Original article
Radioiodine therapy in Graves’ disease: Is it possible to
predict outcome before therapy?
Serkan Isgorena, Gozde Daglioz Gorura, Hakan Demira and Fatma Berka,b
Objective To assess the predictability of outcome and
evaluate the factors that may lead to treatment failure in
patients with Graves’ disease who are treated with a single
dose of radioiodine.
Materials and methods This is a retrospective study of
123 patients (M: 42; F: 81) with Graves’ disease who
received radioiodine therapy with a single fixed (10 mCi)
dose for hyperthyroidism. Pretreatment age, sex, BMI, type
of anti-thyroid drug used, propylthiouracil doses, iodine
uptake, uptake ratio (4/24 h radioiodine uptake), and
thyroid volume of the patients in whom radioiodine therapy
succeeded or failed were compared.
Conclusion Uptake ratio is a simple index that may be
used to predict the patients in whom therapy may fail or
succeed. In patients with Graves’ disease who have an
uptake ratio of less than 1, radioiodine appears to be an
effective dose with high success rates. In contrast,
because of the high rates of failure in patients with an
uptake ratio of at least 1, use of radioiodine therapy at a
dose of 10 mCi does not seem to be appropriate. Nucl Med
c 2012 Wolters Kluwer Health |
Commun 33:859–863 Lippincott Williams & Wilkins.
Nuclear Medicine Communications 2012, 33:859–863
Keywords: Graves, hyperthyroidism, outcome, radioiodine, uptake
Results Post-therapy follow-up revealed that therapy
failed in 22% of the patients. Iodine uptakes and uptake
ratios and volumes were found to be significantly higher in
patients in whom therapy failed. It was observed that
uptake ratio was at least 1 in 25 patients (20%), and
therapy failed in 20 (80%) of these patients. Of the 98
patients (80%) in whom uptake ratio was less than 1,
therapy was unsuccessful in only seven (7%).
Department of Nuclear Medicine, Faculty of Medicine, Kocaeli University,
Kocaeli, Turkey and bDepartment of Diagnostic Radiology, Oregon Health and
Science University, Portland, Oregon, USA
Introduction
Patients and methods
Graves’ disease (GD) is the most common cause of
hyperthyroidism (HT). The treatment of HT associated
with GD includes administration of anti-thyroid drugs
(ATDs), thyroidectomy, and radioiodine therapy (RIT)
[1]. RIT is being used increasingly more often in GD
treatment as it is simple, inexpensive, effective, and
reliable. Administration of radioiodine (RAI) results in
destruction of the overfunctioning thyroid tissue, elimination of HT with a high success rate, and in development of euthyroidism or hypothyroidism [2,3]. However,
therapy failure and increased exposure to radiation due
to a second dose of RIT may pose a problem. Although
the failure rate can be reduced using higher RAI doses
initially, administration of higher doses of RAI may
increase the radiation dose [3–7]. Despite the fact that
this therapy has been used reliably for seven decades,
there are still differing points of view with regard to
determination of the appropriate dose [8–10]. Fixed RAI
doses result in different outcomes in different patients,
which indicates that many factors other than the
administered dose affect therapy outcome [3,11–13].
This study aims to evaluate the factors that may cause
failure in GD patients who are given 10 mCi fixed-dose
RAI as well as assess the predictability of treatment
outcome.
We conducted a retrospective study of 123 patients (M/F:
42/81) who received a single dose of RIT for HT
associated with GD between 2006 and 2010 and who
had regular follow-up after the therapy. GD diagnosis was
confirmed with clinical, laboratory, thyroid scintigraphy,
ultrasonography, and RAI uptake results in all patients.
All patients had a documented relapse after anti-thyroid
medication treatment. As part of administration of ATDs,
33 patients were given methimazole and 90 were given
propylthiouracil (PTU) before RIT.
c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
0143-3636 a
Correspondence to Serkan Isgoren, MD, Department of Nuclear Medicine,
School of Medicine, Kocaeli University, Kocaeli, Turkey
Tel: + 90 262 303 8066; fax: + 90 262 303 8003;
e-mail: [email protected]
Received 18 January 2012 Revised 12 April 2012 Accepted 7 May 2012
A fixed-dose regimen was used in the treatment of
hyperthyroid patients; this study registered the patients
who were given RAI at a dose of 10 mCi, which is our
most commonly preferred dose in the treatment of GD.
Moderate-to-severe ophthalmopathy or previous treatment with thyroidectomy were the exclusion criteria in
the study.
All patients had RAI uptake measurements taken 4 and
24 h after 50 mCi RAI administration using a thyroid
uptake probe. The intake of ATDs of the patients was
interrupted 3 days before taking RAI uptake measurements and administering RIT. They were resumed 3 days
after the therapy and gradually discontinued 1 month
after therapy. In addition, the patients were started on a
DOI: 10.1097/MNM.0b013e3283559ba1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
860 Nuclear Medicine Communications 2012, Vol 33 No 8
low-iodine diet for 10 days before the therapy. The
median interval between RAI uptake measurements and
RIT administrations was 12 days (range: 4–21 days). An
uptake ratio (UR) was calculated by dividing 4-h iodine
uptake value by 24-h iodine uptake value. Ultrasonography was used to measure the pretherapy thyroid volume
using an ellipsoid model [length (cm) width (cm) depth (cm) 0.5248].
Patients were followed up for 1–3 months after RIT
administration within the first year and for 6–9 months
between the first and third years, using a questionnaire to
inquire about possible symptoms of HT or hypothyroidism and thyroid function tests (free T3, free T4, thyroidstimulating hormone). The median follow-up period was
12 months (range: 12–36 months).
Patients who had hypothyroidism or euthyroidism,
diagnosed on the basis of thyroid function tests, were
categorized as those in whom treatment had been
successful. In contrast, those who had to use ATD or
who received a second dose of RIT at the end of the first
year were considered as those in whom treatment had
been a failure. Patients who had elevated thyroidstimulating hormone in post-therapy follow-up visits
continued to be followed up for at least 6 more months
to exclude the possibility of temporary hypothyroidism.
The relationship between pretherapy clinical factors, in
the form of laboratory results [age, sex, BMI, type of ATD
(PTU or methimazole), PTU doses, iodine uptake, UR,
and thyroid volume], and treatment failure was evaluated.
Statistical analysis
All statistical analyses were carried out using SPSS version
16.0 for Windows (SPSS Inc., Chicago, Illinois, USA). The
Kolmogorov–Smirnov test was used to evaluate normality
of distribution for continuous variables. The t-test was
used for normally distributed data and the Mann–Whitney
test was used for non-normally distributed data to
compare continuous variables in the two groups (patients
who experienced success or failure with RIT); the w2-test
was used to compare categorical variables. P values less
than 0.05 were considered statistically significant. The
odds ratio at the 95% confidence interval was calculated
for patients with UR of at least 1 and compared with those
with UR less than 1.
and for all patients taken together were 15 months
(range: 12–30 months), 24 months (range: 12–36
months), 12 months (range: 12–18 months), and 12
months (range: 12–36 months), respectively. The median
cure time was 3 months (range: 1–6 months). Of the 27
patients in whom RIT failed, 22 were administered a
second dose of RIT. The second dose of RIT was given
after a median period of 12 months (range: 9–18 months)
following the first dose. Twenty patients were administered a dose of 15 mCi and two were administered a dose
of 20 mCi as the second RAI dose. The median follow-up
period after the administration of the second dose was 12
months (range: 9–18 months). Follow-up results after the
second dose showed that, of the 22 patients, 19 (86%)
developed hypothyroidism and two (9%) developed
euthyroidism. The second dose therapy failed in only
one patient (5%), who developed hypothyroidism after
the administration of the third dose of 20 mCi.
Factors that affected cure
The effects of pretherapy clinical and laboratory factors
on the failure of the first RIT dose are presented
in Table 1. No statistically significant relationship was
identified between failure of RIT and age, sex, BMI, type
of ATD used (PTU or methimazole), and daily PTU dose
(P > 0.05).
There was a statistically significant relationship between
4-h uptake, 24-h uptake, UR, and thyroid volume and
treatment failure. Four-hour uptake, 24-h uptake, UR
values, and thyroid volume were significantly elevated in
patients in whom RIT failed, compared with patients in
whom the therapy succeeded.
It was noted that in 25 (20%) patients (17 female and
eight male) who received RIT 4-h iodine uptake values
were greater than or equal to 24-h iodine uptake values
(UR Z 1). Baseline features of patients with UR of at
least 1 and UR less than 1 have been summarized
in Table 2. RIT failed in 20 of 25 patients (80%) whose
UR was at least 1, whereas RIT failed in only seven of
98 patients (7%) whose UR was less than 1. The odds
ratio showed that patients with a UR value of at least 1
had a 52-fold risk for RIT failure (95% confidence
interval =14.965–180.693).
Discussion
Results
This study analyzed the results of 123 GD patients who
received a single fixed dose (10 mCi) of RAI in our
department between 2005 and 2009. Post-RIT follow-up
results showed that RIT was successful in 96 (78%)
patients and failed in 27 (22%). Of the 96 patients in
whom RIT was successful, 71 developed hypothyroidism
and 25 developed euthyroidism. The median follow-up
time periods for patients with hypothyroidism, for those
with euthyroidism, for those in whom treatment failed,
There are three options for treatment of GD, a common
cause of HT: ATD, RIT, and surgery. Of these, RIT has
being used more commonly in the treatment of GD as
either first-line or second-line treatment for more than
seven decades [1,14]. When compared with the other two
therapeutic options, RIT is the easiest to administer and
the most inexpensive treatment with the fewest side
effects [10,13]. However, treatment failure, which may
occur in 8–50% of cases after the first dose of RIT, still
poses a problem [6,13,14].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Prediction of radioiodine therapy outcome Isgoren et al.
Table 1
861
Effects of pretherapy clinical and laboratory factors on the failure of the first dose of RIT
Variables
Age (years)
Sex (female)
BMI
Type of ATD (PTU)
PTU (mg/day)
4-h uptake (%)
24-h uptake (%)
UR
UR Z 1
Volume (ml)
All (n = 123)
Failure (n = 27)
Success (n = 96)
*P value
42.4±13
81/123 (66%)
25±4
90/123 (73%)
205±175
41.1±19
49.9±16
0.8±0.2
25/123 (20%)
32.3±18
44±15
16/27 (59%)
24±4
19/27 (71%)
230±185
56.9±15
56.4±14
1±0.2
20/27 (70%)
48±18
42±13
65/96 (67%)
25±4
71/96 (74%)
200±175
36.6±18
48.1±17
0.7±0.2
5/96 (5%)
27.9±15
0.46 (NS)
0.55 (NS)
0.61 (NS)
0.91 (NS)
0.46 (NS)
< 0.01
0.011
< 0.01
< 0.01
< 0.01
All values are expressed as mean±SD for continuous variables and as the number of patients (percentage) for categorical variables.
ATD, anti-thyroid drug; PTU, propylthiouracil; UR, uptake ratio.
*Statistical difference between failure and success groups.
Table 2
Baseline features of patients with UR Z 1 and UR < 1
UR Z 1
Age (years)
Sex (female)
4-h uptake (%)
24-h uptake (%)
UR
Volume (ml)
UR < 1
All (n = 25)
Failure (n = 20)
Success (n = 5)
All (n = 98)
Failure (n = 7)
Success (n = 91)
42±12
17/25 (68%)
60±17
53±15
1.1±0.1
48±18
43±15
14/20 (70%)
60±16
54±15
1.1±0.1
48±18
41±11
3/5 (60%)
60±19
52±17
1.1±0.1
48±19
43±14
64/98 (65%)
39±15
51±15
0.7±0.1
30±15
45±15
2/7 (28%)
47±12
63±9
0.7±0.1
44±18
42±13
62/91 (68%)
35±17
48±17
0.7±0.1
26±14
All values are expressed as mean±SD for continuous variables and as the number of patients (percentage) for categorical variables.
UR, uptake ratio.
The major parameters that determine the outcome of RIT
include the iodine dose administered and the dose absorbed by the thyroid tissue [7,15]. Although several
dosimetric studies were conducted to obtain a high treatment success with the smallest dose, there is still no
consensus on the optimal dose and the mode of determining the actual dose to be administered [6,15–17]. RAI dose
can be determined by using either a fixed dose or a patientspecific calculated dose. The fixed-dose approach may vary
between a low and ablative dose [18,19]. In the calculated
dose regimen, the dose calculation relies on the use of two
or more of the following variables: thyroid volume, thyroid
uptake values, and/or RAI effective half life [15,19,20].
Although requiring complex dosimetric calculations and
additional time, the calculated dose regimen produced
treatment successes similar to those obtained with the
fixed-dose regimen; therefore, nowadays many centers
prefer using the simpler fixed-dose regimen [2,3,17,20,21].
In our study, which included a homogenous group of GD
patients who suffered a relapse after anti-thyroid treatment and who received a single fixed dose of 10 mCi RAI,
we observed 22% treatment failure and 78% treatment
success (58% hypothyroidism, 20% euthyroidism), which
is consistent with other studies that used the same
dose [8]. Other studies including different patient groups
and using different dose regimens in the literature have
reported treatment failure rates between 8 and
50% [6,22,23]. Although the lowest treatment failure
rates were obtained using the ablative dose regimen, as
higher doses are administered to patients who could be
treated with lower doses, they have serious limitations,
such as ignoring the ALARA principle and increasing
whole-body radiation exposure [22,23]. Besides, lower
dose administrations, which could be preferred to ablative
dose administrations, may result in higher rates of failure
and require second and third RIT administrations more
commonly. These procedures not only violate the ALARA
principle but also increase whole-body exposure. That is
the major reason for the uncertainty surrounding the ideal
dose alternatives. In our study, 22 patients were given a
second dose and one patient was given a third round of
RIT because of treatment failure.
There are several studies in the medical literature
exploring the risk of cancer development following
radioactive iodine treatment. Some studies have found
an elevated risk of stomach, kidney, and breast cancers in
association with the cumulative RAI dose increase [24].
However, there are also studies involving large series that
do not support this result [25]. None of the patients in
our series developed any tumor of thyroidal or extrathyroidal origin throughout our short follow-up period.
Several studies were conducted to evaluate the factors
that may affect the development of treatment failure and
predict the patients in whom the treatment may fail.
They showed correlations between treatment failure and
many parameters, including turnover rate, thyroid size,
biological half life, exophthalmos, uptake values, and UR
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
862
Nuclear Medicine Communications 2012, Vol 33 No 8
in RIT [3,11–14]. However, no practical method to
predict outcome and reduce or prevent treatment failure
was reported. In this study, we tried to evaluate the
parameters that might affect outcome by comparing
patients in whom the treatment had been successful with
those in whom the treatment had failed. We did not find
any statistically significant relationship between treatment failure and age, sex, BMI, type of ATD used, and
PTU dose. However, we found that 4- and 24-h RAI
uptake, UR, and thyroid volume values were higher in
patients in whom therapy had failed in comparison with
those in whom the treatment had been successful
(P < 0.05).
The increase in thyroid iodine turnover rate in hyperthyroid patients causes RAI to be rapidly eliminated from the
thyroid and its effective half life to be shortened, thus
reducing the success of RAI treatment [16,26–30].
Furthermore, in the presence of a rapid turnover, elevated
radiolabeled thyroid hormone in the circulation of these
patients increases the amount of radiation that all body
organs are exposed to [7,31]. Effective half-life measurements determine that the patients with rapid turnover
may require more than 10 measurements to be taken over
7 days. However, this method is rarely used, as it is labor
intensive [15,16,32]. UR is a simple index that can be
used to identify patients with a high iodine turnover, and
there are only a few studies in the literature that
investigate the relationship between UR and therapy
outcome [16,26,27]. In a study in which a calculated dose
regimen was used in hyperthyroid patients [26], UR was
at least 1 in 15% of the patients in whom treatment
failure was about 50%, and the failure rate in patients
with a UR less than 1 was 11%. In our study we found a
UR value of at least 1 in 20% of the patients. Treatment
failure rate was 80% in patients with a UR value of at least
1, whereas the failure rate was only 7% in those with a UR
value of less than 1.
There are some studies in the literature that aimed to
reduce the turnover rate and increase treatment success
in HT patients. It has been shown that cold iodine or
lithium administrations, together with RAI treatment,
can be used to prolong the effective half life of RAI in the
thyroid gland and increase the dose of radiation absorbed
by the thyroid tissue [7,13,26–28]. However, there is no
study that showed the effect of RIT combined with cold
iodine or lithium application on treatment success in
patients with a UR value of at least 1.
The most commonly preferred treatment option in
patients in whom RAI treatment fails is a second dose
of RAI. Treatment success rate was as high as 95% with
this second dose of RAI, which is in congruence with that
reported in the literature [19].
Conclusion
The main purpose of RIT is to achieve optimum
treatment success with a minimum RAI dose, which
may be determined by a simple method. The UR may be
used to predict the patients in whom therapy fails or
succeeds. This practical index can be calculated using a
pretreatment thyroid uptake test. The results of the
present study showed that 10 mCi RAI is an ideal dose
with an optimal treatment efficacy in GD patients with a
UR value of less than 1. In contrast, 10 mCi was seen to
be a dose that fails in efficiency in the case of a UR value
of at least 1. Patients who have a UR value of at least 1
should be informed, before administration of RIT, that
the treatment has a high chance of failure and that they
may require a second dose. Further and more detailed
studies need to be conducted to evaluate the efficiency
of ablative dose applications and RIT combinations with
medications like cold iodine or lithium, which aim to
reduce the rate of RAI turnover.
Acknowledgements
Conflicts of interest
Both our study and similar outcome studies have
demonstrated that thyroid uptake and thyroid volume
values are parameters that correlate with treatment
failure [3,11,12,14,33]. However, predicting which patients will have a treatment failure on the basis of these
parameters does not seem to be feasible.
Nevertheless, it has been seen that patients who can be
successfully treated and those in whom treatment will be
a failure can be easily predicted, and patients with a high
turnover can be determined using UR values, which can
be easily calculated by conducting a thyroid uptake test
before the treatment. The RAI uptake test is widely used
in GD both in the differential diagnosis of HT and to
decide on the RAI treatment dose [34,35]. However, in
some centers, it is not preferred for diagnosis and
treatment planning, as the patient incurs additional
expenditure and additional time is required to conduct
the test.
There are no conflicts of interest.
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