Quality of Life and Effectiveness Comparisons of Thyroxine Withdrawal,Triiodothyronine Withdrawal,and Recombinant Thyroid-Stimulating Hormone Administration for Low-Dose Radioiodine Remnant Ablation of Differentiated Thyroid Carcinoma

Abstract

Background:

Few reports have examined the use of recombinant human thyroid-stimulating hormone (rhTSH) for ablation of postsurgical thyroid remnants after low-dose radioactive iodine (RI) therapy, compared with conventional thyroid hormone withdrawal. We investigated whether patient preparation using rhTSH was comparable to conventional thyroid hormone withdrawal with respect to efficacy of postsurgical remnant ablation in low-risk patients receiving a 30 mCi RI. In addition, we also evaluated the impact of rhTSH (rhTSH vs. conventional thyroid hormone withdrawal) on quality of life (QoL) of thyroid cancer patients undergoing RI ablation.

Methods:

This study included three groups of patients, enrolled consecutively. From February 2006 to March 2007, 291 patients were enrolled and randomized, after total thyroidectomy: (1) withdrawal of levothyroxine (LT4) for 4 weeks (T4-WD Group, n = 89), (2) withdrawal of LT4 for 4 weeks plus 2 weeks on and then 2 weeks off liothyronine (LT3) (T3-WD Group, n = 133), and (3) rhTSH administration (rhTSH Group, n = 69). QoL was determined at the time of ablation.

Results:

Patients in the three groups did not differ significantly in baseline characteristics or tumor, node and metastasis (TNM) staging. In all study groups, serum TSH levels showed very good stimulation (mean, 82.24 ± 18.21 mU/L), without significant between-group differences (p = 0.5213). Follow-up examinations were performed 12 months after ablation to assess ablation outcome in each group by 131 whole body scans (WBSs), serum thyroglobulin measurement after TSH stimulation, and neck ultrasonography. The successful ablation rate was 91.0% in T4-WD Group, 91.7% in T3-WD Group, and 91.3% in rhTSH Group, without significant between-preparation differences (p = 0.2061). QoL was better preserved in rhTSH Group than in T4-WD and T3-WD Groups (p < 0.0001). However, there was no QoL difference at the time of ablation between T4-WD and T3-WD Groups.

Conclusions:

Our study indicates that use of rhTSH preserves QoL in patients undergoing RI ablation and affords an ablation success rate comparable to that seen after thyroid hormone withdrawal. Notably, ablation preparation using withdrawal of LT3 for 2 weeks did not prevent development of profound hypothyroidism, as also occurred when LT4 alone was withdrawn for 4 weeks.

Introduction

I nitial treatment for differentiated thyroid carcinoma (DTC) is total or near-total thyroidectomy that is often followed by [¹³¹I] radioactive iodine (RI) ablation of remnant thyroid tissue after 4 weeks of levothyroxine (LT4) withdrawal. Long-standing hypothyroidism has profound effects on many organs and systems and causes cognitive impairment, emotional dysfunction, physical discomfort, and health risks in patients who are elderly and frail or have concomitant illnesses. Withdrawal of thyroid hormone may also have a profound negative impact on quality of life (QoL) and ability to work in healthy young subjects (1 –3).

The standard protocol of RI ablation involves withdrawal of thyroid hormone to stimulate endogenous thyroid-stimulating hormone (TSH), thereby inducing long-standing hypothyroidism. In the current protocol, remnant ablation after thyroid hormone withdrawal promotes RI uptake in residual thyroid cells. The consensus of the European Thyroid Association and the guidelines of the American Thyroid Association for patients undergoing RI therapy or diagnostic scanning is that LT4 can be withdrawn for at least 3 weeks or, alternatively, liothyronine (LT3; Cytomel^®; Theramed, Mississauga, Canada) can be administered for 2 weeks followed by LT3 withdrawal for 2 weeks (4,5).

In recent years, the development of more effective DTC treatment and the introduction of new follow-up modalities have led to modifications in patient management to improve QoL. Recombinant human TSH (rhTSH; TSHα; Thyrogen; Genzyme Corp., Cambridge, MA) has become available. The use of rhTSH has been invaluable in DTC management. Hypothyroidism is now avoidable at the time of RI ablation. The use of rhTSH permits maintenance of good QoL (3,4,6), without side effects, and requires only minor whole-body irradiation (7 –9). rhTSH use has been approved by the European Medicine Agency and the United States Food and Drug Administration for DTC patients treated with 3.7 GBq (100 mCi) RI. However, a postoperative low-dose (30 mCi) RI ablation of remnant thyroid tissue, after rhTSH patient preparation, remains controversial. To date, only four prospective studies have explored the efficacy of low-dose (30 mCi) RI ablation after such preparation (10 –13), because low RI doses have not been commonly used in medical centers (11 –13).

This study was designed to investigate whether patient preparation using rhTSH was comparable to conventional methods (LT4/T3 withdrawal) with respect to efficacy of postsurgical remnant ablation in low-risk patients receiving a fixed 30 mCi RI dose. In addition, a between-method comparison of peri-ablation QoL was performed.

Materials and Methods

Inclusion criteria

Patients with newly diagnosed DTC, more than 18 years old, who had recently undergone total or near-total thyroidectomy with central compartment neck dissection, were eligible for this study. Exclusion criteria were evidence of distant metastases (M1), lateral neck node metastases (N1b), and/or significant extrathyroidal invasion (T4) (6th tumor, node and metastasis [TNM] classifications) (14). As individually assessed by the principal investigator at each site, included patients had no clinically significant abnormalities on routine hematological or blood chemistry tests, and serum creatinine concentrations were normal. No patient had any major concurrent medical disorder, including other malignancies, within the past 5 years, and no patient had recently been prescribed drugs affecting thyroid or renal function, including iodine-containing medications or radiocontrast agents. The study was approved by our Institutional Review Board and written informed consent was obtained from each patient.

Study design

This study was a randomized, controlled, open-label, single-center study. The study was designed to compare the efficacies of various patient preparation methods prior to postsurgical remnant ablation using low-dose (30 mCi) RI and to explore QoL in patients undergoing RI treatment.

All patients underwent total thyroidectomy with central compartment neck dissection. After operation, all patients began treatment with a TSH-suppressing dose of LT4 (2 μg/kg). After at least 30 days of LT4 supplementation, patients were randomized into three groups by RI preparation protocol. In T4 withdrawal (T4-WD) Group, patients discontinued LT4 for 4 weeks; in T3 withdrawal (T3-WD) Group, patients discontinued LT4 for 4 weeks plus 2 weeks on and then 2 weeks off LT3; and in rhTSH injection (rhTSH) Group, patients received rhTSH with a short stoppage (4 days) of LT4 from the day before rhTSH until iodine administration to emphasize the interference of iodine content of LT4 on the effectiveness of radiometabolic treatment.

RI treatment was performed on all patients after 2 weeks on a low-iodine diet. Patients received written instructions and were assisted by a dietician (15,16). Measurements of circulating thyroid hormone, TSH, thyroglobulin (Tg), and anti-Tg antibodies (TgAbs) were performed at ablation, and before and after thyroid hormone withdrawal.

In the rhTSH Group, each patient received two injections of rhTSH: 0.9 mg intramuscularly at 24 and 48 hours before the administration of the RI therapeutic dose, and a WBS was performed at 48 hours after RI treatment. Serum TSH, free T4 (fT4), T3, Tg, and TgAbs were measured on the day before the first administration of rhTSH and the day after the second rhTSH administration. Serum samples for Tg and TgAbs assessment were taken at 3 days after the second rhTSH injection. Serum TSH and fT4 were measured by chemiluminescence immunoassay (Centaur; Bayer Health Care, Mannheim, Germany), and similarly for T3 (E-170 assay kit; Roche Diagnostics, Mannheim, Germany). Serum Tg was measured by immunoradiometric assay (Dynotest TgS; Brahms, Berlin, Germany), and similarly for TgAbs (Anti-Tgn RIA; Brahms). The Tg assay had a sensitivity of 0.2 ng/mL. TgAbs status was considered negative when readings were less than 20 IU/mL. Patients with potentially interfering levels of TgAbs were excluded from statistical analysis of serum Tg changes. To eliminate contamination by stable iodine, urinary iodine excretion over 24 hours was measured in all patients at initial RI treatment and at 12 months follow-up RI scan. The 24-hour urine samples are collected on the final day of the low-iodine diet for determination of urinary iodine and creatinine excretion. Iodine measurements were performed in a central laboratory (the Seoul Clinical Laboratories [SCL] Facility of the Asan Medical Center, Seoul, Korea); an iodine-selective colorimetric method was employed.

To measure remnant thyroid activity, a tracer dose of RI was given orally to all patients the day before therapeutic RI administration. Images were obtained 24 hours later using a single-head gamma camera (Koroid, Seyong, Korea) featuring a 3/8-inch-thick crystal and a pinhole collimator. Residual thyroid bed uptake was evaluated both qualitatively (positive or negative) and quantitatively. Posttherapy WBSs were acquired 48 hours after RI treatment.

Measurement of QoL

We aimed to determine clinical QoL. We designed a seven-item written, anonymous questionnaire exploring hypothyroidism consequences for daily living during thyroid hormone withdrawal. The survey items focused on physical symptoms, signs, problem duration, impact on social life, mood changes, and medical resource utilization. Our psychometric study was a modified version of the self-rating Kellner symptoms questionnaire, the Hamilton depression scale, and Luster's 13-item scale for measurement of hypothyroidism (2,17). The minimum possible score is 0 and the maximum score is 31. At the time of RI ablation, our questionnaires were utilized, in a double-blinded fashion, to assess the hypothyroidism status of the patients. The same observer, blinded to the patient's clinical state, administered the questionnaires at all time. Both the observer and the patients were blinded to the treatment group being assigned. Appendix 1 contains an English translation of the questionnaires.

Assessment of ablation success

In all patients, serum TSH, fT4, T3, Tg, and TgAbs levels were periodically measured. After 12 months, ablation outcomes were assessed in each group by follow-up WBS, serum Tg measurement after TSH stimulation, and neck ultrasonography (US). To image thyroid remnants, a tracer dose of 74 MBq RI was administered to all patients. Neck US was performed by a radiologist specializing in head-and-neck evaluation, using a Philips-ATL HDI 5000 instrument equipped with a 12 MHz linear transducer.

Statistical analysis

All data were expressed as means ± standard deviations, proportions, or absolute numbers. The Mann–Whitney U test and Kruskal–Wallis assessment were used to analyze between-group differences, and the Wilcoxon rank sum test was used for paired analysis within a group. The t-test was employed to explore the significance of differences between unpaired data. The χ ² test was used to compare between-group clinical and pathological features. A p-value of <0.05 was considered significant. SPSS for Windows version 12.0 (SPSS, Chicago, IL) was used for all analyses.

Results

Patient characteristics

Between February 2006 and March 2007, 291 patients were randomized, after total thyroidectomy, to (1) withdrawal of LT4 for 4 weeks (T4-WD Group, n = 89), (2) withdrawal of LT4 for 4 weeks plus 2 weeks on and then 2 weeks off LT3 (T3-WD Group, n = 133), and (3) rhTSH administration (rhTSH Group, n = 69). The three groups did not differ in clinical characteristics or TNM classifications. Urinary iodine concentration (on the final day of low-iodine diet) before RI ablation was not significantly different between groups (Table 1).

Table 1.

Epidemiological and Clinical Characteristics of Study Patients

	T4-WD group	T3-WD group	rhTSH group	p-Value for T4/T3-WD vs. rhTSH
Age (years)	50.1 ± 6.8	49.0 ± 10.2	46.7 ± 9.8	0.2151
Gender (female/male)	83/6	118/15	64/5	0.1583
Body mass index (kg/m²)	23.4 ± 4.68	21.9 ± 5.63	22.8 ± 5.41	0.2572
Papillary/follicular carcinoma	88/1	131/2	68/1	0.8551
TNM staging
T1	48 (53.9%)	61 (45.9%)	28 (40.6%)
T2	2 (2.2%)	12 (9.0.0%)	1 (1.4%)
T3	39 (43.9%)	60 (45.1%)	40 (58.0%)	0.7541
N0	51 (57.3%)	78 (58.6%)	45 (65.2%)
N1a	38 (42.7%)	55 (41.4%)	24 (34.8%)	0.1425
Urinary iodine concentration (μg/dL, 24 hours)	12.3 ± 8.3	17.6 ± 12.5	13.8 ± 6.1	0.5214

See Results section for group definitions.

Stimulated serum TSH and RI uptake

At ablation, serum TSH was elevated in T4-WD Group (mean, 81.2 ± 19.0 mU/L; range, 33.1–100.0 mU/L), T3-WD Group (mean, 73.6 ± 19.4 mU/L; range, 30.1–100.0 mU/L), and rhTSH Group (mean, 86.6 ± 17.6 mU/L; range, 33.1–100.0 mU/L), without significant between-group differences (p = 0.5213).

The 24-hour thyroid bed uptakes (% values) after administration of tracer RI were 2.2% ± 1.4% (range, 0.1–9.8%) in T4-WD Group, 3.1% ± 2.5% (range, 0.2–19.5%) in T3-WD Group, and 1.8% ± 1.6% (range, 0.1–13.4%) in rhTSH Group. Thyroid RI uptake after 24 hours tended to be lower in rhTSH Group than in T4-WD Group or T3-WD Group, although the differences were not statistically significant (p = 0.0952).

Serum Tg response to TSH stimulation

At the time of RI ablation, mean serum TSH was comparable in the three groups. Serum Tg level was 0.95 ± 1.16 ng/mL (range, 0.1–4.7 ng/mL) in T4-WD Group, 1.12 ± 1.22 ng/mL (range, 0.1–5.1 ng/mL) in T3-WD Group, and 0.95 ± 1.63 ng/mL (range, 0.1–9.0 ng/mL) in rhTSH Group, with no significant between-group differences (p = 0.1084). Three days after RI ablation, serum Tg was 2.30 ± 2.46 ng/mL (range, 0.2–13.3 ng/mL) in T4-WD Group, 2.72 ± 2.45 ng/mL (range, 0.1–10.4 ng/mL) in T3-WD Group, and 2.53 ± 2.92 ng/mL (range, 0.1–11.1 ng/mL) in rhTSH Group, again with no statistically significant between-group differences (p = 0.2015). After 12 months of follow-up, mean serum Tg levels after TSH stimulation were 0.18 ± 0.14 ng/mL (range, 0.1–2.9 ng/mL) in T4-WD Group, 0.14 ± 0.19 ng/mL (range, 0.1–3.2 ng/mL) in T3-WD Group, and 0.14 ± 0.05 ng/mL (range, 0.1–0.2 ng/mL) in rhTSH Group, once again with no significant differences between groups (p = 0.1094).

Ablation outcomes (correlation between neck RI scans, stimulated Tg levels, and neck US data)

To assess the effectiveness of each preparation method, each patient underwent a WBS using a tracer RI dose, and neck US, 12 months after ablation. Stimulated Tg measurement after 4-week LT4 withdrawal was scheduled for each patient. The successful ablation rates are shown in Table 2. When correlating ablation outcomes with patient preparation methods before RI ablation, we found that rhTSH injection offered an ablation success rate equivalent to that achieved by thyroid hormone withdrawal.

Table 2.

Ablation Success Rate at 12 Months After Radioactive Iodine Treatment

	T4-WD group	T3-WD group	rhTSH group	p-Value for T4/T3-WD vs. hTSH
No visible uptake or uptake <0.1% with negative neck ultrasonography (%)	84/89 (94.4)	125/133 (94.0)	63/69 (91.3)
Serum thyroglobulin ≤1.0 ng/mL after TSH stimulation (%)	81/89 (91.0)	122/133 (91.7)	64/69 (92.8)
Total ablation success rate (%)	81/89 (91.0)	122/133 (91.7)	63/69 (91.3)	0.2061

We next analyzed the results of ablation in patients who were excluded from ablation success. In T4-WD Group, detectable serum Tg (>1.0 ng/mL) (n = 8) was associated with persistent thyroid residue in six patients and with two lymph node metastasis detected by RI scan and neck US. In T3-WD Group (n = 10), detectable serum Tg was associated with persistent thyroid residue in seven patients and with lymph node metastases detected by neck US in three patients but missed by RI scan in one patient. In rhTSH Group, detectable serum Tg (n = 5) was associated with persistent thyroid residue in three patients and with lymph node metastases detected by RI scan in two patients by neck US but missed by RI scan in one patient.

As far as the lymph node metastases are concerned, in five patients (two in T4-WD Group, two in T3-WD Group, and one in rhTSH Group), lymph node metastases (persistent after surgery) disappeared after the second ablative dose of RI, as demonstrated by negative diagnostic RI scan, negative neck US, and undetectable serum Tg, and in two patients (one in T3-WD Group and one in rhTSH Group) missed by diagnostic RI scan but detected by TSH-stimulated Tg and neck US (confirmed by fine needle aspiration biopsy [FNAB]).

Quality of life

Table 3 compares scores reflecting physical signs, social activities, mood changes, and use of medical resources, between the three groups. There was a highly significant difference in QoL status between the thyroid hormone withdrawal groups (T4-WD Group and T3-WD Group) and rhTSH Group. However, there was no difference in QoL during preparation for RI between patients in T4-WD Group and T3-WD Group.

Table 3.

Comparison of Quality of Life Scores Between Groups

	T4-WD group	T3-WD group	rhTSH group	p-Value for T4/T3-WD vs. hTSH
Symptoms and signs (0–4)	2.9 ± 0.7	3.0 ± 0.7	0.7 ± 0.4	<0.001
Duration of symptoms (0–3)	1.8 ± 1.2	1.9 ± 1.0	0.2 ± 0.1	<0.001
Daily life (0–3)	1.3 ± 0.7	1.1 ± 1.0	0.1 ± 0.0	0.002
Social life (0–3)	2.1 ± 1.1	2.0 ± 0.9	0.1 ± 0.0	<0.001
Mood change and cognitive dysfunction (0–9)	3.5 ± 1.9	3.7 ± 1.7	1.8 ± 0.9	0.004
Genital symptoms (0–3)	1.8 ± 1.0	1.5 ± 1.1	0.8 ± 0.3	0.015
Medical resource utilization (0–6)	1.5 ± 0.4	1.9 ± 0.8	0.7 ± 0.5	0.453
Total	15.1 ± 3.1	15.8 ± 4.1	4.2 ± 1.9	<0.001

Discussion

DTC is on the increase worldwide, although the figures may reflect enhanced detection of small incidentalomas rather than an actual increase in DTC levels (18,19). Although proper management of small incidentalomas remains controversial, there is a general agreement that total thyroidectomy and/or thyroid remnant ablation using RI are required.

The optimal RI dose necessary for successful ablation in patients with low-risk DTC remains contentious. Some authors have employed dosimetric and kinetic methodology to define effective ablative doses, but most centers prefer to administer standard doses, varying with institutional preferences. Generally, the larger the dose the better will be the remnant ablation. However, the concept that should be stressed is that thyroid ablation with excessive RI dose is still a procedure exposing the patient to some danger and should not be used when a beneficial effect is not proven, like in low-risk patients (4,20 –22). Moreover, higher activity of RI was associated with a longer stay in a radioprotected isolation unit (10,20,21). When using low doses of RI (30–50 mCi), several authors have reported ablation rates greater than 70–80%, similar to those achieved with higher doses (20 –23). Thus, the issue of the minimal effective activity that can be used for thyroid ablation in low-risk patients remains open. In Korea, there are a few points about RI treatment where we may differ because of our state of things. The most serious problem in Korea is an insufficiency of isolation unit for RI treatment in patients with thyroid carcinoma. Therefore, for several years, we have been using 30 mCi RI for routine ablation of thyroid remnants based on the possibility to use this dose on an outpatient basis in low-risk patients. In our hands, the rate of successful ablation with such a protocol is nearly 80–90% (our unpublished observation). This work also showed that a RI dose of 30 mCi ablated most, if not all, thyroid remnants in patients prepared either by thyroid hormone withdrawal or rhTSH injection.

Indisputable advantages of rhTSH use in patient preparation for thyroid remnant ablation after total thyroidectomy are the improved QoL and the need for less whole-body irradiation (3,4,6 –9,24,25). Previous reports on rhTSH use to these ends found that the procedure was efficacious in most patients who were given high doses (over 100 mCi) of RI (2,4,7 –9). Few reports have addressed rhTSH use in patients receiving low-dose (30 mCi) RI. One pilot study suggested that rhTSH use was less effective than LT4 withdrawal when the RI dose was 30 mCi (6). However, several other reports have shown that rhTSH patient preparation in low-dose RI patients compared favorably with preparation using thyroid hormone withdrawal (11 –13). The efficacy of rhTSH when low-dose (30 mCi) RI treatment is planned is still controversial. Our results suggest that rhTSH use is at least as effective as thyroid hormone withdrawal in preparation of low-risk patients for 30 mCi RI treatment. Considering about interference of iodine during ablation, this study was designed such that the short interruption of LT4 and 2-week iodine restriction diet could decrease the size of iodine pool and that stimulation of rhTSH in this condition allows a rate of ablation that is at least the same as in the hypothyroid state. To avoid, at least partially, iodine interference coming from T4 metabolism, we chose the modified rhTSH injection protocol with a short stoppage of LT4 from the day before rhTSH until iodine administration (11). In fact, urinary iodine excretion could measure stable iodine intake before RI treatment. Our study also shows that median urinary iodine levels were below the conventional 20 g/dL threshold in all study patients and showed no significant between-group differences.

The 12-month follow-up scans assessing ablation were performed after LT4 withdrawal, based on previous evidence that postablation RI scan and follow-up neck US data were not significantly different between the three groups. Indeed, serum Tg measurement under TSH stimulation combined with neck US examination has been reported by several research groups to be the best indicator of complete remission in follow-up after initial treatment (26,27). By this measure, the successful ablation rates did not differ significantly between the three groups (p = 0.2061).

However, our study had several limitations including the lack of long-term outcomes. This question can be answered only by patient follow-up in future years. Another unresolved issue in this work is whether patient ablation using low-dose (30 mCi) RI impacts on long-term outcomes, compared with using higher doses of RI. Our results indicate the need for further clinical trials using the same protocol with higher doses of RI to define the lowest effective activity of RI.

Recently, the well being of DTC patients has assumed greater importance, and several studies have reported impaired QoL associated with RI (1 –3,6,25). It is important to reduce both the duration and extent of hypothyroidism caused by LT4 withdrawal. The use of rhTSH has greatly assisted in avoiding hypothyroidism. Another alternative, used empirically, is substitution of LT4 withdrawal by temporary cessation of LT3 therapy. LT3 has a shorter half-life than LT4 and may be withdrawn for a shorter period of time. Even though LT3 withdrawal should reduce hypothyroidism duration, this has never been clearly established. Few reports have addressed this topic. Leboeuf (2007) first explored QoL after LT3 withdrawal, compared with conventional LT4 withdrawal (28), and found (perhaps unexpectedly) that patients receiving additional LT3 after LT4 withdrawal showed a rate of hypothyroidism similar to that of patients in whom LT4 was withdrawn (28). The cited authors sought to explain the data by claiming that thyroid hormone levels in the brain are controlled mainly by local transformation of T4 to T3, with little contribution from exogenous T3 (29). Another explanation was that thyroid hormone receptors were not evenly distributed across all areas of the central nervous system, causing thyroid hormone effects to be variable in different brain regions (30). This might explain why we found no differences in hypothyroidism status between T4-WD Group and T3-WD Group. As expected, the symptoms and signs of hypothyroidism, and subjective QoL perceptions, were significantly better in rhTSH patients than in the thyroid hormone withdrawal groups. However, we also found that LT3 substitution after LT4 withdrawal in DTC patients did not prevent development of profound hypothyroidism, as measured by a modified Korean QoL questionnaire.

In conclusion, rhTSH safely and effectively stimulated RI uptake by thyroid remnants in low-risk DTC patients and was associated with clear clinical benefits in a substantial proportion of patients. In patients with low-risk DTC, the use of rhTSH prior to postsurgical thyroid remnant ablation with 30 mCi RI appears to represent the best treatment option. Notably, LT3 substitution after LT4 withdrawal did not prevent development of profound hypothyroidism.

Footnotes

Disclosure Statement

This work was supported by research funds of Yonsei University College of Medicine in 2006.

Modified Pilot Questions for Determining Effects of Hypothyroidism (English Version)

1) Hypothyroidism symptoms and signs:

Which types of symptoms disturbed you during the preparation period (choose all that apply)?

Fatigue ( ): 0.5

Weight gain ( ): 0.5

Edema of extremities ( ): 0.5

Facial edema ( ): 0.5

Insomnia ( ): 0.5

Dry skin ( ): 0.5

Bowel habit change ( ): 0.5

Cold intolerance ( ): 0.5

Total ( ) (0–4)

2) Duration of symptoms:

For how long did you experience symptoms?

Never (0)

Less than 1 week (1)

1–2 weeks (2)

More than 2 weeks (3)

Total ( ) (0–3)

3) Daily life:

During the preparation for radioactive iodine (RI) treatment, were there any restrictions on your daily life, or were you unable to perform your daily activities as usual?

Never (0)

At intervals (1)

Sometimes (2)

Always (3)

Total ( ) (0–3)

4) Social life:

During the preparation for 131RI treatment, did you have any problems in your social life or at work?

Never (0)

At intervals (1)

Sometimes (2)

Always (3)

Total ( ) (0–3)

5) Mood changes and cognitive dysfunction:

During the preparation for 131RI treatment, have you experienced any of the following feelings?

5-1) Depression

(Gloomy attitude, pessimism about the future, feeling of sadness, tendency to weep, low morale misery, discouragement, hopelessness, emptiness, unhappiness, distress, pessimism)

Never (0)

At intervals (1)

Sometimes (2)

Always (3)

5-2) Anxiety

(Subjective tension and irritability, loss of concentration, worrying about minor matters, apprehension, fears expressed without questioning, feelings of panic, feeling jumpy)

Never (0)

At intervals (1)

Sometimes (2)

Always (3)

5-3) Retardation

(Slowness of thought or speech, impaired concentration, decreased motor activity)

Never (0)

At intervals (1)

Sometimes (2)

Always (3)

Total ( ) (0–9)

6) Genital symptoms

(Loss of libido, impaired sexual performance, menstrual disturbances)

Not at all (0)

One or two times (1)

Less than 1 week (2)

More than 1 week (3)

Total ( ) (0–3)

7) Medical resource utilization:

7-1) During the preparation for 131RI treatment, did you consult your physician about related symptoms?

Not at all (0)

One time (1)

More than two times (2)

7-2) During the preparation for 131RI treatment, were you treated in a hospital for relief of your symptoms?

Not at all (0)

One time (1)

More than two times (2)

7-3) During the preparation for 131RI treatment, did you take additional medications?

No (0)

Yes (1)

7-4) Did you have to be accompanied to the hospital?

Not necessary (0)

Necessary (1)

Total ( ) (0–6)

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