Large, Compressive Goiters Treated with Radioiodine

Methods

Patients

Twenty-one patients, 18 women and 3 men (mean age ±SD, 67 ±14 years; range, 46 to 86 years), were entered into the study. All patients had a large, multinodular goiter (>100 mL) that caused tracheal compression. Multinodularity was confirmed by thyroid scintigraphy that was done 2 hours after intravenous administration of 37 MBq (1 mCi) of sodium iodide (Iodine-123). Nineteen patients had intrathoracic extension of the goiter of more than 2 cm, as shown on MRI. One patient had a completely intrathoracic goiter. There was no clinical suspicion of thyroid malignancy in any patient. In two patients with a large cold nodule, examination of fine-needle aspiration biopsy specimens showed no signs of malignancy. Radioiodine treatment was chosen because of the high operative risk primarily related to cardiopulmonary disease or because the patient refused to have surgery.

Seventeen patients were clinically euthyroid and had serum free thyroxine (fT₄) and total triiodothyronine (T₃) levels within the normal range of our laboratory (fT₄, 9.0 to 17.0 pmol/L; T₃, 1.5 to 3.5 nmol/L). In 5 of these patients, the serum TSH level was clearly suppressed (<0.1 mU/L). For treatment of hyperthyroidism, 4 patients received a thyroid-blocking dose of methimazole, which was combined with L-thyroxine to prevent hypothyroidism. Thyroid surgery had been done in 8 patients (in 1 patient twice and in another three times) 4 to 50 years before radioiodine treatment. One euthyroid patient had been treated with 1.1 GBq (40 mCi) of radioiodine for hyperthyroidism 4 years before entering into our study. In 3 of the euthyroid patients, previous TSH-suppressive treatment with L-thyroxine had not reduced goiter size and had been stopped 3 months before radioiodine treatment.

Radioiodine Therapy

Radioiodine was given as a single intravenous dose on an in-patient basis. Corticosteroids were not administered routinely. The administered activity was aimed at delivering 3.7 MBq (100 microcuries) of ¹³¹I/g of thyroid tissue retained at 24 hours according to the following formula: administered activity (GBq) = (thyroid weight [g] × 0.37)/24-hour thyroid radioactive iodide uptake (%) [11]. Twenty-four hours after patients orally ingested 7.4 MBq (200 microcuries) of Iodine-131, we measured thyroid radioactive iodide uptake (normal range, 10% to 59%) and made a rectilinear thyroid scintigram. We estimated thyroid weight from the planimetric surface on the scintigram using the formula of Doering and Kramer [12]: thyroid weight (g) = 0.326 x (surface in cm²)^3/2. After radioiodine therapy, euthyroid patients were treated with L-thyroxine to keep serum TSH levels below 1.5 mU/L. Hyperthyroid patients continued to receive the combination therapy with methimazole and L-thyroxine during the first 6 months after radioiodine therapy (patients did not receive methimazole for 3 days before and 3 days after therapy).

Assessment of Anatomical and Functional Results

We assessed anatomical and functional measurements before and 1 year after radioiodine therapy. In a medical interview and physical examination, special attention was paid to compressive symptoms and signs (such as inspiratory stridor, dyspnea, voice changes, and the Horner syndrome). The same observer measured maximal neck circumference and central venous pressure before and 1 year after radioiodine therapy. Blood samples were obtained for measurement of serum levels of TSH (Delfia hTSH Ultra, Wallac Oy, Turku, Finland), T₄ (in-house radioimmunoassay), T₃ (Amerlex-M T3, Kodak Clinical Diagnostics Ltd., Amersham, United Kingdom), fT₄ (SPAC fT4, Byk-Sangtec Diagnostica, Dietzenbach, Germany) and thyroglobulin (IRMA-mat Thyroglobulin, Byk-Sangtec Diagnostica). We determined 24-hour thyroid radioactive iodide uptake as described above.

Thyroid volume was measured with MRI (Siemens Magnetom 63SP, Erlangen, Germany) operating at a field strength of 1.5 tesla). We obtained T₁-weighted images (TR [relaxation time] = 270 ms, TE [echo time] = 15 ms) by using a Helmholtz neck coil and covering the entire thyroid in the coronal, sagittal, and axial planes. The thyroid outline was drawn manually on each slice, and a computer program calculated the surface of the traced areas. To calculate the thyroid volume, we multiplied the sum of the traced surfaces in each plane by the slice distance (0.88 cm). Thyroid volume, as used hereafter, is the mean of the measurements in the three imaging planes. Precision of this method is high. In patients with a large, multinodular goiter, the intraobserver coefficient of variation is 2.2% ±2.0%, and the interobserver coefficient of variation is 4.1% ±2.2% [10]. We used axial MRI slices to measure the largest deviation of the center of the tracheal lumen from the midline (oriented on the center of the vertebral canal and the spinous processes and supraspinal ligaments). The smallest cross-sectional area of the tracheal lumen, a measurement of tracheal compression [13], was measured planimetrically in axial MRI slices. All measurements were done blinded.

We measured forced inspiratory volume in 1 second (FIV₁) as a functional index of upper airway obstruction. We compared values of our patients with values obtained from age- and sex-matched normal persons [14]. Reference values are described by the following equation: FIV₁ (mL) = ( −0.0025 x age in years + 0.69) x total lung capacity (mL). An FIV₁ that was more than 20% less than the reference value was considered below normal. An otolaryngology specialist tested the vocal cord motility of all patients before and 1 year after radioiodine therapy.

Statistical analyses were done using the Wilcoxon sign-rank test for paired observations (P values denoted as P) and the Spearman rank-correlation test (P values denoted as P*). The mean values ±1 standard deviation are given.

Results

After intravenous administration of Iodine-131 at a dose of 2.6 ±1.0 GBq (71±26 mCi) (range, 1.4 to 5.6 GBq [37 to 150 mCi]), patients were hospitalized for 5 to 21 days. We observed no exacerbation of compression symptoms after patients received radioiodine. Two patients had a sore throat that was probably caused by radiation sialadenitis or esophagitis, but spontaneous and complete recovery was reached within 4 weeks. We observed no symptoms or signs of thyrotoxicosis caused by radiation thyroiditis.

Of the 21 patients who entered the study, 19 could be evaluated 1 year after radioiodine therapy. An 84-year-old euthyroid woman had died of an unrelated cardiac cause 1 month after radioiodine therapy. A 67-year-old hyperthyroid woman had thyroid surgery because of insufficient relief of tracheal compression despite a second dose of Iodine-131 that was given 7 months after the first dose (total dose, 6.4 GBq [173 mCi]). Thyroid volume was reduced 10% as measured by MRI at the time of operation (10 months after the first dose of Iodine-131), and the smallest cross-sectional area of the tracheal lumen and the FIV₁ had not changed.

Anatomical Results

Table 1 shows anatomical results for the 19 patients who were evaluated before and 1 year after radioiodine therapy. Before therapy, thyroid volume as measured with MRI was 269 ±153 mL (range, 109 to 825 mL). One year after radioiodine therapy, thyroid volume was 154 ±73 mL (range, 57 to 381 mL; P < 0.001). Expressed as the percentage of pretreatment thyroid volume, reduction was 40% ±15% (range, 19% to 68%) (Figure 1). Neck circumference decreased by 3 ±2 cm [range, 0 to 8 cm]. The circumference of one patient with a completely intrathoracic goiter decreased 0 cm). The decrease in neck circumference was significantly correlated with the percentage of volume reduction (r = 0.557; P* < 0.02).

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Figure 1. Data are expressed as percentages of pretreatment values. Thyroid volume (left), maximal deviation of the tracheal center from the midline (middle), and smallest cross-sectional area of the tracheal lumen (SCAT) (right) measured before and 1 year after radioiodine therapy in 19 patients with a large, compressive multinodular goiter.

The maximal deviation of the trachea from the midline was 1.9 ±0.8 cm (range, 0.2 to 3.1 cm) before and 1.5 ±0.7 cm (range, 0.2 to 2.6 cm) 1 year after radioiodine therapy (P < 0.001). The mean decrease was 20% ±20% (range, −4% to 73%) (Figure 1). In 13 patients, tracheal deviation decreased more than 10% (including a 20% to 30% decrease in four patients and a greater than 30% decrease in four patients).

The smallest cross-sectional area of the tracheal lumen was 0.78 ±0.38 cm² (range, 0.29 to 1.70 cm²) before therapy and 1.04 ±0.48 cm² (range, 0.30 to 2.19; P < 0.001) after therapy. The mean increase was 36% ±38% (range, −3% to 124%) (Figure 1). We observed an increase of more than 10% in 15 patients (including an increase of 50% to 100% in six patients and an increase of more than 100% in two patients). In four patients, the smallest cross-sectional area of the tracheal lumen changed very little (<5%). Increase of the smallest cross-sectional area of the tracheal lumen was significantly correlated with the decrease in thyroid volume (r = 0.727; P* < 0.001).

Functional Results

The FIV₁ was 2285 ±1145 mL before therapy (range, 675 to 4450 mL) and 2515 ±1129 mL after therapy (range, 775 to 4600 mL; P < 0.01). In 8 of 18 patients, the FIV₁ increased more than 10% (11% to 20% in 3 patients, 21% to 30% in 2 patients, 31% to 50% in 2 patients, and 120% in 1 patient). Before radioiodine treatment, FIV₁ was below normal (that is, more than 20% less than the reference value) in 6 patients. One year after therapy, it had returned to normal in 2 of these patients and had considerably improved in 2 others. The 2 patients in whom FIV₁ had not improved had vocal cord paralysis caused by previous surgery. Symptoms of superior vena cava obstruction disappeared in 1 patient Figure 2, and elevated central venous pressure returned to normal in another patient.

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Figure 2. 6 GBq (150 mCi) of Iodine-131. Note the distended neck veins and edematous face as signs of compression of the superior vena cava before therapy (A) and their improvement 1 year after therapy (B). Published by permission of patient. Patient 17 before and 1 year after treatment with 5.

Table 2 shows the effects of radioiodine treatment on subjective patient reports that were related to compression of the trachea and esophagus. Dyspnea and stridor improved in 8 of 12 patients, and dysphagia improved in 7 of 8 patients. As reported by the patients, the most important subjective improvement was achieved within the first 3 months after radioiodine treatment.

Thyroid Function after Radioiodine Therapy

Hyperthyroidism was eliminated within 6 months in the four hyperthyroid patients. Patient 9, who was clinically euthyroid before therapy and had normal fT₄ and T₃ levels and a suppressed TSH level, developed hyperthyroidism 7 months after radioiodine treatment. At that time, antithyroglobulin and antimitochondrial antibodies were negative. The 3-hour thyroid radioactive iodide uptake was 64% (normal range, 5% to 30%), and examination of a scintigraph of the thyroid showed an almost diffuse Iodine-123 uptake in the whole thyroid gland. The patient was treated with methimazole for 9 months and received a second dose of radioiodine (1.8 GBq or 67 mCi) 16 months after the first radioiodine treatment. We could not accurately assess the effects on thyroid function in the other euthyroid patients because of L-thyroxine treatment after radioiodine therapy. The 24-hour thyroid radioactive iodide uptake was 40% ±15% (range, 24% to 72%) before radioiodine treatment and 19% ±14% (range, 2% to 58%) 1 year after therapy. One year after therapy, four patients had a 24-hour thyroid radioactive iodide uptake that was less than normal (<5%). We observed no consistent changes in serum thyroglobulin levels.

Discussion

Our study clearly shows the efficacy of treatment with radioiodine in patients with a large, compressive multinodular goiter. One year after radioiodine therapy, thyroid volume as measured with MRI was reduced by 40%. Even more clinically important is our finding of a significant decrease in tracheal compression after radioiodine treatment: We observed a widening of the tracheal lumen at its narrowest point by an average of 36%. The tracheas of 15 of 19 patients widened more than 10%, and deviation of the trachea from the midline decreased more than 10% in 13 of 19 patients. Improvement of these anatomical measurements was accompanied by improvement in clinical signs and symptoms in 8 of 12 patients with dyspnea and inspiratory stridor. Furthermore, symptoms of obstruction of venous flow improved in both patients with compression of the superior vena cava. Forced inspiratory volume in 1 second improved by more than 10% in 8 patients.

Few other reports have described the results of radioiodine therapy on volume reduction of large goiters [15-18]. However, the techniques used to estimate volume reduction in these studies—palpation, measurement of maximal neck circumference, and planar thyroid scintigraphy—are notoriously imprecise; none of these investigators evaluated tracheal compression with objective methods. Having used ultrasound to measure thyroid volume, Nygaard and colleagues [19] recently reported effects of radioiodine treatment in small nontoxic goiters (median volume, 73 mL). These investigators observed a 42% volume reduction 1 year after radioiodine therapy. However, ultrasound cannot be used for large goiters because of frequent intrathoracic extension [20, 21]. We therefore used MRI, which is not limited by intrathoracic extension of the goiter, to evaluate the effect of radioiodine treatment in large goiters (mean volume, 269 mL).

The routine prescription of L-thyroxine after radioiodine treatment prevented us from accurately assessing the rate of hypothyroidism. However, only 4 of 19 patients had a below-normal 24-hour radioiodine uptake 1 year after therapy. Nygaard and colleagues [19] also observed a relatively low rate of hypothyroidism. They calculated a 22% rate of hypothyroidism after 5 years using the life-table method. In contrast, Verelst and colleagues [18], despite the use of doses of radioiodine similar to those used by Nygaard and coworkers, found that 30% of the patients studied had hypothyroidism 3 years after therapy; after 8 years, all living patients were hypothyroid. Hyperthyroidism developed in one of our euthyroid patients 7 months after radioiodine treatment. Other investigators [19, 22] have also observed this late development of hyperthyroidism and have suggested that it is an autoimmune phenomenon triggered by irradiation-induced antigen release [22]. Furthermore, patients should be watched carefully for signs of thyrotoxicosis caused by radiation thyroiditis, especially in the first weeks after radioiodine therapy for a large goiter.

Radioiodine is a widely accepted treatment for thyrotoxicosis. However, most clinicians are reluctant to administer radioiodine to reduce the volume of large, compressive goiters for fear of exacerbating compressive symptoms and because of concern for too-high absorbed doses of radiation. We observed no exacerbation of compression symptoms necessitating corticosteroid medication after radioiodine treatment. This is in accordance with the experience of other investigators [15-19]. Thus, radiation thyroiditis causing thyroid swelling and an increase in compression symptoms appears to be rare. In our study, patients received 3.7 MBq (100 microcuries) of ¹³¹I/g of thyroid tissue, a dose commonly used for treating hyperthyroidism caused by diffuse or nodular goiter [23]. For toxic nodular goiter, even higher doses are frequently used [24-26]. In a separate dosimetric study in patients with large toxic and large nontoxic multinodular goiters (mean thyroid volume, 200 mL in both groups), we calculated mean radiation absorbed doses of 80 Gy (8000 rad) in the thyroid, 4 Gy (400 rad) directly near the thyroid, and 0.05 to 0.6 Gy (5 to 60 rad) in other tissues; we observed no significant differences between hyperthyroid and euthyroid patients (unpublished data). The effective dose to the whole body was 4 sievert (400 rem) for both hyperthyroid and euthyroid patients. The observed absorbed doses in extrathyroidal tissues are higher than those after radioiodine treatment of small goiters. The risk for leukemia and cancer after radioiodine therapy in patients with small goiters does not appear to be elevated [27]. Such data are not available for patients with large goiters treated with higher doses of radioiodine. Because radiation-induced carcinogenesis is a late effect, this risk is less important in elderly patients. In view of these considerations, we believe radioiodine treatment of large goiters should be restricted to elderly patients.

Our study has some limitations. First, follow-up was restricted to 1 year after radioiodine treatment. Further follow-up will show whether the excellent anatomical and functional results, as shown in our study, persist. In this respect, it is of interest that in the study of Nygaard and colleagues [19], the volume of small nontoxic goiters was reduced 42% 1 year after radioiodine therapy but was reduced 60% after a median follow-up of 60 months. Second, we cannot exclude with certainty the possibility that the observed effects of radioiodine therapy are influenced by the use of L-thyroxine after radioiodine treatment in the euthyroid patients or by the combination therapy of methimazole and L-thyroxine in the hyperthyroid patients. It is unlikely, however, that the routine prescription of L-thyroxine after radioiodine therapy in our study contributed substantially to the observed reduction in thyroid volume because this medication was administered in non-TSH-suppressive doses and because even TSH-suppressive doses are not likely to effectively reduce the volume of large, multinodular goiters [9]. Methimazole, which shortens the biological half-life of radioiodine in the thyroid, could have negatively affected the effectiveness of radioiodine. However, in three of the four hyperthyroid patients, thyroid volume was reduced more than 35% 1 year after therapy. Third, the administered amounts of radioiodine in our study were not based on accurate measurements of the functional volume within the thyroid gland. Single-photon emission computed tomography or positron emission tomography may prove to be useful tools for more accurate planning of therapeutic doses of radioiodine for nodular goiters. The accuracy of these techniques and the therapeutic surplus value of more accurate measurements of the functional volume of nodular goiters should be evaluated in further studies.

In conclusion, our study shows a 40% reduction of thyroid volume and clinically significant decompression of vital structures 1 year after treatment with radioiodine and L-thyroxine in patients with a large, compressive goiter. We recommend this treatment as an effective alternative for surgery in elderly patients.