Journal of Radiation Research and Applied Sciences 16 (2023) 100633
Available online 26 July 2023
1687-8507/© 2023 The Authors. Published by Elsevier B.V. on behalf of The Egyptian Society of Radiation Sciences and Applications. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Evaluating the effectiveness of a fixed little dose of radioactive iodine (I 131 ) in treatment for Graves ’ disease
Saeed Mueed Al-Qahtani
a,1,*, Maram Bandar Al-osaimi
b,1, Mahmoud Abdelalim
c, Marwan Ahmed Althomali
a, Ali Hamed Alomari
d, Omemh Abdullah Bawazeer
a, Asaad H. Ismail
e, Abdul-Wali Ajlouni
aaPhysics Department, College of Applied Sciences, Umm Al-Qura University, Prince Sultan bin Abdulaziz Road, Alabdia Suburb, Makkah, Saudi Arabia
bNuclear Medicine Department, King Faisal Medical Complex, Taif, Saudi Arabia
cNuclear Medicine Department, Medicine College, Benisuef University, Egypt
dPhysics Department, Al-Qunfudah University College, Umm Al-Qura University, Makkah, Saudi Arabia
eRadiation and Medical Physics, Physics Department, Education College/Scientific Departments, Salahaddin University-Erbil, Kurdistan Region, Iraq
A R T I C L E I N F O Keywords:
Graves’ disease Radioactive iodine Successful ablation Hyperthyroidism.
A B S T R A C T
Radioiodine (I131) therapy is a clinically established method for hyperthyroidism treatment. The most suitable dose for successful treatment is still controversial since it is affected by several factors. Thus, there are two techniques for proper dose adjustment; Fixed and calculated.
This study aims to evaluate the response difference of hyperthyroidism to a low fixed dose of 5 mCi (185 MBq) in comparison with other fixed doses of 10 mCi and 15 mCi (370 and 555 MBq) radioactive iodine treatment protocols. It also aims to raise the possibility of euthyroid state after successful ablation with such a low fixed dose rather than hypothyroid results and long-life replacement therapy.
A prospective study of 100 patients were clinically and scintigraphically diagnosed with Graves’ disease (GD) from the endocrinology department at King Faisal Medical Complex. The kind and size of the patient’s thyroid were determined before treatment and then randomized into three groups, based on the administrated radio- active iodine dose, (5 mCi, Group I), (10 mCi, Group II) and (15 mCi, Group III). The thyroid function tests were performed after 3 and 6 months, as a follow-up, for the assessment of the outcome.
Similar responses for fixed doses of 5, 10 and 15 mCi were determined, with no significant difference between the three study groups. Successful ablation was achieved in 23 (71.9%), 27 (84.4%) and 22 (71.0%) patients in the 5, 10, 15 mCi groups respectively without a significant difference between the groups with p-value of 0.695.
Moreover, all considered related factors to the outcomes show no effect except the thyroid size with a p-value
<0.001. The baseline size of the thyroid gland was significantly smaller in the Successful ablation group and the Euthyroidism group as compared to the Hyperthyroidism group (51.36 ±4.32 and 53.73 ±5.19 vs. 70.54 ± 8.70; p <0.001).
Fixed little doses of 5, 10 or 15 mCi of I131 show comparable remission rates. These outcomes were not affected by any factor related to the thyroid except thyroid size. Larger thyroid glands have less chance of remission. So, we envisage that a 5 mCi of radioactive iodine dose is recommended as a routine treatment for patients diag- nosed with GD.
* Corresponding author. Physics Department, College of Applied Sciences, Umm Al-Qura University, Prince Sultan bin Abdulaziz Road, Alabdia Suburb, Makkah, Saudi Arabia.
E-mail addresses: [email protected] (S.M. Al-Qahtani), [email protected] (M.B. Al-osaimi), [email protected] (M. Abdelalim), [email protected] (M.A. Althomali), [email protected] (A.H. Alomari), [email protected] (O.A. Bawazeer), [email protected] (A.H. Ismail), [email protected] (A.-W. Ajlouni).
1 Equally contributed.
Contents lists available at ScienceDirect
Journal of Radiation Research and Applied Sciences
journal homepage: www.journals.elsevier.com/journal-of-radiation-research-and-applied-sciences
https://doi.org/10.1016/j.jrras.2023.100633
Received 11 May 2023; Received in revised form 19 June 2023; Accepted 14 July 2023
1. Introduction
Radioactive iodine (RAI) I131 therapy is utilized in the treatment of different thyroid disorders (Muhammad, 2009). Graves’ disease (GD) is a part of autoimmune thyroid disease that results in excess secretion of thyroid hormones causing hyperthyroidism. In GD, RAI has offered su- perior remedy rates compared with antithyroid drugs and surgery.
There are two acceptable techniques for defining the appropriate I131 dose; denoted as calculated and fixed techniques (Abraham & Acharya, 2010; Ross et al., 2016). The calculated approach is defined as a ratio of a dose in the range of 75–200 μCi/gm of the thyroid gland volume to the percentage of radioiodine uptake during 24 h, known as 24-h RAIU (Meier et al., 2002). As this is quite complex, several research in liter- ature proposed fixed doses, such as 10 mCi (370 MBq) and 15 mCi (555 MBq) because it is simpler and more effective (Abraham & Acharya, 2010; Alexander & Larsen, 2002; Canadas et al., 2007; Gupta et al., 2010; Kayode Solomon and Eniojukan, 2013; Lewis et al., 2013; Nor- dyke & Gilbert, 1991; Santos et al., 2012; Schneider et al., 2014; Wong et al., 2018). They found both fixed doses were effective with no link to age or gender, but the successful cure has an inverse relationship with gland size, T4 level and past anti-thyroid drugs.
Although the treatment with RAI is recognized as an effective approach for the treatment of GD (Francis et al., 2020), controversy exists concerning the optimal practice for determining the required ac- tivity to the thyroid and hence achieving the best clinical outcome (Duntas, 2021). Administration to patient with a large dose of 1131 may result in permanent hypothyroidism and subsequently requires ongoing hormonal replacement therapy (Dietlein, 2020).
Administration of low dose of RAI is necessary to reduce behavioral constraints especially for out-patients after RAI therapy and avoiding undesirable radiation effects (Varghese et al., 2021). However, the failure rate of curing hyperthyroidism after treatment with I131 leads to difficulty of determining the appropriate dose (Iizuka et al., 2019).
The usage of 5 mCi (185 MBq) hasn’t been well investigated in the treatment of GD (Esfahani et al., 2005; Malapure et al., 2020). Thus, the purpose of the current study is to examine the effect of such a low fixed dose and also raise the possibility of euthyroid state after successful ablation, rather than hypothyroid with long-life replacement therapy.
2. Materials and methods 2.1. Study design and population
The population of this study was composed of patients presenting to our Nuclear Medicine Unit at the King Faisal Complex Hospital in Taif city, Saudi Arabia, and found to be suffering from Graves’ hyperthy- roidism. This study has received ethics approval from relevant com- munities and patient consent forms were obtained, and all patients’ data will be kept confidential, according to the ethical guidelines. This pro- spective study consisted of 100 patients (78 female and 22 male) being referred from our endocrinology outpatient clinics, for I131 treatment.
Several fundamental data of the patients were acquired including gender, age, existence of eye illness (exophthalmos), type and size of goiter, existence time of hyperthyroidism, previous treatment with anti- thyroid medications before RAI therapy, and time of therapy cessation before administration of RAI. Clinical signs and biochemical data such as the presence of widespread goiter, ophthalmopathy, and antibodies to thyroid stimulating hormone (TSH) receptors were used to diagnose hyperthyroidism.
2.2. Inclusion and exclusion criteria
The study included patients who: a) suffered from diffuse goiter based on physical palpation and/or thyroid scan, b) were not in Anti- thyroid Drugs (ATD) course for minimum three days before the administration of iodine dose, c) Not having any prior use of
medications that might interfere with the iodine uptake (as lithium, amiodarone and metformin). The exclusion criteria were patients with:
a) multinodular goiter, b) single independently functioning nodule, c) previous use of medications that might interfere with the iodine uptake.
d) previous treatment with radioiodine for hyperthyroidism, e) lost patients during follow up examination within 6 months since I131 therapy.
2.3. Data collection (case diagnosis)
At diagnosis, the thyroid was classified in terms of type and volume into four categories. Normal size (none), thyroid enlarged but not noticeable (small), thyroid enlarged and noticeable (medium or large).
The characteristics of the thyroid size were confirmed by ultrasound measurements. All suspected patients were scanned with 111–185 MBq (3–5 mCi) pertechnetate (TcO−4) using dual-head gamma camera two weeks before I131 treatments. The scan was also performed after treat- ment in the 1st, 2nd, 3rd, 6th month. Thyroid function tests such as TSH, FT4 and FT3 were performed for the subjects at diagnosis and before taking RAI in the laboratory department of our hospital, with its normal reference values as follows: FT4 [12.3–20.2 pmol/L], FT3 [3.6–6.9 pmol/L], TSH [0.3–4.2 mU/L](Ross et al., 2016).
2.4. Treatment protocol
Anti-thyroid medicines and seafood consumption were halted five days before radioiodine procedure and were not suggested for at least one week following treatment. Patients were evaluated and counselled by a nuclear medicine physician a week ahead of therapy with I131. Empirical and random doses of I131 were administrated to the patients despite of gland size, degree of uptake and toxicity of hormonal profile.
Oral doses of 5, 10 or 15 mCi (185, 370 or 555 MBq) were given to patients who are divided into “three groups” according to applied dose respectively. Thyroid function tests were observed throughout future follow-up, and thyroid condition was examined for all individuals six weeks, three months, and six months following radioiodine treatment.
2.5. Outcome of treatment
“Successful ablation” was considered as the required amount of radioiodine dose to treat hyperthyroidism resulting in patients with either “euthyroid” or “hypothyroid”. Relapse was considered as the relapse of hyperthyroidism within 6 months after therapy.
2.6. Statistical analysis
The data were collected and analyzed using the SPSS version 25 (Statistical Package for the Social Science; IBM Corp, Armonk, NY, USA).
Qualitative analysis was performed to determine minimum, maximum, mean, and standard deviation. Quantitative assessment using Chi Square test (χ2) for evaluating the interrelation between categorial variables while exact test was utilized for small samples frequency. Moreover, One-way ANOVA test was applied for comparison between means of more than two unrelated groups (treatment groups, treatment outcome) with a normal distribution. Tukey’s post-hoc test was performed to assess the difference significance between pairs of group means after the ANOVA analysis was employed. At p-values of 0.05, differences were judged significant. ANOVA’s total p-value was calculated and recorded, and post hoc analysis p-values were given in the comments when it is statistically significant. P-values of less than 0.05 were considered sta- tistically significant.
3. Results
The present study included 100 patients at the study beginning but five cases were eliminated due to their absence during follow-up, out of
the remaining 95 cases, 32 cases received empirical 5 mCi of I131, 32 cases received empirical 10 mCi of I131, and the remaining 31 cases received empirical 15 mCi of I131.
Table 1 demonstrates the baseline data among the studied three groups. The age of participant was ranging from 25 to 54 years with a mean age of 38.01 ± 6.91 years, where female patients comprised 64.2% of the study population. The results show that there was no sig- nificant difference between the studied three groups regarding their gender and age with p-values >0.05. Regarding the thyroid size, it was ranging from 41.20 to 80.20 g with an average size of 54.41 ±8.53 g.
The size of the thyroid between the three studied groups showed no significant difference with p-value >0.05.
Table 2 and Fig. 1 exhibit the reasons for RAI treatment. A ratio of 82.21% of the patients were treated with RAI dose after a failure response to antithyroid medication as initial treatment plan (53.7%), or because of disease recurrence (28.5%) while RAI was used as first-line treatment in 17.89%. The statistical analysis between the three groups confirmed no significant difference regarding the indication of RAI treatment.
Table 3 and Fig. 2 illustrate a comparison between responses after the 1st RAI dose in the three studied groups. Successful ablation (hypothyroidisim) was obtained in 23 (71.9%) among 5 mCi group, 27 (84.4%) among 10 mCi group and 22 (71.0%) among 15 mCi group without a significant difference between the groups with p-value of 0.695.
Comparison of success and failure in groups after RAI is shown in Table 4. In the success ablation and the Euthyroidism groups, the baseline size of the thyroid gland was significantly smaller compared to the Hyperthyroidism group (51.36 ± 4.32 g 53.73 ± 5.19 g and vs.
70.54 ±8.70 g; p <0.001). On the other hand, there was no significant difference between the Successful ablation and Euthyroidism groups in terms of baseline size of the thyroid gland (p-value =0.203), as illus- trated in (Fig. 3).
Regarding the other studied factors such as age, gender, disease duration and indication of RAI, there was non-statistically significant association with success and failure in the studied groups after RAI.
4. Discussion
Several studies in literature suggested the use of empirical doses as a treatment procedure of hyperthyroidism. They have demonstrated its superiority over the calculated method as it provides similar remedy rate as well as less time consuming and more cost-effective. Research done by Lewis et al. (Lewis et al., 2013) and Gupta et al. (Gupta et al., 2010) investigated the effectiveness of a fixed doses of 15 mCi RAI for GD patients. They found high percentage cure rate with 78% and 79.5%
respectively with no superiority of a calculated method regarding final clinical outcome.
A randomized trial research conducted by Peters et al. comparing a standard activity of 15 mCi to the calculating approach in patients diagnosed with Graves’ thyrotoxicosis. It reported a succussful curing rate of 71% versus only 58% respectively. However, these rates showed an inversely relationship to the thyroid gland size over 75 g with higher
decrease of the fixed dose to only 25% versus 45% of the calculated dose (Peters et al., 1995).
The ideal I131 activity regimen remains controversial; hence, the purpose of the current study was to evaluate the clinical consequence of treating GD patients with three different fixed activities of I131 5, 10 and 15 mCi (185, 370 and 555 MBq).
Quantitative data analysis shows non-statistically significance in cure rate between the three I131 (5, 10 and 15 mCi) regimens, The results of the current study come to an agreement with a similar study examines the efficacy of two different fixed doses, 10 mCi and 15 mCi, of I131 for treating patients with Graves hyperthyroidism. It concluded that the two fixed doses provided similar remission rates without any statistical dif- ference after 12 months follow-up of treatment (Canadas et al., 2007;
Santos et al., 2012).
Similarly, Nordyke et al. (Nordyke & Gilbert, 1991) have found that the best dose for achieving cure was 111–370 MBq (3–10 mCi), with no significant link between treatment and age or gender. The cure of hy- perthyroidism and thyroid weight had an inverse connection (Chi-s- quare for slope, 0.01p0.02). They came to the conclusion that starting with 370 MBq and increasing it to account for only big thyroid glands or uncommon instances.
On the other side, the results of a study similar to the current study contradict our results. It reported significantly higher success rate (P = 0.005) of 76% in 10 mCi Group as compared to 61.5% in 5 mCi Group.
They concluded that the higher dose of I131 is essential to achieve euthyroidism or hypothyroidism (Malapure et al., 2020).
Esfahani et al., in a randomized trial has reported higher cure rate for administrating patients with a single dose of 10 vs. 5 mCi (88.5 vs.
48.5% respectively for 2 years). They stated that the 5 mCi (185 MBq) group revealed less response to treatment, further inspection by the physician and persistence of hyperthyroidism in comparison to the 10 mCi (370 MBq) group. Therefore, this study advocates an administration dose of 10 mCi (370 MBq) for successful treatment of GD (Esfahani et al., 2005).
The effectiveness of a dose of 8 mCi was also investigated in another trial by Alexander E et al. during a seven-year period with 261 partici- pants. After a year of treatment, 86% of the patients reached the desired level of euthyroidism or hypothyroidism, whereas 14% needed further Table 1
Baseline data among the studied three groups; (N =95).
Studied groups Total N =95 p-value
5 mCi I-131 N =32 10 mCi I-131 N =32 15 mCi I-131 N =31
Age (years) Mean ±SD 38.64 ±6.69 38.31 ±6.90 37.04 ±7.26 38.01 ±6.91 0.629
Range 27.80–54.00 25.50–53.00 26.70–52.50 25.50–54.00
Sex N (%) Female 22 (68.8%) 19 (59.4%) 20 (64.5%) 61 (64.2%) 0.736
Male 10 (31.3%) 13 (40.6%) 11 (35.5%) 34 (35.8%)
Disease Duration (years) Mean ±SD 2.38 ±0.83 2.42 ±0.88 2.72 ±0.64 2.50 ±0.80 0.181
Range 1.0–4.0 1.0–4.0 1.0–4.0 1.0–4.0
Thyroid size (g) Mean ±SD 54.91 ±8.39 53.42 ±7.99 54.92 ±9.38 54.41 ±8.53 0.728
Range 45.30–78.30 41.20–78.90 43.80–80.20 41.20–80.20
Table 2
Indication of RAI treatment among studied cases, N=(95).
Studied groups Total N =
95 p-
value 5 mCi I-
131 N = 32
10 mCi I- 131 N = 32
15 mCi I- 131 N = 31 Failure of
antithyroid drugs
18 (56.3%) 17
(53.1%) 16
(51.6%) 51
(53.7%) 0.963 Recurrence post
antithyroid drugs
10 (31.3%) 9 (28.1%) 8 (25.8%) 27 (28.5%) First-line
treatment 4 (12.4%) 6 (18.8%) 7 (22.6%) 17 (17.89%)
treatment for persistent hyperthyroidism. They suggested that patients with a potential treatment failure such as young patients, those with higher T4 levels, larger glands, and with anti-thyroid medications course prior treatment should receive higher dose of I131 (Alexander & Larsen, 2002).
In the current study potential variables that might have a negative impact on the development of successful ablation (hypothyroidism) after treatment were investigated. We found non-statistically significant association with age, gender, disease duration and previous ATDs which
come in agreement with those results revealed by Santos et al., (2012).
Some studies have reported that the use of ATDs prior to the I131 therapy limits the effectiveness of a single I131 treatment, and thus, reducing the possible remission rate of the hyperthyroidism (Alexander
& Larsen, 2002). In contrast, other trials reported no relation between
patient with previous ATD treatment and an increase of persistent hy- perthyroidism (Husseni, 2016; Isgoren et al., 2012). The results of the current study agree with the latter ones where neither prior medical therapy nor disease duration had a considerable influence on the development of hypothyroidism among the entire study population or in individual group separately.
Regarding thyroid gland volume which was considered to be the fundamental factor affecting the RAI therapy outcome, we found that the baseline size of thyroid gland was significantly smaller in Successful ablation group as compared to the Hyperthyroidism group (51.36 ± 4.32 vs. 70.54 ±8.70; p <0.001). Also, among the Euthyroidism group, the baseline size of thyroid gland was significantly smaller as compared to the Hyperthyroidism group (53.73 ±5.19 vs. 70.54 ± 8.70; p <
0.001). This means that a fixed dose procedure is simple and effective but the success of this approach may degrade with severe hyperthy- roidism or larger goiter. This result is in accordance with previous studies confirming that the increase size of the thyroid gland negatively Fig. 1.Indication of RAI treatment among studied cases.
Table 3
Comparison between responses after 1st RAI dose in the three studied groups.
Studied groups Total N
=95 p- value 5 mCi I-
131 N = 32
10 mCi I- 131 N = 32
15 mCi I- 131 N = 31 Successful
ablation 23
(71.9%) 27
(84.4%) 22
(71.0%) 72
(75.8%) 0.695 Euthyroidism 3 (9.4%) 2 (6.3%) 6 (19.3%) 11
(11.6%) Hyperthyroidism 6 (18.8%) 3 (9.4%) 3 (9.7%) 12
(12.6%)
Fig. 2. Comparison between responses after 1st RAI dose in the three studied groups.
influences RAI treatment outcome and hence, patients with greater thyroid gland sizes are more likely in need of an additional dose of radioiodine (Allahabadia et al., 2001; Arık et al., 2021; Lewis et al., 2013).
The current study has some limitations. We didn’t report the adverse effects as a consequence of the I131 administration at the different regimen applied. The short follow-up period that may result in missing a number of patients who could suffer from hypothyroidism.
Therefore, we recommend further complementary studies with more follow-up intervals up to 10 years, to confirm the safety of low doses regarding the risk for thyroid cancer due to the "non-killed" thyroid cells exposed to low doses of radiation with minor alteration in its DNA sequences.
Also, prolonged follow-up for the outcome is essential for monitoring the probability of recurrence of toxicity in individuals who developed euthyroid state from exposure to the therapeutic low doses of iodine.
5. Conclusion
This study aimed to investigate the treatment response to three different RAI fixed doses regimes of 5, 10 and 15 mCi (185, 370 and 555 MBq) on 100 patients with Grave Disease. The study shows similar remission rates for the three regimes of treatment, and the size of the thyroid gland was the only variable that had an impact on the patients’ outcome where patients with large goiters have less chance of remission.
So, we recommend 185 MBq (5 mCi) of RAI dose as a routine treatment regimen for all patients with GD except for patients with palpable large
thyroid gland size.
Funding
This research has not funded.
Declaration of competing interest None.
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Table 4
Factors related to outcome after first radioactive iodine dose among the studied cases; (N =95).
Cure rate after one dose of RAI p-value
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Gender Female 48 (66.7%) 4 (44.4%) 9 (64.3%) 0.675
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First-line treatment 22 (30.6%) 3 (33.3%) 2 (14.3%)
Post-surgical 3 (4.2%) 0 (0.0%) 1 (7.1%)
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