symptom scores were and , respectively, which represented a significant improvement (Fig. 1, Table 3, p = 0.002). Changes in objective salivary gland dysfunction Salivary flow rates. Pretreatment mean unstimulated and stimulated SFRs were and ml/min, and posttreatment unstimulated and stimulated SFRs were and ml/min, respectively (Table 3). Unstimulated SFR showed a nonsignificant increasing trend Table 2. Patient Characteristics Age Mean/range (years) 50.7/25 71 Sex Female/male 50/11 RAI-administered activity Mean/range (mci) 163/ Time to diagnosis Median/range (months) 10.1/1 36 Follow-up period Median/range (months) 13.3/7 32 Histology Papillary/follicular 61/0 T stage T1 28 T2 3 T3 29 T4 1 N stage N0 27 N1 34 Nx 0 M stage M0 61 M1 0 TNM stage I 25 II 9 III 26 IV 1 Thyroid hormone level Euthyroid/hypothyroid 58/3 RAI, radioactive iodine. FIG. 1. Subjective changes in xerostomia-related symptoms after pilocarpine treatment. Posttreatment symptom scores were significantly lower ( p = 0.002). after treatment (Fig. 2A, p = 0.078). However, pretreatment and posttreatment stimulated SFRs were similar (Fig. 2B, p = 0.941). Salivary gland scintigraphy. UR and MA (both salivary uptake indices) and T min and MS (salivary excretion indices) were measured. Table 3 and Figures 3 and 4 summarize salivary functional results of parotid and submandibular glands as determined by scintigraphy. In parotid glands, no UR or MA changes were observed after treatment (Fig. 3A and 3B, both p > 0.05), whereas T min and MS values showed a nonsignificant trend toward improvement (Fig. 3C and 3D, both p > 0.05). In submandibular glands, all parameters were unchanged after treatment (Fig. 4A 4D, all p > 0.05). Discussion Saliva plays an essential role in the maintenance of oral homeostasis. It provides lubrication, aids chewing and swallowing, cleanses the oral cavity, enhances taste perception, facilitates the initial steps of digestion, achieves oral microflora balance, provides immunity against pathogens, and facilitates speech (17). Accordingly, the consequences of SG hypofunction extend well beyond xerostomia. The common oral symptoms of RAI-induced chronic sialadenitis are xerostomia, dysphonia, dysphagia, a burning sensation in the mouth, altered taste, and oral ulcers. Jeong et al. (8) reported approximately 20% of 213 patients who received RAI ablation after thyroidectomy for thyroid cancer exhibited objective SG dysfunction by SGS and that 16.4% of patients complained of xerostomia at 5 years after RAI ablation (18). Attempts are commonly made to treat these symptoms using sugar-free chewing gum, frequent hydration, saliva substitutes, gland massage, artificial saliva, and oral lubricants (19). In the present study, we investigated the therapeutic efficacy of pilocarpine administration with respect to improvements in SG subjective symptoms and the prevention of functional SG deterioration, and found that salivary stimulation therapy may reduce the subjective symptoms of RAI-induced chronic sialadenitis, but that it does not significantly affect functional restoration. Alexander et al. (2) found no significant difference between patients who were given or not given pilocarpine during RAI therapy. Silberstein (20) performed a blind

4 842 CHOI ET AL. Table 3. Comparisons of Symptomatic Scores, Salivary Flow Rates (Unstimulated and Stimulated), and of Salivary Gland Scintigraphy Parameters Before and After Pilocarpine Treatment Parameter Before After p Comment Symptom score * Salivary flow (unstimulated) ns Salivary flow (stimulated) ns UR Parotid ns Submandibular ns MA (%) Parotid ns Submandibular ns MS (%) Parotid ns Submandibular ns T min (minutes) Parotid ns Submandibular ns *Significant ( p < 0.05). ns, non-significant ( p > 0.05); UR, uptake ratio; MA, maximum accumulation; MS, maximum secretion. controlled study on 60 patients to whom pilocarpine was given (5 mg) every 8 hours for a week after RAI therapy with the intention of preventing RAI-induced sialadenitis, but concluded that pilocarpine treatment did not reduce its occurrence. However, these studies were designed to determine whether pilocarpine can prevent the development of sialadenitis, and to the best of our knowledge, no study has yet addressed the therapeutic effects of SG stimulation using a cholinergic drug in a background of RAI-induced chronic sialadenitis. Furthermore, salivary function was not studied objectively in previous studies; instead patients were simply asked whether they suffered from a dry mouth and to answer in binary mode. On the other hand, in the present study, we measured SFRs and performed SGS, which provides an objective means of determining SG function after stimulatory treatment. Saliva collection remains one of the most widely accepted methods of assessing salivary functions, and SGS provides a simple, noninvasive means of evaluating SG function. Furthermore, variables quantified by SGS have been reported to be well correlated with salivation volume (21). We did not detect significant changes in SFR values after treatment. Patients were instructed not to eat, drink, or smoke for 2 hours before SFRs were measured to avoid possible effects on salivation, and saliva samples were collected between 8:00 and 12:00 am to avoid diurnal variations. However, most patients fasted overnight, and thus, dehydration may have been a confounding factor. In addition, all patients did not take a pilocarpine tablet on test days because we wanted information on basic SFRs in the absence of pilocarpine. In one study, it was reported that salivary flow was stimulated within 15 minutes of oral pilocarpine administration; flow rate increased 2- to 10-fold, peak flow rate was maintained for 1 to 2 hours, and the elimination half-life of pilocarpine was 0.76 hours after the administration of 5 mg 3 times daily (22). Accordingly, functional tests allowed the contribution of pilocarpine to the restoration of salivation capacity to be assessed. In the present study, although many patients experienced an increase in saliva flow immediately after pilocarpine administration and subjective symptoms improved after 3 months of treatment, they did not show any significant improvement in salivation capacity. However, the salivary functions of the 61 patients, who all complied with treatment, showed no further deterioration with time. These observations suggest that salivary stimulation therapy with pilocarpine (a cholinergic agent) does not restore RAI-damaged SG functions. In a previous study, we found that RAI severely damaged SGs in ductal areas and in acinar parenchyma (5), and that the extent of RAI-induced SG damage was variable according to RAI dosage. Similarly, in the present study, sensitivities to pilocarpine appeared to vary on an individual basis and to depend on the amount of functional SG tissue remaining after FIG. 2. Objective changes in SG function as determined by (A) unstimulated SFRs and (B) stimulated SFRs. Neither unstimulated nor stimulated SFRs (ml/min) were significantly increased after pilocarpine treatment. ( p = 0.078, p = 0.941, respectively). SG, salivary gland; SFRs, salivary flow rates.

5 SALIVARY STIMULATION AND THE TREATMENT OF SIALADENITIS 843 FIG. 3. Objective scintigraphic parameters of the parotid gland. (A) UR, (B) MA, (C) T min, and (D) MS. All parameters were similar pretreatment and posttreatment. UR, uptake ratio; MA, maximum accumulation; MS, maximum secretion. RAI therapy. Individual differences in unstimulated SFRs after treatment also varied appreciably, which made it difficult to achieve statistical significance, although unstimulated SFRs did show an increasing trend. Furthermore, pretreatment and posttreatment stimulated SFRs, which reflect parotid gland function, were similar. The scintigraphic parameters of parotid and submandibular glands were also found to be similar after treatment. We attribute this finding to different amounts of remnant functional tissue and sensitivities to pilocarpine. Nakada et al. (10) found subjective symptoms were not matched by SGS findings, and similarly, Bohuslavizki et al. (23) showed that objective scintigraphic findings were not predictive of clinically relevant xerostomia after RAI therapy. This type of therapy usually does not completely destroy SGs and preserves stimuli-induced responses in adequately functional parenchyma (24). Furthermore, in the present study, although patients complained of xerostomia-related symptoms, it is probable that not all SGs exhibited RAI-induced hypofunction, and thus, compensation by relatively normal glands could have masked relations between scintigraphic parameters and xerostomiarelated symptoms. Accordingly, the scintigraphic results of patients with RAI-induced chronic sialadenitis require careful interpretation. Several studies have demonstrated the safety of pilocarpine for the treatment of RAI-induced sialadenitis (25 28). Aframian et al. (8) reported on the safety of a 5 mg daily dose in five patients with thyroid cancer who underwent adjuvant RAI therapy and found no changes in systolic or diastolic blood pressure, pulse, or body temperature. Similarly, in the present study, no significant changes in pulse rate, blood pressure, or body temperature were observed. Consequently, FIG. 4. Objective scintigraphic parameters of the submandibular gland. (A) UR, (B) MA, (C) T min, and (D) MS. All parameters were unchanged after treatment. UR, uptake ratio; MA, maximum accumulation; MS, maximum secretion.

6 844 CHOI ET AL. we conclude that pilocarpine is safe and well tolerated in patients with chronic RAI-induced sialadenitis after thyroidectomy for the treatment of differentiated thyroid cancer. However, it should be noted that pilocarpine is contraindicated in patients with uncontrolled asthma, acute iritis, or narrow-angle glaucoma, and careful administration is recommended in patients with controlled asthma, chronic bronchitis, chronic obstructive pulmonary disease, or cardiovascular disease, particularly, in patients taking medications such as beta-adrenergic antagonists or drugs with parasympathomimetic or anticholinergic effects (22). In particular, pilocarpine should be prescribed under close observation in patients taking antihypertensives or medications for cardiac diseases (29). This study was undertaken to determine whether salivary stimulation treatment with pilocarpine administration, ameliorates the symptoms of sialadenitis and restores SG function in patients with recalcitrant RAI-induced chronic sialadenitis. Our subjective and objective functional assessments show that salivary stimulation treatment for 3 months can improve subjective symptoms but cannot restore SG function. We suggest a prospective, randomized, placebo-controlled study be performed to prove that pilocarpine truly improves salivary symptoms and to determine the duration of its effects. Nevertheless, despite additional long-term study being needed to confirm our speculations, we believe that the present study provides first evidence that salivary stimulation therapy ameliorates the obstructive and xerostomic symptoms of chronic RAI-induced sialadenitis. Conclusion Salivary stimulation treatment with pilocarpine is suggested to ameliorate the subjective symptoms of chronic RAI-induced sialadenitis. However, SFRs and scintigraphic parameters demonstrated no significant restoration of salivary gland function after three months of treatment. A longterm prospective randomized study is needed to confirm our speculations. Acknowledgment This research was supported by an Inha University research grant. Author Disclosure Statement No competing financial interests exist. References 1. Mandel SJ, Mandel L 2003 Radioactive iodine and the salivary glands. Thyroid 13: Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM 1998 Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 39: Walter MA, Turtschi CP, Schindler C, Minnig P, Muller- Brand J, Muller B 2007 The dental safety profile of highdose radioiodine therapy for thyroid cancer: Long-term results of a longitudinal cohort study. J Nucl Med 48: Kita T, Yokoyama K, Higuchi T, Kinuya S, Taki J, Nakajima K, Michigishi T, Tonami N 2004 Multifactorial analysis on the short-term side effects occurring within 96 hours after radioiodine-131 therapy for differentiated thyroid carcinoma. Ann Nucl Med 18: Choi JS, Park IS, Kim SK, Lim JY, Kim YM 2013 Morphometric and functional changes of salivary gland dysfunction after radioactive iodine ablation in a murine model. Thyroid 23: Kim YM, Choi JS, Hong SB, Hyun IY, Lim JY 2014 Salivary gland function after sialendoscopy for treatment of chronic radioiodine-induced sialadenitis. Head Neck 2014 Jul 4. [Epub ahead of print]; DOI: /hed Newkirk KA, Ringel MD, Wartofsky L, Burman KD 2000 The role of radioactive iodine in salivary gland dysfunction. Ear Nose Throat J 79: Aframian DJ, Helcer M, Livni D, Markitziu A 2006 Pilocarpine for the treatment of salivary glands impairment caused by radioiodine therapy for thyroid cancer. Oral Dis 12: Kim HW, Ahn BC, Lee SW, Lee J 2012 Effect of parotid gland massage on parotid gland Tc-99m pertechnetate uptake. Thyroid 22: Nakada K, Ishibashi T, Takei T, Hirata K, Shinohara K, Katoh S, Zhao S, Tamaki N, Noguchi Y, Noguchi S 2005 Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer? J Nucl Med 46: Liu B, Kuang A, Huang R, Zhao Z, Zeng Y, Wang J, Tian R 2010 Influence of vitamin C on salivary absorbed dose of 131I in thyroid cancer patients: a prospective, randomized, single-blind, controlled trial. J Nucl Med 51: Van Nostrand D, Atkins F, Bandaru VV, Chennupati SP, Moreau S, Burman K, Wartofsky L 2009 Salivary gland protection with sialagogues: a case study. Thyroid 19: Ship JA 2002 Diagnosing, managing, and preventing salivary gland disorders. Oral Dis 8: Chao KS, Deasy JO, Markman J, Haynie J, Perez CA, Purdy JA, Low DA 2001 A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. Int J Radiat Oncol Biol Phys 49: Kalk WW, Vissink A, Spijkervet FK, Bootsma H, Kallenberg CG, Nieuw Amerongen AV 2001 Sialometry and sialochemistry: diagnostic tools for Sjogren s syndrome. Ann Rheum Dis 60: Aung W, Yamada I, Umehara I, Ohbayashi N, Yoshino N, Shibuya H 2000 Sjogren s syndrome: comparison of assessments with quantitative salivary gland scintigraphy and contrast sialography. J Nucl Med 41: Pedersen AM, Bardow A, Jensen SB, Nauntofte B 2002 Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis 8: Jeong SY, Kim HW, Lee SW, Ahn BC, Lee J 2013 Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: Direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Thyroid 23: Van Nostrand D 2011 Sialoadenitis secondary to 131I therapy for well-differentiated thyroid cancer. Oral Dis 17: Silberstein EB 2008 Reducing the incidence of 131Iinduced sialadenitis: the role of pilocarpine. J Nucl Med 49: Solans R, Bosch JA, Galofre P, Porta F, Rosello J, Selva- O Callagan A, Vilardell M 2001 Salivary and lacrimal

7 SALIVARY STIMULATION AND THE TREATMENT OF SIALADENITIS 845 gland dysfunction (sicca syndrome) after radioiodine therapy. J Nucl Med 42: Wiseman LR, Faulds D 1995 Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs 49: Bohuslavizki KH, Klutmann S, Brenner W, Mester J, Henze E, Clausen M 1998 Salivary gland protection by amifostine in high-dose radioiodine treatment: results of a double-blind placebo-controlled study. J Clin Oncol y 16: Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA 1999 Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Physics 45: Horiot JC, Lipinski F, Schraub S, Maulard-Durdux C, Bensadoun RJ, Ardiet JM, Bolla M, Coscas Y, Baillet F, Coche-Dequeant B, Urbajtel M, Montbarbon X, Bourdin S, Wibault M, Alfonsi M, Calais G, Desprez P, Pene F, Lapeyre M, Vinke J, Maral J 2000 Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study. Radiother Oncol 55: Leek H, Albertsson M 2002 Pilocarpine treatment of xerostomia in head and neck patients. Micron 33: Haddad P, Karimi M 2002 A randomized, double-blind, placebo-controlled trial of concomitant pilocarpine with head and neck irradiation for prevention of radiationinduced xerostomia. Radiother Oncol 64: Gorsky M, Epstein JB, Parry J, Epstein MS, Le ND, Silverman S, Jr The efficacy of pilocarpine and bethanechol upon saliva production in cancer patients with hyposalivation following radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97: Aframian DJ, Helcer M, Livni D, Robinson SD, Markitziu A, Nadler C 2007 Pilocarpine treatment in a mixed cohort of xerostomic patients. Oral Dis 13: Address correspondence to: Jae-Yol Lim, MD, PhD Department of Otorhinolaryngology-Head and Neck Surgery Inha University School of Medicine 27, Inhang-ro, Jung-gu Incheon Republic of Korea jylim@inha.ac.kr