Factors Influencing the Choice between Radioactive Iodine and Surgery in the Treatment of Graves' Disease

Abstract

There are three established treatment options for Graves' disease: Antithyroid drugs (ATDs), radioactive iodine (RAI) therapy, and surgery. Although ATDs are often selected as the first-line treatment, the optimal treatment approach when ATDs cannot be used or when transitioning from ATDs to other treatment options remains unclear. In this study, we analyzed the factors influencing the choice between RAI and surgery for such patients referred to our department. During the study period, 141 patients (56.4%) were treated with RAI and 109 (43.6%) with surgery; 96% of the patients had previously been treated with ATDs. Among those undergoing surgery, surgery was unavoidable in 38.5%, as RAI was contraindicated for reasons such as pregnancy, breastfeeding, ophthalmopathy, adolescence, comorbid thyroid cancer, or a strong desire by the patient to avoid RAI. The remaining 61.5% opted for surgery, which was recommended for them by clinicians based on several factors, including younger age, severe adverse reactions to ATDs, history of thyroid crisis, and greater thyroid weight. Although these factors independently contributed to the decision to select surgery, they did not entirely rule out the possibility of RAI treatment. The final decision was influenced by both clinical factors and the preferences of the patients and clinicians, indicating the potential for the treatment choice to vary across different medical facilities. This study highlights the importance of a personalized approach in selecting between RAI and surgery for patients with Graves' disease.

 

MissingLinkText

Keywords

Graves' disease - antithyroid drug - radioactive iodine - thyroidectomy - treatment selection

Introduction

Antithyroid drug (ATD) therapy, radioiodine (radioactive iodine: RAI) therapy, and surgery were established as treatment options for Graves' disease in the 1940s and are still in use today.[1] Although all these treatment modalities are effective, they each have their own advantages and disadvantages, including possible adverse reactions. However, there are no universally applicable algorithms for determining the best option for a particular patient. The American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis recommend that clinicians discuss the risks and benefits of each option with the patient before choosing any one of the treatment options, with consideration of the patient's values and preferences, among other factors.[2] In Japan, ATD therapy is commonly used as the first-line treatment for Graves' disease,[3] and the Japanese guidelines for the treatment of Graves' disease also state that all untreated patients are candidates for pharmacotherapy in principle.[4]

At our hospital, the Department of Diabetes and Metabolism is in charge of ATD therapy, whereas our department is responsible for RAI therapy and surgery. When a patient is referred to our department, we provide them with an explanation of the overview of the treatment of Graves' disease and choose between RAI therapy and surgery together with the patient before either treatment is initiated. Surgery is associated with risks of scarring in the anterior cervical region and possible complications, such as recurrent laryngeal nerve paralysis, superior laryngeal nerve paralysis, hypoparathyroidism, and postoperative bleeding, whereas RAI is generally safer and less invasive. Moreover, given that it involves radiation exposure, RAI therapy is contraindicated for pregnant or breastfeeding women and children younger than 5 years. Although specific recommendations for choosing among these options vary across internationally published guidelines, it is recommended that RAI therapy be avoided whenever possible in patients under 10 years of age in the United States and Europe and in patients under 18 years of age in Japan.[2] [4] [5] Even in adult patients, no consensus has been reached about whether or not RAI therapy increases the incidence of thyroid or non-thyroid malignant tumors.[6] [7] Moreover, RAI therapy is generally avoided in patients with moderate to severe Graves' ophthalmopathy because of the risk of exacerbation due to increased thyroid-stimulating hormone receptor antibodies (TRAbs).[4] Surgery is selected when RAI therapy is not a viable option for these reasons. In other cases, surgery is selected based on its superiority over other options. For example, surgery can immediately ameliorate the increased pressure in the cervical region caused by large goiters, whereas it takes several months for RAI therapy to reduce the goiter volume.[8] In addition, thyroid function quickly declines after surgery, whereas transient hyperthyroidism may occur due to thyroid destruction after RAI therapy. When surgery is selected based on these superior features, multiple patient background factors, including the course of symptoms, are taken into consideration; however, few reports have described the specifics of this selection process. Against this background, we retrospectively explored the factors influencing the choice between RAI therapy and surgery for the treatment of Graves' disease in our department.

 

MissingLinkText

Materials and Methods

Participants

A total of 250 patients who underwent RAI therapy or surgery between 2013 and 2021 for the treatment of Graves' disease in our department were included in this study. All patients were referred from the Department of Diabetes and Metabolism at our hospital or from another medical institution. After providing an explanation of the procedures, typical treatment courses, and advantages and disadvantages of ATD therapy, RAI therapy, and surgery in the context of Graves' disease, we discussed the treatment method with each patient and selected the method based on their informed consent. As a result, 141 patients (56.4%) and 109 patients (43.6%) underwent RAI therapy and surgery, respectively. Participants in whom ATD therapy was initiated or continued after their referral to our department were not included in this study.

The participants were surveyed about the use/nonuse of previous ATD therapy, any problems that they experienced in association with ATD therapy, if ATD therapy was used previously, and reasons for selecting RAI therapy or surgery, rather than ATD therapy, if ATD therapy was not used previously. Regarding the choice between RAI therapy and surgery, surgery was considered the only viable option for patients who were pregnant, planned to become pregnant, were breastfeeding, were aged ≤18 years, had concomitant thyroid cancer, had moderate to severe ophthalmopathy, or explicitly refused RAI therapy. Among patients in whom surgery was not the only viable option and was selected based on comparisons and patients in whom RAI therapy was selected, the following patient background factors, including treatment history, were surveyed: Age, sex, number of years since diagnosis, any serious adverse reactions (agranulocytosis, antineutrophil cytoplasmic antibody-associated vasculitis, and skin rashes or liver dysfunction refractory to antiallergic agents) to ATDs (thiamazole and propylthiouracil), history of thyroid crisis and periodic paralysis, thyroid weight estimated by ultrasonography, and levels of free T4, free T3, and TRAb measured at the time of making the decision between RAI therapy and surgery.

This study was approved by the ethics committee of our hospital (approval no.: 30-S02-005).

 

MissingLinkText

Radioactive Iodine Therapy

RAI therapy was performed on an outpatient basis, with the radiological dose adjusted based on the estimated thyroid weight. The maximum dose in single-dose therapy was 13 mCi (1,110 MBq). When the thyroid glands were large, multiple doses were administered systematically. In addition, multiple doses were administered when the expected efficacy was not achieved with single-dose therapy. The primary treatment goal was to suppress thyroid function; however, the treatment also aimed to maintain euthyroidism for as long as possible, if the patient requested this.

Before finalizing their decision, the patients were provided with an explanation including the following information about RAI therapy: (1) They had to follow a low-iodine diet for 1 week before RAI therapy. (2) To avoid the effects of radiation on the patient's environment, they were required to follow radiation protection guidelines for 1 week after RAI therapy. (3) They could experience transient hyperthyroidism due to discontinuation of ATD therapy before RAI therapy and thyroid gland destruction after RAI therapy. (4) At least several months were required for RAI therapy to reduce thyroid function and goiter size. (5) They would take oral thyroid hormone preparations for the rest of their lives due to their reduced thyroid function. Being pregnant, planning to become pregnant within 6 months, and breastfeeding were considered contraindications for RAI therapy. RAI therapy was always avoided when the patient was younger than 5 years, and was avoided as a rule when the patient was ≤18 years of age. At our department, RAI therapy was not recommended for patients with moderate to severe ophthalmopathy, while the combined use of steroids has been reported as a treatment option for Graves' ophthalmopathy.[4] [9] Regarding the possibility that RAI would increase the incidence of malignant tumors in adults, before 2019, we explained to patients that RAI therapy has no clear effects, whereas from 2019 onwards, we provided the patients with the information that large-scale studies reported slightly increased incidence rates of malignant tumors in association with this therapy.[6] [7]

 

MissingLinkText

Surgery

The surgical procedure used in principle was total thyroidectomy under general anesthesia on an inpatient basis. Subtotal thyroidectomy was selected in some cases (26 cases). Before finalizing their decision, the patients were provided with an explanation including the following information about surgery: (1) A skin incision would be made in the anterior cervical region. (2) Possible complications included intraoperative and postoperative bleeding, postoperative hypoparathyroidism, superior laryngeal nerve paralysis, and recurrent laryngeal nerve paralysis. (3) Hypothyroidism required treatment with oral thyroid hormone preparations for the rest of their lives. (4) The TRAb level is expected to decrease after total thyroidectomy, and a lower TRAb level may be advantageous for Graves' ophthalmopathy and future pregnancy.

 

MissingLinkText

Statistical Analysis

The StatPlus mac Pro software (AnalystSoft, VA) was used for all statistical analyses in this study. Fisher's exact test was used to test frequency distributions, whereas the nonparametric Mann–Whitney U test was used to compare distributions of numerical values. Nonparametric analysis was performed because free T3 and TRAb measurements had an upper limit, and the distribution of estimated thyroid weights was skewed. Logistic regression analysis was used for multivariate analysis. Differences with a p-value of ≤0.05 were considered significant.

 

MissingLinkText

 

MissingLinkText

Results

Use/Nonuse of Prior ATD Therapy, Problems Associated with ATD Therapy, and Selection of RAI Therapy or Surgery

Of the 250 patients included in this study, only 10 (4%) underwent RAI therapy or surgery without previous pharmacotherapy with ATDs ([Table 1]). Of the 10 patients, 4 did so to avoid adverse ATD reactions, 2 did so because their parents had experienced adverse ATD reactions, 1 did so because the patient had previously experienced a severe adverse reaction to a non-ATD drug, and 1 did so because they already had liver dysfunction. An additional three patients wanted to shift from unstable hyperthyroidism treatment to stable treatment as quickly as possible because they planned to relocate overseas or were busy with work. Three patients underwent surgery after being diagnosed with concomitant thyroid cancer and Graves' disease during screening for hyperthyroidism or thyroid tumors.

Table 1 Choice between radioactive iodine therapy and surgery according to reasons for not using pharmacotherapy previously and reasons for switching pharmacotherapy to other options

	RAI (n)	Surgery (n)	p-Value
Reasons for not using prior pharmacotherapy (n = 10, 4%)
To avoid adverse ATD reactions	3	1	–
To shift quickly from hyperthyroidism treatment	3	0	–
Concomitant thyroid cancer	0	3	–
Reasons for switching prior pharmacotherapy to other options (n = 240, 96%)
Prolonged ATD treatment	60[a]	22	<0.01
Adverse ATD reactions	33	36	0.10
Insufficient efficacy against hyperthyroidism	14	25[a]	0.01
Recurrence after remission	19[a]	3	<0.01
Low drug compliance	6	8	0.30
Problems not related to drugs	3	11[a]	0.01
Total number of patients (%)	141 (56.4%)	109 (43.6%)

Abbreviations: ATD, antithyroid drug; RAI, radioactive iodine.

^a Significantly more common choice (p < 0.05).

–, statistical test was not performed due to the small sample size.

Among the remaining 240 patients (96%) who previously underwent ATD therapy, the choice between RAI therapy and surgery as the subsequent treatment differed depending on the problems the patients had experienced with ATD therapy ([Table 1]). In patients in whom the disease had persisted despite long-term (≥2 years) ATD therapy (82 of 240, 34%), RAI therapy was selected significantly more commonly than surgery (60 of 82 cases, 73%). Among cases in which patients experienced adverse ATD reactions (69 cases, 29%), RAI therapy and surgery were chosen in 33 and 36 cases, respectively, with no significant difference between these frequencies. In patients in whom previous ATD therapy was insufficiently effective against hyperthyroidism, surgery was selected significantly more commonly than RAI therapy (25 vs. 14 cases). In patients in whom the disease relapsed after remission, RAI therapy was chosen more commonly (19 of 22 cases). No difference in the treatment choice was noted in patients with low drug compliance; specifically, RAI therapy and surgery were selected in six and eight cases, respectively. Meanwhile, 14 patients experienced no problems in association with previous ATD therapy before they were referred to us. Of these patients, nine were referred to us because they had large goiters causing compression, while four were referred to us because they needed to achieve remission early for the treatment of other diseases or work. In this group, surgery was selected more commonly than RAI therapy (11 vs. 3 cases).

 

MissingLinkText

Background to the Decision to Choose Surgery Over RAI Therapy

Among 109 patients in whom surgery was chosen over RAI therapy, surgery was the only viable option in 42 patients (38.5%; [Table 2]). In terms of the reasons why RAI therapy was not an option, these included being pregnant, planning to become pregnant, or breastfeeding (11 patients); ophthalmopathy (10 patients); age (7 patients); and thyroid cancer (4 patients). Among the 10 patients who explicitly refused RAI therapy, the reasons for doing so were to avoid exposing themselves and their family members to radiation (8 patients) and the inability to have a low-iodine diet (2 patients).

Table 2 Background of the decision to select surgery over radioactive iodine therapy

Surgery was selected because RAI therapy was not a viable option	(n = 42, 38.5%)
Pregnancy, plan to get pregnant, breastfeeding	n = 11
Ophthalmopathy	10
Age (≤18 years)	7
Concomitant thyroid cancer	4
Refusal of RAI therapy	10
Surgery was selected based on comparative judgment	(n = 67, 61.5%)

Abbreviation: RAI, radioactive iodine.

In the other 67 cases, surgery was chosen over RAI therapy based on relative comparisons. The background factors in these 67 patients were compared with those in the 141 patients for whom RAI therapy was chosen ([Table 3]). Univariate analysis revealed that the age distribution of patients in the surgery cases was significantly skewed toward younger ages. Patients with severe adverse reactions to ATDs, those who experienced adverse reactions to two different ATDs, and those with a history of thyroid crisis were significantly more common among those selecting surgery. A history of periodic paralysis was also more common among patients who selected surgery; however, the difference was not significant. The estimated thyroid weight and TRAb level were significantly higher among patients who chose surgery. Meanwhile, the male-to-female ratio and the number of years since diagnosis of Graves' disease did not differ between the RAI therapy and surgery groups. Moreover, no significant differences in free T4 and free T3 levels were observed between the two groups at the time of selecting the treatment strategy. Multivariate analysis identified age, adverse reactions to ATD therapy, a history of thyroid crisis, and thyroid weight as independent predictors for selecting surgery.

Table 3 Background of patients for whom surgery or radioactive iodine therapy was chosen based on comparisons

	RAI (n = 141)	Surgery (n = 67)	Univariate analysis p-value	Multivariate analysis p-Value
Age	51 (23–88)	47 (22–78)	<0.01[a]	<0.01[a]
Sex, female/male	102/39	45/22	0.52	–
Number of years since diagnosis	4.0 (0–34.0)	3.0 (0.1–21.0)	0.20	–
Severe adverse ATD reactions or adverse reactions to two different ATDs
/Mild or no adverse reactions	13/128	19/48	<0.01[a]	<0.01[a]
With/Without thyroid crisis	5/136	14/53	<0.01[a]	<0.01[a]
With/Without periodic paralysis	1/140	3 / 64	0.10	–
Estimated thyroid weight, g	33. 4 (9–175)	72.6 (9–631)	<0.01[a]	<0.01[a]
Free T4: ng/mL	1.16 (0.4–4.20)	1.18 (0.4–4.29)	0.75	–
Free T3: pg/mL	3.57 (1.9 to >30)	3.81 (2.0 to >30)	0.23	–
TRAb: μIU/mL	6.5 (0.9 to >40)	11.1 (0.8 to >40)	0.03[a]	0.60

Abbreviations: ATD, antithyroid drug; RAI, radioactive iodine; TRAb, thyroid-stimulating hormone receptor antibody.

Numbers (number–number): median (minimum and maximum); number/number: ratio of number of cases.

^a Significant difference between the RAI and surgery groups (p < 0.05).

–, not included in multivariate analysis.

 

MissingLinkText

 

MissingLinkText

Discussion

The preferred treatment for Graves' disease varies from one region to another and has changed over time. According to a survey of thyroid specialists in 2011, 58.6% of clinicians in North America selected RAI therapy as the first-line treatment for patients with Graves' disease and no complications, whereas 40.5% of them selected ATD therapy. Meanwhile, 85.7% and 13.3% of clinicians in Europe selected ATD therapy and RAI therapy, respectively. Among clinicians in Asia and Oceania, 70.6% and 29.4% chose ATD therapy and RAI therapy, respectively.[10] Studies have also reported that, in the United States, RAI therapy has been the most commonly used treatment; however, the prevalence of ATD therapy has been increasing recently, and that of RAI therapy has been decreasing.[11] [12] This trend is related to increased awareness of the adverse effects of RAI on ophthalmopathy and the safety of long-term use of ATDs, as well as patients' demands for remission without hypothyroidism.[11] [13] [14] In fact, Japanese and European guidelines recommend ATD therapy as first-line treatment.[4] [5] [15] [16] In particular, a 1988 survey in Japan has already shown that 90% of patients were treated with ATDs. Consistent with previous findings, the present study showed that 96% of patients who underwent RAI therapy or surgery had received ATD therapy previously. There were also clear reasons for exclusion from this group: Avoidance of adverse ATD reactions; needing to shift quickly to stable treatment to compensate for reduced thyroid function, rather than unstable treatment to suppress hyperthyroidism using ATDs; or requiring surgery for thyroid cancer.

Among the patients referred to us because of problems associated with ATD therapy, RAI therapy was frequently chosen for patients in whom the disease persisted despite long-term ATD therapy or in whom Graves' disease relapsed after remission ([Table 1]). The likelihood of remission decreases in patients undergoing ATD treatment for ≥18 months, and a new line of treatment is proposed for patients without remission despite several years of ATD treatment.[2] [4] [5] [17] These patients are appropriate candidates for RAI therapy because they can continue ATD therapy and have no problem continuing treatment, even if it took a long time. Adverse reactions to ATD therapy can vary in severity from mild to severe; however, adverse reactions of any severity can be a reason to modify the treatment strategy. Patients who adversely react to one of the two ATDs (thiamazole and propylthiouracil) are likely to experience cross-reactivity with the other one. Once adverse reactions occur to the two ATDs, it is difficult to control them and continue ATD treatment. In patients who needed to switch from ATD therapy to another therapeutic option due to adverse reactions, RAI therapy or surgery was chosen as the next line of treatment equally frequently. However, surgery was selected more frequently for patients in whom ATD therapy was insufficiently effective even at the maximum dose. Under such circumstances, surgery is the preferred choice because it can quickly reverse hyperthyroidism and avoid transient hyperthyroidism, which can occur after RAI therapy. None of the problems associated with ATD therapy was definitively identified as a determinant of the choice between RAI therapy and surgery as the next treatment.

RAI therapy is generally considered less invasive than surgery. However, certain conditions, such as absolute and relative contraindications, precluded RAI therapy in 38.5% of patients who underwent surgery in our department ([Table 2]). In the remaining 61.5% of patients who underwent surgery instead of RAI therapy, we explored the background factors influencing this choice ([Table 3]). Our results showed that patients who underwent surgery were younger than those who underwent RAI therapy, even after excluding patients aged ≤18 years, for whom surgery was the only viable option. Multivariate analysis identified being younger as an independent factor predicting the decision to choose surgery as the next treatment. Regarding the relationship between RAI therapy and the development of malignant tumors, which remained controversial since a 2019 report by Kitahara et al.,[6] studies have demonstrated no clear data that RAI therapy for Graves' disease increases the incidence of or the mortality from malignant tumors compared with that from other treatments; however, the possibility that these rates increase at higher absorbed doses cannot be ruled out.[7] [18] It is advisable to avoid the use of radiation in younger patients, whenever possible, considering potential future effects on reproductive function and the risk of malignant tumors. This applies even when the patient is not planning to become pregnant or explicitly refuses radiation exposure. The sharing of this opinion among medical professionals in our department may have influenced discussions and decision-making with patients.

In patients requiring prolonged ATD treatment necessitated initiation of the next line of treatment, RAI therapy was selected more frequently, as described above ([Table 1]). However, the duration of ATD treatment was long in patients in whom RAI therapy was chosen and patients in whom surgery was chosen, with no difference in this variable between the two groups; specifically, the median number of years of ATD treatment after the diagnosis of Graves' disease was 4 years in the former group and 3 years in the latter ([Table 3]).

In patients in whom adverse ATD reactions became problematic and necessitated initiation of the next line of treatment, RAI therapy and surgery were chosen at comparable frequencies ([Table 1]); however, surgery was more commonly chosen in patients who experienced serious adverse reactions or adverse reactions to both types of ATDs ([Table 3]). In patients ineligible for ATD therapy, potassium iodide is administered orally to suppress thyroid function. However, potassium iodide is often effective only for a limited period. It appears that, when making their decision regarding their treatment course, the patients prioritized more rapid and reliable relief from hyperthyroidism by surgery, while also considering the severity of hyperthyroidism.

A history of thyroid crisis was a factor significantly associated with the decision to select surgery; however, RAI therapy was selected in some cases with such a history. In terms of a history of periodic paralysis, the number of such cases might have been insufficient to detect a statistically significant association. Nevertheless, the findings of this study show that both long-term ATD treatment and RAI therapy can be viable options for patients with complications of Graves' disease if thyroid function can be controlled by ATD therapy.

Thyroid weight was also a factor significantly associated with the decision to select surgery. The maximum estimated thyroid weight in patients who received RAI therapy was 175 g, and surgery was chosen in patients in whom the thyroid glands were even larger. According to the ATA guidelines, goiter-related features that should prompt the consideration of surgery include the presence of compressive symptoms and a goiter weight of ≥80 g.[2]

Thyroid function at the time of choosing between RAI therapy and surgery was not a significant factor influencing this choice. The TRAb level, which reflects disease activity, was higher in the surgery cases; however, it was not identified as an independent predictor in the multivariate analysis. Factors relevant to the feasibility of controlling the disease with pharmacotherapy, including thyroid gland size, patient age, and adverse drug reactions, appeared to be more important issues than the severity of hyperthyroidism.

Although RAI therapy was not contraindicated in 61.5% of patients who underwent surgery in our department, surgery was nonetheless selected after a clinician in our department provided the patient with an explanation and discussed with the patient—their background (including the previous treatment course) and other relevant factors. Being younger, experiencing serious adverse ATD reactions or adverse reactions to the two different ATDs, having a history of thyroid crisis, and having heavier thyroid glands were identified as factors independently influencing the decision to choose surgery; however, none of them definitively ruled out RAI therapy. Surgery was selected after considering multiple background factors for each patient. It is likely that the rates at which RAI or surgery are selected differ depending on the treating institution. Nevertheless, in any institution, the treatment strategy should be determined after discussion between the clinician and patient based on the patient's adequate understanding of the condition and being provided with sufficient information by the clinician.

 

MissingLinkText

Conclusion

We analyzed the selection of RAI therapy (141 cases) or surgery (109 cases) for the treatment of Graves' disease in our department. Of all the patients analyzed, 96% had previously received pharmacotherapy with ATDs. RAI therapy was selected more commonly for patients in whom prolonged ATD treatment or recurrence after remission necessitated modification of the treatment strategy. Surgery was selected more commonly for patients requiring such a modification to address the insufficient therapeutic efficacy of ATD therapy.

Surgery was selected either because RAI was absolutely contraindicated or relatively contraindicated or because surgery was clearly requested by the patients in 38.5% of cases in which surgery was performed. Being younger, experiencing severe adverse ATD reactions or adverse reactions to both types of ATDs, having a history of thyroid crisis, and having heavier thyroid glands were independent factors associated with the decision to choose surgery; however, none of these factors absolutely ruled out the option of choosing RAI therapy. Surgery was chosen after considering background factors for each patient. Patients should make treatment decisions based on a thorough understanding of their condition, with adequate guidance and sufficient information provided by their clinicians.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

None declared.

• References

• 1 Cope O. Diseases of the thyroid gland (Part I, concluded). N Engl J Med 1952; 246 (11) 408-417
• 2 Ross DS, Burch HB, Cooper DS. et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 2016; 26 (10) 1343-1421
• 3 Nagayama Y, Izumi M, Nagataki S. The Japan Thyroid Association. The management of hyperthyroidism due to Graves' disease in Japan in 1988. Endocrinol Jpn 1989; 36 (02) 299-314
• 4 Japan Thyroid Association. Guidelines for Treatment of Graves' Disease 2019. Tokyo: Nankodo; 2019
• 5 Mooij CF, Cheetham TD, Verburg FA. et al. 2022 European Thyroid Association Guideline for the management of pediatric Graves' disease. Eur Thyroid J 2022; 11 (01) e210073
• 6 Kitahara CM, Berrington de Gonzalez A, Bouville A. et al. Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism. JAMA Intern Med 2019; 179 (08) 1034-1042
• 7 Biondi B. Radioactive iodine treatment in hyperthyroidism and cancer mortality—a still controversial issue. JAMA Netw Open 2021; 4 (09) e2126361
• 8 Mizokami T, Hamada K, Maruta T, Higashi K, Tajiri J. Utility of outpatient fractionated radioiodine therapy for Graves' disease involving a large goiter measuring more than 100 mL in volume. Endocr J 2021; 68 (09) 1117-1125
• 9 Shiber S, Stiebel-Kalish H, Shimon I, Grossman A, Robenshtok E. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Thyroid 2014; 24 (10) 1515-1523
• 10 Burch HB, Burman KD, Cooper DSA. A 2011 survey of clinical practice patterns in the management of Graves' disease. J Clin Endocrinol Metab 2012; 97 (12) 4549-4558
• 11 Brito JP, Payne S, Singh Ospina N. et al. Patterns of use, efficacy, and safety of treatment options for patients with Graves' disease: A nationwide population-based study. Thyroid 2020; 30 (03) 357-364
• 12 Sundaresh V, Brito JP, Thapa P, Bahn RS, Stan MN. Comparative effectiveness of treatment choices for Graves' hyperthyroidism: A historical cohort study. Thyroid 2017; 27 (04) 497-505
• 13 Törring O, Watt T, Sjölin G. et al. Impaired quality of life after radioiodine therapy compared to antithyroid drugs or surgical treatment for Graves' hyperthyroidism: A long-term follow-up with the thyroid-related patient-reported outcome questionnaire and 36-item short form health status survey. Thyroid 2019; 29 (03) 322-331
• 14 van Kinschot CMJ, Soekhai VR, de Bekker-Grob EW. et al. Preferences of patients and clinicians for treatment of Graves' disease: a discrete choice experiment. Eur J Endocrinol 2021; 184 (06) 803-812
• 15 Sugino K. Indications and reality of surgical treatment for Graves' disease. JOHNS 2019; 35: 746-749
• 16 Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association guideline for the management of Graves' hyperthyroidism. Eur Thyroid J 2018; 7 (04) 167-186
• 17 Allannic H, Fauchet R, Orgiazzi J. et al. Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration. J Clin Endocrinol Metab 1990; 70 (03) 675-679
• 18 Kitahara CM, Preston DL, Sosa JA, Berrington de Gonzalez A. Association of radioactive iodine, antithyroid drug, and surgical treatments with solid cancer mortality in patients with hyperthyroidism. JAMA Netw Open 2020; 3 (07) e209660

Publication History

Received: 11 October 2024

Accepted: 27 February 2025

Article published online:
25 July 2025