2021 Volume 68 Issue 9 Pages 1117-1125
Contrary to large multinodular goiters, reports on 131I radioiodine therapy (RIT) for Graves disease (GD) involving a large goiter are scarce. We retrospectively reviewed a total of 71 consecutive patients (25 males, 46 females) with GD involving a large goiter (>100 mL) who had received RIT in our clinic. Patients with a history of thyroid surgery or with large thyroid nodules and those who had dropped out less than one year after the initial RIT session were excluded. A fixed 131I activity of 481 MBq was administered in most cases. RIT was repeated at intervals of 1–47 months, typically 3–6 months. The follow-up duration after the initial RIT session was 13–233 (median: 81) months. The thyroid volume was estimated using ultrasound. The number of 131I doses were 1 dose in 13 patients, 2 doses in 29, 3 doses in 17, 4 doses in 5, 5 doses in 5, 6 doses in 1, and 8 doses in 1. Sixty-six patients had remission from overt hyperthyroidism after RIT: overt hypothyroidism in 45 patients, subclinical hypothyroidism or euthyroidism in 13, and subclinical hyperthyroidism in 8. Their thyroid volume decreased from 101–481 (median: 126) mL to 1.4–37 (8.2) mL. Three patients still had overt hyperthyroidism under treatment with methimazole after one to three doses, and two dropped out less than six months after the third or sixth dose. Even in GD patients with a large goiter (>100 mL), repeated RIT with an activity of 481 MBq could sufficiently shrink goiters and remit overt hyperthyroidism.
SURGERY is generally indicated for the definitive treatment of Graves disease (GD) involving a large goiter, especially that complicated with compressive symptoms [1]. It has an immediate effect and promptly relieves symptoms related to the compression of the neck, including the trachea and/or esophagus. However, the risk of post-operative complications (hypoparathyroidism, laryngeal nerve palsy, postoperative bleeding, and complications related to general anesthesia) is increased in patients with a large goiter [1]. Furthermore, certain patients with GD refuse surgery or are not suited for surgery due to pre-existing comorbidities.
131I radioiodine therapy (RIT) is another definitive treatment for GD. It is not contraindicated in large goiters, even partly retrosternal or intrathoracic cases [2]. However, RIT for large goiters require high activities of 131I, and its effect takes a longer time to manifest than surgery. Since the upper limit for outpatient treatment in Japan is an activity of 500 MBq, large goiters often need repeated 131I doses. There have been many repots on RIT for large multinodular goiters, and 131I activities over 1.1 GBq have been used in RIT to manage large multinodular goiters (toxic or non-toxic multinodular goiters) with a thyroid volume exceeding 100 mL in a single dose or in fractionated doses [3, 4]. However, reports on RIT for GD involving a large goiter are scarce [5, 6].
We have performed outpatient fractionated RIT in a limited fashion for patients with GD involving a large goiter who refused surgery. We evaluated the utility of outpatient fractionated RIT with a fixed 131I activity of 481 MBq (13.0 mCi) per session for GD with a large goiter measuring more than 100 mL in volume.
We evaluated a total of 7,981 patients with GD at our clinic between July 1999 and December 2017. Four hundred and thirty-five patients underwent surgery, and 2,790 underwent outpatient RIT during the same time period (including both surgery and RIT in 45 patients). We reviewed the clinical records and collected data on 86 consecutive patients with GD involving a large goiter (>100 mL) who had undergone initial RIT in our clinic between July 1999 and December 2017. We evaluated the treatments and outcomes of a total of 71 patients, excluding 2 with a history of thyroid surgery for GD, 6 with large thyroid nodules (adenomatous goiter), and 7 who dropped out less than 1 year after the initial RIT session.
GD was diagnosed based on serum levels of elevated free thyroxine (T4) and suppressed thyrotropin (TSH), positive TSH receptor antibodies (TRAb) and a diffusely elevated uptake of radioiodine or technetium-99m (99mTc)-pertechnetate within the thyroid.
The present study was approved by the ethics committee of Tajiri Thyroid Clinic, and we obtained informed consent to perform RIT from all of the patients.
RIT for GD patients with a large goiterAll patients were initially treated with an antithyroid drug (ATD) (methimazole [MMI], or propylthiouracil [PTU]). Since around 2000, we have avoided using PTU as a first-line treatment due to its serious adverse effects, such as severe liver injury and anti-neutrophil cytoplasmic antibody-associated vasculitis. Some severely thyrotoxic patients were treated with both ATD and potassium iodide (KI), and some patients switched from ATD to KI due to the adverse effects of ATD. We recommended surgery as the definitive treatment for GD patients with a large goiter; RIT was offered in cases where patients refused surgery. We also informed all patients with a large goiter prior to RIT that repeated doses of 131I were usually required to achieve remission from hyperthyroidism. Patients with active Graves ophthalmopathy (GO), pregnancy, breastfeeding, or thyroid cancer were excluded from the indication of RIT. Regarding cases of GD with a large goiter, RIT was not indicated for female patients who wished to bear children in the near future.
Each RIT session was performed as an outpatient treatment, and a fixed 131I activity of 481 MBq was administered for patients with GD involving a large goiter (>100 mL), irrespective of the thyroid volume. However, 131I of 185–370 MBq was used from the second RIT session in some patients with a relatively small goiter. RIT was repeated at intervals of 1 to 47 months, typically every 3 to 6 months, in order to achieve remission from overt hyperthyroidism. The additional administered activities of 131I and intervals of RITs varied among patients based on their medical condition, including their thyroid function and volume, as well as patients’ wishes for early remission from hyperthyroidism, at the attending physician’s discretion. Thyroid scans and uptake measurements were performed to confirm hyperthyroidism (to exclude the destruction of thyroid tissue) at 1–6 h (mainly at 3 h) after the ingestion of radioiodine capsules with tracer activities or at 20 minutes after the intravenous injection of 99mTc-pertechnetate, prior to the administration of therapeutic 131I on the same day. ATD, KI, and levothyroxine (LT4, block and replacement therapy) were discontinued 2 days, 2 to 5 days (depending on the degree of hyperthyroidism), and 2 days to 1 month (depending on the degree of hyperthyroidism) before 131I administration, respectively. ATD and/or KI were resumed with either the same dosage or a reduced dosage two days after the 131I dose to control hyperthyroidism and were continued in appropriated doses until hyperthyroxinemia had abated. The dietary iodine intake was restricted at least two days prior to RIT, and restrictions were lifted two days after RIT.
Follow-up after RITThe follow-up durations after the initial RIT session ranged from 13 to 233 (median: 81) months. Responses to RIT were assessed by monitoring the thyroid volume as well as the thyroid function. All patients underwent ultrasonography of the thyroid gland before and after RIT. From one year after RIT, ultrasonographic examinations were performed at intervals of six months to one year. In cases with no noticeable findings after reducing the thyroid volume below 5.0 mL, the intervals of ultrasonographic examinations were extended to every 2 years. However, some patients transiently interrupted their visits to our clinic for regular follow-up. GO was evaluated by subjective symptoms and visual inspection, and orbital magnetic resonance imaging was performed in patients with some symptoms or signs of active GO.
The evaluation of the thyroid volumeThe thyroid volumes were determined with ultrasound using the following ellipsoid formula: the sum of the left and right lobe volumes, the volume of lobe (mL) = width of lobe (cm) × height of lobe (cm) × length of lobe (cm) × π/6, as previously reported [7]. Computed tomography (2-mm-thick slices) was used to determine the thyroid volume in one patient with a huge goiter (Fig. 1).
The largest goiter among the present patients. Computed tomography of the neck revealed tracheal compression and stenosis due to the diffusely enlarged thyroid. The lower poles of the enlarged thyroid intruded into the upper mediastinum.
Statistical analyses were performed using Spearman’s rank correlation coefficient and the Mann–Whitney U test.
The subjects were 25 males and 46 females, and their ages at the initial RIT session were 20 to 74 (median: 39) years old. The thyroid volumes just prior to RIT were 101 to 481 (median: 128) mL. Data on the treatment immediately before the initial RIT session were available in 66 patients. The distributions of the above variables are shown in Table 1. The dosages of MMI, PTU, KI, and LT4 used for blocking and replacement therapy prior to initial RIT were 10–60 (median: 20) mg/day, 300–450 (median: 400) mg/day, 15–150 (median: 50) mg/day, and 25–75 (median: 50) μg/day, respectively.
| Age (n = 71) | Thyroid volume (n = 71) | |||
| (n) | sex (M/F) | (mL) | (n) | |
| 20s | 20 | (4/16) | 101–110 | 18 |
| 30s | 17 | (8/9) | 111–150 | 31 |
| 40s | 17 | (6/11) | 151–200 | 12 |
| 50s | 11 | (4/7) | 201–250 | 7 |
| 60s | 4 | (1/3) | 251–300 | 2 |
| 70s | 2 | (2/0) | 481 | 1 |
| Treatment (n = 66) | Duration unitl RIT (n = 56) | |||
| (n) | (months) | (n) | ||
| MMI | 39 | 1–11 | 15 | |
| KI | 9 | 12–23 | 5 | |
| MMI + KI | 11 | 24–59 | 10 | |
| MMI + LT4 | 4 | 60–119 | 10 | |
| PTU + KI | 2 | 120–179 | 9 | |
| PTU + KI + LT4 | 1 | 180– | 7 | |
RIT, radioiodine therapy; MMI, methimazole; PTU, propylthiouracil; KI, potassium iodide; LT4, levothyroxine.
The clinical records of 56 patients were available as follows: The time intervals from the initiation of ATD therapy to initial RIT were 1 to 400 (median: 51) months, with distributions as Table 1. A large goiter was the main reason for performing RIT, and 1 or more of the following were additional main reasons for performing RIT: an absence of remission during long-term pharmacotherapy (≥2 years) in 36 patients, adverse effects of MMI in 3 (neutropenia in 2 and liver injury in 1), uncontrolled hyperthyroidism with MMI or with both MMI and KI in 3, and desire for early definitive therapy in 1.
Activities of the administered 131I and effects of RIT on the thyroid function and volume Patients who achieved remission from overt hyperthyroidism (n = 66)Sixty-six patients eventually achieved remission from overt hyperthyroidism (Fig. 2). The total 131I activities administered were 481 to 3,848 (median: 962) MBq. The numbers of 131I doses were as follows: 1 dose in 12 patients, 2 doses in 28, 3 doses in 15, 4 doses in 5, 5 doses in 5, and 8 doses in 1. The initially administered activity of 131I was 481 MBq in all patients, but 131I activities of 185–370 MBq were administered for relatively small goiters from the second RIT session in 13 patients (total 19 doses). Second RIT sessions (n = 54) were performed 1 to 29 (median: 6) months after the first session. Each RIT session and the intervals of RIT are shown in Table 2. Patients with larger goiters tended to need greater 131I activities than those with smaller goiters (r = 0.493, Fig. 3). The influence of KI pretreatment on the therapeutic effect of 131I was evaluated in 61 patients whose data on the treatment prior to RIT were available. The total activities of administered 131I per pre-RIT thyroid volume were not significantly different between patients without KI treatment (4.3–21.0 [median: 8.3] MBq/mL, n = 39) and those with KI treatment (1.8–22.2 [median: 7.4] MBq/mL, n = 22) (p = 0.290).
The thyroid function after radioiodine therapy (RIT) and cumulative remission rate from overt hyperthyroidism (n = 66). Red: overt hyperthyroidism, orange: subclinical hyperthyroidism, white: a normal thyroid function, light blue: subclinical hypothyroidism, dark blue: overt hypothyroidism. Patients who underwent more than one session of RIT were regarded as having hyperthyroidism until the final RIT.
| Total 131I doses, their interval of RIT, and the number of patients | ||
| (months) | (n) | |
| 1 dose | — | 12 |
| 2 doses | (1–16 [median 6]) | 28 |
| 3 doses | (2–23 [median 6], 3–18 [median 10]) | 15 |
| 4 doses | (2, 3, 7), (2, 3, 5), (3, 7, 11), (3, 8, 18), (8, 6, 9) | 5 |
| 5 doses | (1, 1, 2, 4), (2, 1, 5, 9), (3, 3, 6, 7), (3, 6, 9, 10), (4, 4, 5, 11) | 5 |
| 8 doses | (3, 10, 3, 1, 1, 47, 12) | 1 |
| Each interval of RIT and the cumulative total number of patients | ||
| (months) | (n) | |
| 1st–2nd | 1–29 [median 6] | 54 |
| 2nd–3rd | 1–18 [median 6] | 26 |
| 3rd–4th | 2–18 [median 9] | 11 |
| 4th–5th | 1–17 [median 9] | 6 |
RIT, radioiodine therapy
Distributions of patients who achieved remission from overt hyperthyroidism after radioiodine therapy (RIT) according to the total 131I activity administered and pre-RIT thyroid volume (n = 66). The figure shows a scatterplot with a regression line (r = 0.493). Blue dots: patients without KI treatment (n = 39), red dots: patients with KI treatment (n = 22), black open circles: patients whose data were not available (n = 5). The number in the arrows indicates the number of 131I doses.
The effect of repeated RIT on the thyroidal 99mTc-pertechnetate uptake was next evaluated. The radioactive iodine uptake just prior to RIT was not measured at the same interval, and the durations of KI withdrawal before RIT varied (2–5 days) among patients. Therefore, we analyzed the data from 28 patients who had undergone repeated RIT sessions with pre-RIT 99mTc-pertechnetate uptake tests. Although the thyroidal uptake of 99mTc-pertechnetate tended to decrease at the second RIT session in comparison to the first session, the uptake did not significantly decrease at the third to fifth RIT session compared with the previous sessions (Fig. 4). Three patients showed a relatively low thyroidal 99mTc-pertechnetate uptake at the second and fourth RIT sessions (1.94% [2nd], 1.40% [2nd], and 1.40% [4th]), and the intervals from the previous session were 2, 5 and 6 months, respectively.
Thyroidal 99mTc-pertechnetate uptake measurements just prior to radioiodine therapy (RIT) and the intervals of RIT in patients who underwent repeated RIT sessions with pre-RIT thyroidal uptake measurements using 99mTc-pertechnetate (n = 28).
At the latest follow-up more than 6 months after the last RIT session, the thyroid functions were overt hypothyroidism on LT4 replacement in 45 patients, subclinical hypothyroidism in 3, euthyroidism (normal thyroid function) in 10, and subclinical hyperthyroidism in 8 (Fig. 2). All patients with subclinical hyperthyroidism or subclinical hypothyroidism were monitored without treatment. All eight patients with subclinical hyperthyroidism at the latest evaluation of the thyroid function had undergone initial RIT less than five years previously. The thyroid volumes markedly decreased from 101–481 (median: 126) mL at the initial RIT session to 1.4–37 (median: 8.2) mL at the latest follow-up in 66 patients (Fig. 5).
The doses of 131I, changes in the thyroid volume, and latest thyroid functions after radioiodine therapy in patients who achieved remission from overt hyperthyroidism (n = 66). Latest thyroid function: black line, overt hypothyroidism: blue line, subclinical hypothyroidism: orange line, a normal thyroid function: red line, subclinical hyperthyroidism.
Among the 12 patients who underwent single RIT, their latest thyroid functions were overt hypothyroidism on LT4 replacement in five patients, subclinical hypothyroidism in one, euthyroidism in three, and subclinical hyperthyroidism in three (Fig. 2). The pre-RIT thyroid volumes were 101 to 110 mL in 9 patients. The remaining 3 patients had goiter sizes of 124, 142, and 272 mL (Fig. 3).
Patients who did not achieve remission from overt hyperthyroidism (n = 5)The 131I activity administered was fixed at 481 MBq in each of these patients. Three patients still showed hyperthyroidism under treatment with MMI after one to three sessions of RIT. However, their goiters shrank from 127 mL to 12 mL at 69 months (pretreatment: MMI + KI) after the first RIT session, from 154 mL to 44 mL at 19 months after the second RIT session (MMI), and from 222 mL to 33 mL at 29 months after the third RIT session (MMI). These patients were satisfied with the relief from the compressive symptoms caused by a large goiter and did not wish to receive additional RIT.
Other 2 patients dropped out less than six months after the third or sixth RIT session without achieving remission from overt hyperthyroidism. The intervals of 131I doses were 2, 9, 3, 11, and 11 months in the patient with 6 sessions of RIT. Their goiters shrank from 177 mL to 25 mL at the third administration of 131I (pretreatment: MMI) and from 210 mL to 124 mL at the sixth administration (MMI).
Complications of RIT and newly detected thyroid nodules after RITNo patients developed any serious complications due to exacerbation of thyrotoxicosis or overt radiation thyroiditis with neck pain or thyroid swelling. GO developed or worsened in two patients after RIT. One patient developed active GO (retro-orbital pain, conjunctival hyperemia) a few weeks after the initial RIT and received oral corticosteroid therapy. He underwent the second RIT session after inactivation of GO by corticosteroid therapy, and flare-up of GO was not observed. The other female patient developed GO (exophthalmos, diplopia) five years after the last RIT session (total of two doses).
Regarding the adverse effects of RIT on offspring, four female patients delivered a total of six babies. One baby developed neonatal GD that required treatment with ATD after birth. Her mother had become pregnant while being treated with KI for hyperthyroidism 2 years after a single RIT session, and the serum level of TRAb was >30 IU/L (reference range: <2.0 IU/L). None of the other babies developed fetal or neonatal GD; their mothers became pregnant 4–14 years after the last RIT session and had overt hypothyroidism on LT4 replacement with serum TRAb levels of <0.80–7.12 IU/L during their gestation periods.
Seven patients had solitary or multiple tiny cysts in the thyroid, and 5 had solid nodules of <1.0 cm prior to RIT. Most pre-RIT thyroid cysts and solid nodules shrank or disappeared after RIT, and the numbers of those cysts and solid nodules decreased in most of the patients. No cysts or solid nodules enlarged after RIT. Thyroidal hypoechoic solid or calcified nodules were newly detected in 4 patients 4 to 17 years after initial RIT. Those nodules were small (<0.7 cm) and had benign appearances. We performed a fine-needle aspiration biopsy for a total of four relatively large nodules with benign cytological diagnoses. None of the patients were diagnosed with thyroid cancer, leukemia, or other cancers during the follow-up period.
Even for large goiters, repeated doses of 131I 481 MBq caused the goiters to shrink and eliminated the need of ATD and/or KI for hyperthyroidism in most of the present patients. None of the patients complained of thyroid pain or swelling after RIT. RIT sometimes causes radiation-induced thyroiditis characterized by neck pain, thyroid swelling and transient thyrotoxicosis [8]. Severe thyroid swelling and respiratory distress are also rarely but occasionally caused by RIT in patients with GD [9]. Although more than 1.1 GBq of 131I are often required for patients with GD involving a large goiter, fractionated dosage of 131I may help prevent the above acute complications through the use of a reduced 131I activity. However, as drawbacks of fractionated 131I dose for large goiters, it takes a longer time for goiters to shrink (i.e. until remission of hyperthyroidism) in such cases than with larger degrees of 131I activity. RIT is a risk factor of GO, and de novo or flare-up of GO is seen in 10–30% of cases after RIT [1, 10]. Although 2 out of 71 patients developed GO or had worsening of their GO after RIT for large goiters, GO was not strictly evaluated in the present patients.
One of the main concerns of RIT for large goiters is the late complications caused by high cumulative activities of 131I. The total activities of 131I administered were more than 1.8 GBq in 12 patients, and the largest total 131I activity administered was 3.8 GBq among the present patients. Although most studies have shown no significant increase in the prevalence of secondary malignancies in adult patients treated with typical 131I activity (370–555 MBq) for GD [2, 11], the relationship between internal exposure to 131I and secondary malignancies remains controversial [11-13]. Recently, Kitahara et al. [14] reported a modest positive association between the total administered 131I activity (interquartile range: 187–422 MBq) and solid cancer mortality among RIT-treated GD patients in their multicenter cohort study. Regarding RIT for differentiated thyroid cancer, the risk for secondary malignancies is increased in cases with a cumulative 131I activity exceeding 3.7–5.5 GBq, and the increase in the risk is significant in cases with cumulative activities of 131I exceeding 18.5 to 22.2 GBq [15]. Salivary gland damage also needs to be monitored in patients with thyroid cancer who receive cumulative 131I activity exceeding 3.7 GBq [16]. Since the biokinetics differ between patients with thyroid cancer and those with GD, data on the effect of high activities of 131I in patients with thyroid cancer cannot be simply extrapolated to patients with GD [17]. Although there is no evidence showing a reduced fertility or increase in offspring’s congenital anomalies after RIT with the typical 131I activity for GD [1], the risk of persistent gonadal dysfunction needs to be considered in patients treated with a high cumulative 131I activity [18]. In terms of the cumulative 131I activity-dependent adverse effects, 131I should be administered at the necessary and sufficient activities, and the administration of excessive 131I should be avoided in the treatment of GD.
The thyroid volume is the most important factor determining the prognosis of RIT when the same activity of 131I is applied [19, 20]. Patients with a larger goiter tended to need a larger degree of 131I activity than those with a smaller goiter in the present patients. In addition, 9 of 12 patients who have achieved remission from overt hyperthyroidism with a single RIT session had a relatively small goiter (101 to 110 mL). Regarding the interval of RITs, overall intervals of RITs were 1 to 47 (median: 6) months among 58 patients who had undergone 2 or more sessions of RIT. The short intervals of RITs were one month in six sessions of RIT, two months in six, and three months in ten in total 181 RIT sessions among 71 patients. We confirmed the preserved uptake of 99mTc-pertechnetate or tracer radioactive iodine just prior to each administration of a therapeutic activity of 131I. However, the biological effect of 131I may have been transiently decreased due to a “stunning effect” by previously administered 131I among patients who underwent repeated RIT during a short period of time [21]. Therefore, some of the present patients who underwent additional RIT with short intervals may have achieved remission from overt hyperthyroidism with fewer RIT sessions than the actual number of sessions administered. As the thyroid volume in RIT-treated patients gradually decreases year by year even after a few months’ drastic decrease in the thyroid volume, a smaller 131I activity may have been sufficient in patients who did not insist on achieving early remission from hyperthyroidism.
ATD and/or KI administration before RIT, severity of hyperthyroidism, the thyroidal uptake of 99mTc-pertechnetate or radioiodine, and serum TRAb level are associated with the outcome of RIT [22-24]. We were unable to identify any clinical or laboratory differences between patients who showed marked efficacy and those who were refractory among the present patients. Since we performed RIT as an outpatient treatment, we rendered the patients euthyroid to mild hyperthyroid with ATD and/or KI prior to RIT in order to reduce the risk of complications due to worsening of hyperthyroidism. Regarding the treatment with KI around RIT, Ross DS et al. [25] reported that the administration of iodine 1 week after 131I administration shortened the duration of hyperthyroidism without adversely affecting the outcome of RIT. Recently, Nishio R et al. [26] demonstrated by analyzing Japanese patients that short-term therapeutic iodine restriction before RIT had not influenced the therapeutic effects of RIT in an iodine-sufficient area. Evaluated by the total administered activities of 131I among the present patients with GD, the efficacy of RIT for GD was not considerably deteriorated in patients treated with KI prior to RIT.
Several limitations associated with the present study warrant mention. Since this is a retrospective cross-sectional study, the durations between RIT and the evaluation of its impact varied. The criteria for additional RIT were not uniform. Several data on clinical and laboratory findings were missing in some patients.
In conclusion, even in patients with GD involving a large goiter (>100 mL), repeated RIT with an activity of 481 MBq could sufficiently shrink goiters and resolve overt hyperthyroidism. Outpatient fractionated RIT may be a viable alternative to surgery in GD patients with a very large goiter who refuse surgery or in patients who are not suited for surgery due to pre-existing comorbidities. Comparative studies on RIT and surgery in terms of complications, including adverse effects caused by a relatively large activity of 131I, the quality of life, and total medical costs are required to verify whether or not RIT is a viable alternative option to surgery for patients with GD who have a large goiter.
The authors have no conflicts of interest to disclose.
