Salivary and Lacrimal Gland Dysfunction After Remnant Ablation with Radioactive Iodine in Patients with Differentiated Thyroid Carcinoma Prepared with Recombinant Human Thyrotropin

Abstract

Background:

One of the adverse effects of radioactive iodine (¹³¹I) treatment in patients with thyroid cancer is damage to the salivary and lacrimal glands. In almost all studies evaluating salivary and lacrimal gland dysfunction, the patients received ¹³¹I after levothyroxine (L-T4) withdrawal. Since the biokinetics of ¹³¹I after recombinant human thyrotropin (rhTSH) is not the same as in hypothyroidism, studies need to evaluate ¹³¹I-induced salivary and lacrimal toxicity after preparation with rhTSH. This prospective study investigated the occurrence of salivary and lacrimal damage after ablation with ¹³¹I using this preparation.

Methods:

One hundred forty-eight patients who had a total thyroidectomy were included in the study. The subjects were evaluated after thyroidectomy during L-T4 use to exclude those who already showed symptoms or had a history of ocular or oral disease. Symptoms were investigated 12 and 18 months after ablation. In patients who had persistent symptoms, specific tests were performed to confirm glandular dysfunction and to rule out other causes.

Results:

Twelve months after ablation, symptoms of salivary or lacrimal dysfunction were observed in 10 (6.7%) patients, including oral symptoms in 8 (5.4%) and ocular symptoms in 6 (4%). Eighteen months after ¹³¹I, symptoms persisted in eight (5.4%) patients, including oral symptoms in seven (4.7%) and ocular symptoms in five (3.4%). In all of the patients, glandular dysfunction was confirmed by specific tests and other causes were ruled out. No symptoms were seen in the patients who received a low ¹³¹I dose (30 mCi). In the patients who received high ¹³¹I doses (100 or 150 mCi), symptoms were noted 12 months after ¹³¹I in 10 patients (9.2%), and 18 months after ¹³¹I in 8 patients (7.4%).

Conclusions:

Apparently, the rates of salivary and lacrimal damage were lower than those reported in prospective studies that used similar ¹³¹I activities, but these studies were performed in patients who were hypothyroid at the time of ¹³¹I ablation. Further studies are needed to compare radiotoxicity between patients prepared for ¹³¹I ablation with rhTSH and those prepared for ¹³¹I ablation with L-T4 withdrawal.

Introduction

O ne of the adverse effects of radioactive iodine (¹³¹I) treatment in patients with thyroid cancer is damage to the salivary and lacrimal glands, which may even occur after the administration of ¹³¹I for remnant ablation (1 –4). The frequency of this damage is relatively high (1 –4). Salivary and lacrimal gland dysfunction can be permanent in some cases (2,3), compromising the quality of life and causing complications in the affected patients (5).

In almost all studies evaluating salivary and lacrimal gland dysfunction, the patients received ¹³¹I after levothyroxine (L-T4) withdrawal. Since the biokinetics of ¹³¹I after recombinant human thyrotropin (rhTSH) is not the same as in hypothyroidism (6 –8), studies are needed to evaluate the ¹³¹I-induced salivary and lacrimal toxicity after preparation with rhTSH. So far, there are only two reports addressing this issue: a prospective study that evaluated hyperamylasemia after 48 hours and sialoadenitis up to 7 days after ablation (1), and another retrospective study that reported symptoms related to salivary damage several months after ablation (2). No study has evaluated the toxic effects of ¹³¹I on the lacrimal glands after rhTSH.

In 2003, when the use of rhTSH was introduced at our institution, we started this prospective study, which routinely and systematically evaluated the occurrence of salivary and lacrimal damage after ablation with ¹³¹I using this preparation. The results of this study are reported here.

Patients and Methods

A prospective study was conducted between August 2003 and August 2010, to study patients with differentiated thyroid cancer who had a total thyroidectomy with complete tumor resection, a postoperative clinical examination, and a chest radiograph with no distant metastases. The subjects were evaluated ∼10 weeks after thyroidectomy during L-T4 therapy to exclude those who already had symptoms or had a history of ocular or oral disease (9,10). In this assessment, the median serum TSH concentration was 1.1 mIU/L (range: 0.05–3.6 mIU/L).

The study included 148 patients. They received 0.9 mg rhTSH for 2 consecutive days followed by ¹³¹I administration on the third day (1.1 GBq [30 mCi], 3.7 GBq [100 mCi], or 5.5 GBq [150 mCi]). The patients were advised to increase their fluid intake and to chew gum, which was made freely available, to promote ¹³¹I discharge from the salivary glands. With the help of the family, we insisted that patients consume at least 2400 mL of nondairy fluid per day and chewed gum every 2 hours when awake for 5 days. The patients were also advised to wake up every 3 hours for the first 2 nights to consume fluid and chew gum. Patients receiving external radiotherapy were excluded.

Symptoms (9,10) were investigated 12 and 18 months after ablation. Six patients using anticholinergic drugs were evaluated after discontinuation for a period of >4 times the half-life of the drug (10). This investigation was done by the same physician (P.W.R.) and consisted of determining the presence of the manifestations shown in Table 1. Lacrimal dysfunction was suspected in the presence of at least two of the symptoms in item Ia or at least one of the symptoms in item Ib of Table 1. Salivary dysfunction was suspected in the presence of at least two of the signs or symptoms in items IIa and IIb or at least one of the symptoms in item IIc of Table 1. In patients who had persistent signs or symptoms (still present 18 months after ablation), specific tests were performed to confirm glandular dysfunction and to rule out other causes (9,10). These tests to confirm glandular dysfunction were only performed when symptoms were present considering that (i) there are no recommendations to perform these tests on asymptomatic patients, (ii) quality of life is impaired in the presence of symptoms, and (iii) treatment is recommended in symptomatic cases (5,9,11). Lacrimal dysfunction was confirmed by the Schirmer test (wetting of 5 mm or less, measured over 5 minutes under basal conditions with the eyes lightly closed) and the Rose Bengal score (≥4 according to van Bijsterveld's scoring system) (9,10). Salivary dysfunction was confirmed by a sequential salivary gland scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of the tracer (9,10). The scintigraphy was performed using 370 MBq (10 mCi) ^99mTc-pertechnetate. Other causes (9,10) were excluded by a clinical examination, serology for hepatitis B and C, HIV, and EBV, and measurement of angiotensin-converting enzyme and anti-Ro and anti-La antibodies.

Table 1.

Manifestations of Ocular and Oral Dysfunction

I.a. Ocular symptoms (9): foreign body sensation, redness, inability to tolerate contact lenses, photophobia, ocular fatigue, eyelids encrusted in the morning.

I.b. Questionnaire (10):

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?

2. Do you have a recurrent sensation of sand or gravel in the eyes?

3. Do you use tear substitutes more than three times a day?

II.a. Oral symptoms (9): Parched mouth, accelerated or unusual dental decay, swollen salivary glands, alteration in taste, difficulty chewing and swallowing dry foods (“cracker sign”), burning and cracking of lips and corners of mouth

II.b. Oral signs (9): Caries at incisal surface or gingival line, premature loss of teeth, loss of filiform papillae of the tongue, angular cheilitis, reduction of infralingual salivary pooling, parotid and/or submandibular enlargement

III.c. Questionnaire (10):

1. Have you had a daily feeling of dry mouth for more than 3 months?

2. Have you had recurrently or persistently swollen salivary glands as an adult?

3. Do you frequently drink liquids to aid in swallowing dry food?

Modified from Carsons, 2001, and Vitali et al., 2002 (9,10).

This study was approved by our local institutional review board.

Results

The characteristics of the patients studied are shown in Table 2. Twelve months after ablation, symptoms of salivary or lacrimal dysfunction were observed in 10 (6.7%) patients, including oral manifestations in 8 (5.4%) and ocular symptoms in 6 (4%). Eighteen months after ¹³¹I administration, symptoms persisted in 8 (5.4%) patients, including oral symptoms in 7 (4.7%) and ocular symptoms in 5 (3.4%). In all of the patients, glandular dysfunction was confirmed by specific tests and the presence of any other cause was ruled out. Patients who were asymptomatic after 12 months continued to be without symptoms after 18 months.

Table 2.

Characteristics of the Patients Studied

Sex (n)
Male	43
Female	105
Age, mean	46.4 years
Histologic type (n)
Papillary	136
Follicular	12
Tumor stage (n)
T1	40
T2	44
T3	64
N0	28
Nx	60
N1	60
M0	148 (all)
¹³¹I activity (n)
30 mCi/1.1 GBq	40
100 mCi/3.7 GBq	60
150 mCi/5.5 GBq	48

131

I, radioactive iodine.

No symptoms were seen in the patients who received a low ¹³¹I dose (30 mCi, n=40), and symptoms were detected only in patients who received high ¹³¹I doses (100 or 150 mCi, n=108); symptoms were detected in 10 (9.2%) patients after 12 months and in 8 (7.4%) after 18 months. Table 3 shows the frequency of persistent and symptomatic glandular dysfunction according to the ¹³¹I dose administered.

Table 3.

Frequency of Symptomatic and Persistent Salivary and/or Lacrimal Dysfunction 18 Months After Ablation According to ¹³¹ I Dose

	¹³¹ I dose
Dysfunction	30 mCi (n=40)	100 mCi (n=60)	150 mCi (n=48)
Salivary	0	3^a (5%)	4^b (8.3%)
Lacrimal	0	2^c (3.3%)	3^d (6.25%)
Salivary or lacrimal	0	3 (5%)	5 (10.4%)

Data are presented as number of patients (percent).

Number of signs and/or symptoms in each patient: ^a3, 5, and 6; ^b2, 5, 5, and 8; ^c2 and 4; ^d2, 4, and 6.

Discussion

The prospective design of this study should be emphasized. The presence of symptoms and a history of salivary or lacrimal disease were systematically evaluated before ablation. Symptoms were actively investigated after ¹³¹I administration, regardless of spontaneous reporting by the patient. In symptomatic subjects, glandular dysfunction was confirmed by specific tests and other causes were ruled out (9,10). Eighteen months after ablation, none of the patients treated with a low ¹³¹I dose (30 mCi) and only 7.4% of those treated with a high dose (100–150 mCi) had symptomatic salivary or lacrimal dysfunction.

One limitation of the present study was the lack of a group exposed to L-T4 withdrawal. Apparently, the rates of salivary and lacrimal damage were lower than those reported in the only two prospective studies that used similar ¹³¹I doses and assessment intervals, but with the patients being hypothyroid at the time of ablation (3,4). In the first study (3), 37% of the patients reported oral symptoms and 15% reported ocular symptoms 1 year after treatment with 3.7 GBq ¹³¹I. In the other study (4), oral symptoms were observed in 21% of the patients 1 year after they had received 2.95–8.6 GBq ¹³¹I. As in the present investigation, patients with symptoms before ¹³¹I therapy were not included, glandular dysfunction was confirmed by specific tests, and other causes were ruled out in those studies (3,4). It would therefore be unlikely that the rates were overestimated and it is possible that a difference between preparations truly exists. Blood and extrathyroid radiation is lower after preparation with rhTSH (6 –8), a fact thereby reducing actinic tissue damage. Furthermore, a lower frequency of acute adverse effects of ¹³¹I after rhTSH has been demonstrated (1,12). However, another study did not confirm this finding in relation to persistent oral symptoms (2).

Further studies are needed to compare the radiotoxicity between patients prepared with rhTSH and those having L-T4 withdrawal.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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