The role of radioactive iodine in salivary gland dysfunction.

Abstract

The use of radioactive iodine has become an important adjunct to the treatment of thyroid cancer. Many normal tissues--including salivary glands, gastrointestinal mucosa, gonads, and lactating breast tissue--have the ability to concentrate radioactive iodine under normal circumstances. Although the mechanism is just beginning to be elucidated, it is this ability that might contribute to the immediate and long-term complications associated with radioactive iodine treatment. In some patients, the salivary complications can be permanent and might compromise daily .functioning. In this article, we examine the salivary gland complications associated with radioactive iodine therapy, and we suggest potential protective mechanisms to circumvent these problems.

Introduction

Salivary glands serve a vital function in the maintenance of periodontal health, the preparation and delivery of nutrients to the alimentary tract, taste discrimination, and speech. The main product of the salivary glands, saliva, plays an integral part in maintaining oral competency, both physiologically (through the presence of proteins such as amylase, immunoglobulins, and lysozyme) and functionally (through lubrication of the oral mucosa). A loss or decrease of salivary flow or production can impair the ability to perform these functions and is associated with increased morbidity. The ability to concentrate iodine and radioactive iodine makes the salivary glands potential targets during and after the use of these modalities.

In this article, we discuss the short- and long-term effects of radioactive iodine on salivary gland function. In addition, we discuss the potential role of modulating and cytoprotective agents, with emphasis on the prevention of salivary gland dysfunction.

Normal anatomy and physiology

Physiology of saliva. The major salivary glands consist of three pairs of tissue: the parotid glands, the submandibular glands, and the sublingual glands. The minor salivary glands--which number between 600 and 1,000--line the oral and nasal mucosa and the upper digestive tract. Embryogenesis of the major and minor salivary glands in the oral cavity begins with the development of the major ducts from ectodermal tissue. [1] Salivary gland development begins during the fourth week of gestation with the development of the parotid glands, followed by the development of the submandibular glands at 6 weeks, the sublingual glands at 8 weeks, and the minor salivary glands at 3 months. The mesenchyme is penetrated by proliferating buds that arborize and terminate in acini. The epithelial buds enlarge and the glands canalize before the completion of acini development.

In the oropharynx, normal physiologic function of the salivary glands involves: (1) lubrication, (2) enhancement of digestion through enzymatic and mechanical manipulation, (3) production of hormones and other metabolically active compounds, (4) immunologic defense, and (5) mediation of taste. These glands are primarily under the control of the autonomic nervous system. Parasympathetic stimulation appears to be the major contributor to saliva production, but sympathetic input also plays a role. [2]

The parotid glands receive their neural input primarily from secretomotor fibers transmitted from the otic ganglion. Sympathetic nerve fibers from the superior cervical ganglion, along with the postganglionic fibers of the parasympathetic nervous system, synapse with intercalated cells, myoepithelial cells, and acinar cells. After interaction with the appropriate receptor, cholinergic stimulation (parasympathetic) via a [Ca.sup.++]-mediated second messenger system causes saliva production in both the parotid and submandibular glands and enzymatic secretion in the parotid glands.

Beta-adrenergic stimulation, via cyclic AMP second messenger systems, increases cellular metabolism and enzymatic secretions. In the submandibular glands, betaadrenergic production has the added benefit of increasing mucin production. Both second messenger systems interact downstream with effector substances that help to bring about the observed effects. In addition, a host of metabolically active compounds has been implicated in the normal physiologic function of the salivary glands. Epidermal growth factor, nerve growth factor, renin, and kallikreins have been found in the salivary glands of many mammalian species, and they might be implicated as playing a role in maintaining normal salivary gland homeostasis.

Saliva typically has a varied composition, which is dynamically altered in response to the complex interaction of many of the stimuli mentioned above. Saliva from the submandibular glands is primarily mucinous, whereas the parotid glands produce a primarily serous secretion. In a 24-hour period, most saliva appears to emanate from the parotid and submandibular glands. The sublingual glands make a minor contribution in terms of volume, but a major contribution in terms of viscosity. The final product is made up of macromolecule proteins (e.g., amylase, lysozyme, carbonic anhydrase, and secretory immunoglobulin A), various ions that influence the normal physiologic pH in the range of 5.4 to 7 (e.g., [Na.sup.+], [K.sup.+], [I.sup.-], [Cl.sup.-], [H.sub.2][[CO.sup.-].sub.3], and [Ca.sup.++]), and water.

The secretory functions of the acinar cells involve the production, storage, and concentration and release of secretory proteins via exocytosis (i.e., the fusion of the secretory granule membrane with the plasma membrane and the release of its contents). During this process, the secretory proteins are subjected to extensive modification by various intracellular organelles (e.g., the rough endoplasmic reticulum and Golgi's apparatus). Stimulated glands produce secretions at a rate of approximately 0.5 to 1.0 ml/min/g of glandular tissue; a total volume of 1 to 1.5 L is produced in a 24-hour period. Flow rates are highest during meals as the glands respond to cognitive, neuronal, and physical stimuli.

Sodium/iodide symporter. In thyroid cells, iodide uptake occurs across the basolateral membrane and is driven by an inwardly directed [Na.sup.+] gradient in an active transport process. [3] The sodium/iodide symporter involved in the concentration of iodide in the thyroid gland has been sequenced and cloned. [4,5] The same receptor has been found to exist in salivary glands, gastric cells, and other extrathyroidal tissues. In salivary glands, the expression seems to be most prevalent in the ductal cells, not the acinar cells, according to immunohistochemical analysis. [6] The sodium/iodide symporter outside the thyroid gland, however, does not appear to be affected by thyroidstimulating hormone, even though the sequence appears identical to that of the thyroid receptor on Northern blot analysis and DNA sequencing analysis. [7] The differential responsiveness to stimulation by thyroid-stimulating hormone might be a result of post-translational modification of the receptor at various sites. A recent finding that has clinical implications is that antibodies to the receptor have been discovered in the sera of patients with autoimmune thyroid disease. [8] It has been suggested that these same antibodies might have a role in the pathogenesis of autoimmune-mediated salivary gland diseases such as Sjogren's syndrome, although no direct investigations have studied this population.

Radioactive iodine in thyroid disease

It was estimated that 17,200 new cases of thyroid cancer--and 1,200 deaths--occurred in the United States in 1998, representing 1.4% of all new cancer cases overall. [9] Most patients with thyroid cancer have well-differentiated carcinomas, either of papillary or follicular origin. The primary treatment of clinically apparent disease is surgery; the degree of resection depends on the histology and the extent of the disease.

In our view, postoperative management should consist of whole-body scanning with either radioiodine 123 or 131 ([I.sup.123] or [I.sup.131]) for the detection of metastatic or residual disease, and it should be followed by ablation therapy with [I.sup.131]. The dose administered for ablative therapy typically ranges from 30 to 150 mCi, although there is some debate in the literature over the appropriate amount.

Several recent reviews address the role of radioactive iodine in the treatment of thyroid diseases, and the reader is referred to them for more in-depth detail. [10,11]

Salivary gland dysfunction

Uptake of radioactive iodine by normal tissues. It has been known for many years that irradiation causes salivary gland dysfunction. This has important implications in the pathogenesis of intraoral disease in patients with head or neck cancer. Typically, irradiation of the head and neck can result in a loss of salivary gland function in about 50 to 80% of patients in a dose-dependent manner. Doses in excess of 50 Gy cause irreversible damage to salivary tissue. Because it has been estimated that 40,000 patients per year receive irradiation to the salivary gland area (from either external-beam sources, internal sources, or [I.sup.131]), this presents a potentially serious problem. [12] Radiation damage can lead to mucositis, a loss of taste acuity, an increase in dental caries, and alterations in nutritional status. The primary damage is to acinar and ductal cells, and it can alter ion, mucous, and serous secretions--that is, the number of sodium and chloride ions is increased and the amount of bicarbonate and serous sec retions is decreased.

The impact of radioactive iodine on salivary gland tissue has been known for more than 40 years. Xerostomia, an increase in dental caries, sialadenitis, and taste disturbances are recognized complications of radioactive iodine therapy. [13,14] Prostaglandins, which have been implicated in stimulating salivary gland function, have been found to be decreased in patients who receive [I.sup.131] treatment for thyroid cancer and hyperthyroidism. [15] It has been suggested that benign thyroid disease states such as hyperthyroidism can influence the composition and flow of saliva, although the exact mechanism is unknown. [16]

As in the thyroid gland, iodide concentrations in salivary glands can reach 30 to 40 times that seen in plasma. Salivary gland uptake can occur to such a degree that it can show up on a scan as uptake and be confused with metastatic thyroid disease. [17] Salivary gland flow is decreased in a dose-related manner in patients who have received radioactive iodine. Malpani et al studied the effects of [[blank].sup.99m]Tc[O.sub.4] - uptake and excretion in response to sialagogue stimulation in 33 thyroid cancer patients who received radioactive iodine (range: 1.369 to 38.702 GBq [37 to 1,046 mCi]; mean: 10.16 [pm] 7.659 GBq [274.594 [pm] 207 mCi]) and in 14 athyrotic patients. [18] More than 70% of the thyroid cancer patients experienced an abnormal uptake and excretion of [[blank].sup.99m]Tc[[O.sup.-].sub.4]. There was also a dosedependent decrease in uptake in response to sialagogue stimulation with higher doses of radioiodine, which affected the parotid glands more than it did the submandibular glands. Mild parenchymal dysfunction can requ ire quantitative analysis, and it can be difficult to assess by functional [Tc.sup.99m] -pertechnetate scanning. [19]

Aside from these short- and long-term functional effects, there is also a theoretical concern about the development of salivary gland neoplasms after radioactive iodine therapy. Prevailing data seem to suggest that the incidence of salivary gland neoplasms after radioiodine therapy is low. [20,21] Few reports have been cited in the literature of salivary gland neoplasms that occurred after radioiodine therapy. [22] Given the small number of patients who receive radioactive iodine therapy, proving a causal relationship between the administration of therapy and the development of malignancy would require a large, prospective, multicenter study.

Assessment of dysfunction. In assessing salivary gland dysfunction, it is important to quantify patients' subjective complaints of xerostomia. The [Tc.sup.99m]-penechnetate is taken up and excreted by salivary gland tissue, and it has been used to evaluate salivary gland function. Spiegel et al used [Tc.sup.99m]-pertechnetate to quantify salivary flow before and after cumulative doses of 170 to 270 mCi of [I.sup.131] in 20 patients who had been diagnosed with thyroid fcancer. [23] Pertechnetate uptake was measured before and after salivary gland stimulation with 2 ml of lemon juice. The authors reported a dose-dependent decrease in salivary gland function, as parotid gland function was reduced by 40% after doses of 270 mCi.

In studying parotid gland function after [I.sup.131] therapy, Maier and Bihl measured stimulated salivary flow rates in a Stenson's duct stent before and 1 week after treatment with [I.sup.131]. [24] Levels of sodium, total protein, and alpha amylase activity were measured with standard techniques. There were three study groups: 16 patients received the first-time dose, which was 70 mCi; 14 patients received their second dose, which was 100 mCi; and six patients received the third dose, which was also 100 mCi and which raised their cumulative dose over the three sessions to 270 mCi. The pretherapeutic flow rates were significantly higher in the first group than in the third group (p[less than]0.001). The authors found that both the protein and sodium concentrations increased significantly in all three groups, but alpha amylase activity increased significantly only in the second and third groups. Three patients developed acute parotitis (one in the second group and two in the third), but parotid flow did not fall below normal in any group. The authors speculated that the ion and protein alterations were secondary to damage to the intraglandular vasculature. Similar alterations have been reported after external-beam radiation in head and neck patients. [25] It might be this type of alteration in saliva composition that accounts for the side effects of radiation therapy. Markers of parotid gland inflammation were also elevated, but the clinical significance of this has yet to be determined.

Complications. Immediate side effects after radioactive iodine are fairly common. Most, however, tend to be short lived, and there are usually no permanent sequelae. Studies have shown that the incidence of salivary gland dysfunction might be as high as 30% in patients who receive [I.sup.131] in cumulative doses as high as 300 mCi and 50 to 60% in those who receive it in the area of 500 mCi. [26] Almost all patients who receive 1 Ci or more experience some form of dysfunction. [27] Khan et al reported the onset of sialadenitis and xerostomia in 34 and 18% of patients, respectively; 50% also experienced nausea. [28] Therefore, even though initial side effects are common after radioactive iodine therapy, from an otolaryngologic perspective it is more relevant to consider the therapy's long-lasting effects.

Caries. Increases in the number of dental caries have been described in patients who have undergone radioactive iodine therapy. [29] This onset of caries is believed to be secondary to radiation-induced xerostomia, which predisposes to an overgrowth of cariogenic flora. Nevertheless, dental complications do not occur nearly as often after radioactive iodine therapy as they do after external-beam radiation to the head and neck. Laupa et al found that stimulated salivary flow rates were 25.6 and 28.9% lower in male and female cancer patients, respectively, than they were in noncancer controls. [29] They also reported that levels of cariogenic Streptococcus mutans were not significantly different in head and neck cancer patients, nor was there a significant incidence of dental caries. In fact, the incidence of dental caries does not appear to be higher in thyroid cancer patients who receive [I.sup.131] therapy than it is in the general population. This might be attributable to the contribution of the subm andibular and sublingual glands to saliva composition, because these glands appear to be less affected by radioiodine therapy.

Xerostomia. The predisposing factor in the development of oral complications following radioiodine therapy is believed to be the decrease in salivary flow that leads to xerostomia. In their study of patients who had received [I.sup.131] therapy for thyroid cancer, Allweiss et al found that 10 of 87 patients (11.5%) had experienced salivary gland dysfunction after a median dose of 100 mCi. [30] Nine of the 10 patients had received between 40 and 280 mCi before the precipitating dose. Symptoms included recurrent salivary gland tenderness (nine patients), salivary gland swelling (nine patients), dry mouth (three patients), and bitter taste (three patients). The parotid glands were involved most often, followed by the submandibular glands. The authors reported that the mean duration of symptoms was 2 years for symptoms that had begun as early as 1 week following therapy. Three patients required antibiotics for suppurative sialadenitis, and one patient required a parotidectomy for intractable pain. Four patients had received external-beam head and neck radiation, but the dosage was unknown. Salivary gland function was not assessed in these patients.

Temporal dysfunction/taste disturbance. Salivary gland dysfunction has been found to occur in patients even after low-dose therapy. Patients usually experience transient side effects during the immediate post-treatment period, but sometimes long-term side effects are encountered. Lin et al studied 56 patients with well-differentiated thyroid cancer who received 40 mCi of [I.sup.131] after wholebody scanning with 2 mCi of [I.sup.131]. [31] Patients were examined for signs and symptoms of salivary gland dysfunction before treatment and on days 2 and 7 after treatment. The most common side effects were xerostomia and nausea, which occurred in about 5% of patients. Most symptoms began within 24 to 48 hours and, except for the xerostomia, resolved within 1 week of therapy; one patient experienced parotid gland tenderness, and one patient had submandibular gland tenderness.

Alexander et al interviewed 203 patients who were being followed for well-differentiated thyroid carcinoma. [32] Patients were advised to increase their fluid and secretagogue intake prior to therapy, and those who could tolerate it were given pilocarpine. Patients were assigned to one of five groups, depending on the cumulative dosage of radioiodine they had received: 134 mCi or less (n=38); 135 to 269 mCi (n=71); 270 to 499 mCi (n=53); 500 to 999 mCi (n=24), and 1 Ci or more (n=17). The duration of complaints was classified as either intermediate (from discharge to 3 mo) or long term ([greater than]3 mo). One-third of these patients (67/203) reported intermediate sialadenitis; the parotid glands were involved in 81% of these cases (54/67) and the submandibular glands in 46% (31/67). Bilateral involvement occurred in the parotid glands in 60% (40/67) and in the submandibular glands in 74% (23/31). Taste disturbance was reported by 27% of the patients (55/203), but it returned to normal within 12 weeks. Alm ost 43% of patients (87/203) reported dry mouth, but complete xerostomia--defined as the inability to swallow food without simultaneously drinking water--was reported by only 4.4% (9/203). Symptoms appeared to be dose dependent. It is interesting that the patients who were given pilocarpine experienced no significant decrease in dysfunction.

Van Nostrand et al described a method of estimating the maximum safe dose of radioiodine by calculating the average beta dose administered to the blood per mCiday. [33] Their dose estimations were based on the total number of sessions (15) that their 10 patients underwent. Symptoms or signs of salivary gland dysfunction occurred during 10 of 15 therapy sessions. Pain occurred in six; tenderness in three; swelling in three; and bitter taste, loss of taste, or dry mouth in five. Only one case of dry mouth persisted beyond three sessions, and it eventually resolved without further intervention. During 60% of the therapy sessions (9/15), salivary gland side effects occurred while patients were in the hospital; following 20% of these sessions (3/15), symptoms still persisted at 3 months. It is interesting that taste disturbances occurred after the administration of doses ranging from 230 to 450 mCi and in patients who had previously received doses of at least 100 mCi (range: 100 to 664 mCi). This indicates that large doses of isotope might be necessary before taste is noticeably affected.

Cancer risk. One of the major concerns about radioiodine is that it can place patients at risk for secondary malignancies. At particular risk are organs that concentrate [I.sup.131]--namely, the salivary glands, the digestive tract, and the bladder. [34] Hall et al examined the records of 1,955 thyroid cancer patients in the Swedish cancer registry between 1950 and 1975. [20] Of this group, 834 patients (43%) received [I.sup.131] therapy (group 1), while the remaining 1,121 patients did not (group 2). The two groups were comparable in terms of mean age and gender distribution. Neck irradiation was administered to 36 and 37% of groups 1 and 2, respectively, and whole-body irradiation was administered to 16 and 6%, respectively. The mean total dose of [I.sup.131] was 123 mCi (range: 13 to 1,360). Of the patients who were irradiated with [I.sup.131], 78% received it to ablate the thyroid and 22% for the treatment of distant metastases. Seventy-eight percent of the patients received only one dose. The estimated radiation doses to the salivary glands, stomach, small intestine, and bladder were 1.9, 2.1, 1.4, and 2.1 Gy, respectively. Papillary cancers were present in 54% of group 1 and 61% of group 2, and follicular cancers were present in 31 and 15%, respectively. The mean period until the development of a second malignancy was 11 years in the [I.sup.131] group and 12 years in the other group. In terms of secondary cancers, group 1 had a higher-than-expected incidence of salivary gland, kidney, female genital, and adrenal gland malignancies. In group 2, a higher-than-expected incidence was seen only in the adrenal glands. Organs that received more than 1.0 Gy (salivary glands, stomach, small intestine, and bladder) had higher-than-expected cancer rates.

Edmonds and Smith reviewed the histories of 241 patients who had received radioiodine therapy for thyroid cancer (mean followup: 11.2 yr). [21] The radiation dose to be delivered to selected organs was estimated on the basis of the amount of [I.sup.131] in the normal thyroid tissue, tumorous thyroid tissue, and other tissues. Ten percent of these patients experienced pain in one of the salivary glands, but none developed a malignancy there, and there were no serious side effects. Three patients did develop nodules, but their etiology was not disclosed. The authors noted that these patients did have a slightly higher risk of bladder cancer and leukemia.

More recently, Ron et al retrospectively reviewed the experience of more than 35,000 patients who had been followed for hyperthyroidism. [35] Some 91% of these patients had Graves' disease, and 65% were treated with [I.sup.131] (mean dose: 6.1 mCi per treatment; mean number of treatments: 1.8). Radioactive iodine was not linked to the incidence of total cancer mortality or to the incidence of any specific cancer other than thyroid cancer. It must be noted that salivary gland malignancy was not noted in this population. This is in contrast to the findings of Hoffman et al, who found an increased risk of salivary gland malignancies in hyperthyroid patients who were treated with radioiodine therapy. [34] Overall, however, based on these studies, it appears that radioactive iodine does not definitively contribute to the development of subsequent salivary gland neoplasia, despite the high doses that these tissues receive.

Modulation of salivary gland dysfunction

Sialagogues and hydration. Sialagogues have an important function in preventing the sequelae of radioiodine therapy. Creutzig reported that the use of salivary stimulants such as lemon products has been suggested to decrease the transit time of radioiodine through the salivary glands, potentially decreasing the amount of radiation exposure to the tissues. [36] He reported a progressive loss of salivary gland function with increasing doses of [I.sup.131], even as long as 6 months after therapy. Hydration and sialagogues are a reasonable treatment option for preventing radiation-induced sialadenitis. However, even with proper precautions, patients still experience side effects, so new strategies ought to be investigated.

Cytoprotective agents. Ongoing work on the prevention of the salivary gland complications of radioactive iodine therapy has focused on agents that protect salivary gland cells without compromising therapeutic efficacy. Several options have been explored, including the use of substances that inhibit catecholamine uptake and metabolism [37] and the use of cholinergic preparations such as pilocarpine. [38] Zinc-containing compounds (e.g., zinc-desferrioxamine) have also been credited with reducing the damaging effects of radiation-induced salivary gland dysfunction in animal models, presumably by acting as free-radical scavengers. [39] Again, further investigations into these areas are required.

Another promising compound is the aminothiol amifostine (WR-2721), developed during the Cold War as part of the military's search for an agent that would protect personnel in case of a nuclear attack. [40-42] Amifostine is a prodrug that is metabolized into its active form by desphosphorylation of the compound by membrane-bound alkaline phosphatases. The active compound (WR-1065) is taken up into cells and is believed to be responsible for the cytoprotective effect against both radiation and chemotherapeutic compounds. In animal models, the compound is differentially taken up by normal cells rather than by tumor cells. One of its mechanisms of action is believed to be the scavenging of free radicals through its free thiol group. [41] The efficacy of this compound in reducing radiation- and drug-induced toxicities while not interfering with their antitumor activity has been proven in numerous preclinical studies on various cell lines, including head, neck, and salivary gland tissue. The use of amifostine migh t be most appropriate in the setting of external-beam radiation, where the local tissue is at a much higher risk of complications such as mucositis, which can be devastating during and after treatment.

Typically, patients who receive radiation doses in excess of 50 Gy are at high risk for complications. Buntzel et al conducted a phase II study of 39 patients with advanced head and neck cancer who received a combination of fractionated radiotherapy and simultaneous carboplatin chemotherapy (total dose: 60 Gy). [43] Twenty-five patients were randomized to receive a 500-mg infusion of amifostine 15 minutes prior to chemotherapy dosing. None of the amifostine patients experienced grade III or IV mucositis, while 12 of the 14 controls did. In addition, the incidence of xerostomia, leukopenia, and thrombocytopenia was significantly lower in the amifostine group. Similar findings were published by McDonald et al. [44]

Amifostine also has potential for patients who undergo radioactive iodine therapy, particularly those who receive multiple treatments and cumulative doses greater than 500 mCi. Amifostine shows a greater amount of uptake in normal salivary gland tissue than in normal thyroid tissue. [45] Bohuslavizki et al prospectively evaluated salivary gland function in 50 patients who had well-differentiated thyroid cancer. [46] In this group, 21 patients received 3 GBq (81.1 mCi) and 29 patients received 6 GBq (162.2 mCi) as their second treatment (which was administered 6 months after their initial 3-GBq dose). Patients in both groups were randomized to receive either IV amifostine (500 mg/[m.sup.2]) or placebo directly before [I.sup.131] therapy. Quantitative salivary gland analysis was performed with 100 to 120 MBq of [Tc.sup.99m]-pertechnetate. Three months later, both parotid and submandibular gland function were significantly diminished in the control group, but not in the amifostine group. After 1 year, 11 of the 25 cont rols (44%) developed xerostomia, compared with none of the 25 amifostine patients. A significant decrease in mean blood pressure was noted in the amifostine group, which forced a temporary suspension of infusion in two patients. The clinical benefits seen in this study mirror the findings of preclinical studies.

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