Rev Esp Med Nucl Imagen Mol.

2019;38(3):195–203

Continuing Education

Radioiodine treatment of differentiated thyroid cancer related to

guidelines and scientific literature夽
M. Estorcha,∗ , M. Mitjavilab , M.A. Murosc , E. Caballerod ,
on behalf of the Grupo de Trabajo de Endocrinología de la SEMNIM
a
Servicio de Medicina Nuclear, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
b
Servicio de Medicina Nuclear, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
c
Servicio de Medicina Nuclear, Hospital Universitario Virgen de las Nieves, Granada, Spain
d
Servicio de Medicina Nuclear, Hospital Doctor Peset, Valencia, Spain

a r t i c l e i n f o a b s t r a c t

Article history: In differentiated thyroid cancer (DTC), radioiodine is administered to eliminate residual normal thyroid
Received 12 December 2018 tissue after thyroidectomy (ablative treatment), to treat residual microscopic disease (adjuvant treat-
Accepted 20 December 2018 ment), and to treat macroscopic or metastatic disease. Currently, treatment of DTC with 131 I is still a
Available online 1 March 2019
matter of controversy due to the absence of prospective clinical trials assessing its benefit in terms of
overall survival and recurrence-free interval. The current recommendations of the experts are based on
Keywords: observational retrospective data and on their interpretation of the literature. Pending the results of the
Radioiodine treatment
131 prospective trials that are currently underway, the use of 131 I seems to be justified not only in high-risk
I
Differentiated thyroid cancer
patients, but also in intermediate-risk and low-risk patients. The guidelines of The American and British
Initial risk stratification Thyroid Association, European and American Societies of Nuclear Medicine, The European Consensus
Dynamic risk stratification Group and the latest edition of National Comprehensive Cancer Network (NCCN) were considered in
drawing up this continuing education document, we also undertook a review of the related scientific
literature.
© 2019 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Medicina Nuclear e
Imagen Molecular.

Tratamiento del cáncer diferenciado de tiroides con radioyodo a la luz de las

guías y de la literatura científica

r e s u m e n

Palabras clave:
Tratamiento con radioyodo
131
I microscópica (tratamiento adyuvante) y para tratar enfermedad macroscópica o metastásica. A día de
Cáncer diferenciado de tiroides
Estratificación inicial de riesgo
Estratificación dinámica de riesgo
En el cáncer diferenciado de tiroides (CDT), el tratamiento con 131 I se administra para eliminar
tejido tiroideo residual sano postiroidectomía (tratamiento ablativo), para tratar enfermedad residual
hoy, el tratamiento con 131 I del CDT es todavía un tema de controversia debido a la ausencia de ensayos
clínicos prospectivos que evalúen su beneficio en cuanto a supervivencia global e intervalo libre de recur-
rencia. Las recomendaciones actuales de los expertos se basan en datos retrospectivos observacionales
y en su interpretación de la literatura. A la espera de los resultados de los ensayos prospectivos actual-
mente en marcha, la utilización del 131 I parece estar justificada no solamente en los pacientes de alto
riesgo, sino también en los de riesgo intermedio y bajo. Para la realización del presente documento de
formación continuada se han considerado las guías de la Sociedad Americana y Británica de Tiroides, de
las Sociedades Europea y Americana de Medicina Nuclear, el consenso del Grupo Europeo y la última edi-
ción del National Comprehensive Cancer Network (NCCN), así como se ha revisado la literatura científica
relacionada.
© 2019 Publi-
cado por Elsevier España, S.L.U. en nombre de Sociedad Española de Medicina Nuclear e Imagen Molecular.

1. Introduction

Differentiated thyroid cancer (DTC) is a papillary or follicular

夽 Please cite this article as: Estorch M, Mitjavila M, Muros MA, Caballero E, en
nombre del Grupo de Trabajo de Endocrinología de la SEMNIM. Tratamiento del
cáncer diferenciado de tiroides con radioyodo a la luz de las guías y de la literatura
científica. Rev Esp Med Nucl Imagen Mol. 2019;38:195–203.
∗ Corresponding author.
E-mail address: mestorch@santpau.cat (M. Estorch).
cancer, and the treatment of patients with these tumors is similar
despite having numerous biological differences.
Surgery is the first treatment to carry out in a patient with DTC.
Afterwards, most patients receive hormone and ablative treatment
with radioiodine (131 I). The follow-up of patients with DTC is per-
formed based on the basal determinations, and when necessary,

2253-8089/© 2019 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Medicina Nuclear e Imagen Molecular.
196 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203
stimulated, of thyroglobulin (Tg) and antithyroglobulin antibodies
(TgAb) is performed as well as imaging techniques according to risk.
Although most patients with DTC do not die from the disease,
prognostic factors associated with high risk of recurrence and death
have been identified, the most important being age at diagnosis,
tumor size and the presence of local or distant tumoral invasion.1–3
Follicular cancer usually appears in older patients and usually has
a more aggressive course with a higher mortality than papillary
cancer. Female sex is related to a better prognosis.
This document of continuing education was prepared consider-
ing the 2015 guidelines of the American Thyroid Association (ATA),
the British Thyroid Society, the European and American Societies of
Nuclear Medicine, the consensus of the European Group an the last
edition of the National Comprehensive Cancer Network (NCCN).4–9
Likewise, we also made an extensive and complete review of the
scientific literature related to DTC.
At present, the decision how to treat and follow patients with
DTC should be made by consensus in a multidisciplinary commit-
tee made up of specialists specifically and preferentially devoted to
thyroid cancer (endocrinology, general surgery or otorhinolaryn-
gology, nuclear medicine, anatomic pathology, medical oncology,
radiodiagnosis and clinical biochemistry) which can provide inte-
grated care with optimization of resources.10
2. Treatment and follow-up of differentiated thyroid cancer
2.1. Surgical treatment
Preoperative ultrasonography with evaluation of the central
lymphatic and laterocervical compartments enable programming
the most optimal surgical procedure in each patient. The choice
of this procedure is currently based on retrospective studies and
consensus documents since there are no prospective studies in this
respect.4,6,8,9
The surgical procedure depends, among other factors, on tumor
size and the presence or not of local extension or locoregional lym-
phatic involvement:
• Tumors ≤1 cm without local or lymphatic extension: lobectomy.
• Tumors >1 cm and ≤4 cm without local or lymphatic extension:
lobectomy or thyroidectomy. Thyroidectomy is performed when
the ultrasonography of the contralateral lobe is not completely
normal or when ablative treatment with 131 I is carried out. The
patient can decide which procedure to undergo.
• Tumors >4 cm, local or lymphatic extension or metastasis: total
thyroidectomy.
• Tumor of any size with a history of cervical irradiation: total
thyroidectomy.
• Multifocal papillary microcarcinoma: total thyroidectomy (espe-
cially for 8–9 mm lesions).
Lobectomy of tumors between 1 and 4 cm in size without local
or lymphatic extension excludes ablative treatment with 131 I, and
makes follow-up with Tg much more difficult. Retrospective stud-
ies have described the utility of treatment with 131 I in DTC of
>1 cm.11 On the other hand, the experience of the surgeon is funda-
mental and is considered in the guidelines of the European Society
of Nuclear Medicine,6 as is postoperative Tg which helps to identify
patients who may benefit from radioiodine.12 It has been shown
that compared to thyroidectomy, lobectomy in tumors >1 cm is
associated with a 15% risk of recurrence and 31% increase in the risk
of death.13 In a recent retrospective study in a group of 394 patients
with DTC of low or low-intermediate risk (1–4 cm), Kluijfhout
et al.14 demonstrated that 19.5% would have required completion
of thyroidectomy and 25.6% would have required treatment with
131 Iif they had been treated with lobectomy. However, there are
also multiple studies reporting that thyroidectomy has no benefits
over lobectomy with regard to survival in tumors ≤4 cm.15,16 The
British guidelines recommend that the type of intervention should
be decided individually based on each clinical scenario (tumor size,
ultrasonography of the doubtful contralateral lobe and/or evidence
of suspicious lymph nodes, patient age, among others) and addi-
tional factors of risk (history of radiation, etc.), and the decision
should always be made by a multidisciplinary committee.5
1. Teaching point
In tumors >1 cm and ≤4 cm without local or lymphatic
extension, the decision as to the surgical technique to perform
should be made by a multidisciplinary committee since lobec-
tomy leaves the non resected lobe without a histological study
and excludes treatment with 131 I and follow-up with Tg.
2.2. Hormone treatment
Following surgery most patients receive hormone replacement
treatment with levothyroxine (LT4) to maintain an euthyroid status
and/or to control tumoral growth.
Patients undergoing lobectomy might not be treated with LT4.
In this case, 6 weeks after surgery, thyrotropin levels (TSH) are
determined to assess the need or not to administer the hormone.
Patients treated with total thyroidectomy should start hormone
treatment when they are not candidates for ablative treatment with
131 I or when this is administered under stimulus with recombi-
nant human TSH (rhTSH). If ablative treatment is administered by
withdrawing hormone treatment, the patient cannot initiate hor-
mone treatment after surgery, provided that 131 I is given at 4/6
weeks (with TSH >30 mU/l). When hormone treatment is admin-
istered after surgery, TSH levels should be determined beforehand
and after, again at 4–6 weeks, to adjust the dose of LT4 if necessary.
2.3. Initial stratification of risk
The need or not to administer additional treatment after surgery
and especially whether 131 I should be administered is decided
based on the initial stratification of risk.
The determination of TSH and Tg 4–6 weeks after surgery pro-
vides an orientation as to the status of the disease. Although
the optimal stimulated and non stimulated Tg levels are not
clearly defined,4 it has been established that non stimulated lev-
els should be <30 ng/ml in the case of lobectomy and <5 ng/ml in
the case of total thyroidectomy. Levels above these indicate the
need for reassessment to complete thyroidectomy and/or admin-
ister radioiodine.17,18
The Tg values can vary according to the method of determination
used and also in the presence or not of TgAb.
2.3.1. Stratification of risk
The stratification of risk is made based on the tumor, node,
metastasis (TNM) classification (8th edition19 ) of the American
Joint Committee on Cancer (AJCC), which can estimate mortality,
and the 2015 ATA stratification of risk system,4 which estimates
the risk of disease persistence or recurrence (Tables 1 and 2,
respectively). Patients are classified into 3 categories of risk (low,
intermediate or high) based on their clinical-pathological charac-
teristics.
 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203 197

Table 1 Table 2
2017 TNM classification of the American Joint Committee on Cancer and the Union Stratification of risk of persistence/recurrence of differentiated thyroid cancer
for International Cancer Control for differentiated thyroid cancer. according to the ATA 2015.

T: primary tumor Low risk

Tx Non localized primary tumor Pillary thyroid cancer including all the following characteristics:
T0 No evidence of primary tumor No local or distant metastasis.
T1 Tumor ≤2 cma Macroscopic resection of all the tumor.
T1a Tumor ≤1 cma No local invasion.
T1b Tumor >1 cm and ≤2 cm Not presenting aggressive histology (tall, columnar, Hürthle cells, etc.).
T2 Tumor >2 cm and ≤4 cma No vascular invasion.
T3 Tumor >4 cma or extension to adjacent muscles No 131 I uptake outside the thyroid bed.
T3a Tumor >4 cma limited to the thyroid glands N0 or ≤5 N1 micrometastasis (<0.2 cma )
T3b Tumor of any size with extension to adjacent muscles Follicular thyroid cancer encapsulated papillary variant.
T4 Tumor of any size with extrathyroid extension Well differentiated follicular thyroid cancer with invasion of the capsule or
T4a Tumor of any size with recurrent extension to subcutaneous minimal vascular invasion (<4 foci).
tissue, larynx, trachea, espophagus or nerve Uni or multifocal papillary microcarcinoma, including BRAF V600E
T4b Tumor of any size with invasion of the prevertebral fascia, mutation.
carotid or mediastinic vessels
Intermediate risk
N: regional lymph nodes Thyroid cancer with at least one of the following characteristics:
Nx Non localized lymph nodes Microscopic invasion of perithyroid soft tissue.
N0 No evidence of lymph nodes Metastatic regional lymph nodes or 131 I uptake in the post ablative
N0a One or more with benign cytology or histology treatment scan.
N0b No radiological or clinical evidence Tumor with aggressive histology (tall, columnar, Hürthle cells, etc.) or
N1 Metastatic lymph nodes vascular invasion.
N1a Uni- or bilateral metastasis at level VI or VII N1 clinical manifestations or >5 N, with all the nodes being <3 cma
N1b Uni, bilateral or contralateral metastasis at level I, II, III, IV or V Multifocal papillary microcarcinoma with extrathyroid extension and
or at a retropharyngeal level BRAF V600E mutation.

M: distant metastasis High risk

M0 No metastasis Thyroid cancer with any of the following characteristics:
M1 Distant metastasis Macroscopic tumoral invasion
Incomplete resection
Staging according to age <55 or ≥55 years Distant metastasis
Postsurgical plasma Tg levels suggestive of distant metastasis.
Age T N M Stage Pathological N1 ≥3 cma
<55 years Any T Any N M0 I Follicular thyroid cancer iwht extensive vascular invasion (>4 foci).
<55 years Any T Any N M1 II ATA: American Thyroid Association; Tg: thyroglobulin.
≥55 years T1 N0/Nx M0 I a
Greatest diameter.
≥55 years T1 N1 M0 II Source: Haugen et al.4
≥55 years T2 N0/Nx M0 I
≥55 years T2 N1 M0 II
≥55 years T3a/T3b Any N M0 II
observed that the risk of recurrence varies based on the response
≥55 years T4a Any N M0 III
≥55 years T4b Any N M0 IVA to the different treatments20 :
≥55 years Any T Any N M1 IVB

AJCC: American Joint Committee on Cancer; TNM: tumor/node/metastasis; UICC:

Union for International Cancer Control.
a
Greatest diameter.
Note: The tumors may be solitary or multifocal. If multifocal, the T is determined by
the tumor of greatest size.
Source: Amin et al.19
Stratification of risk can decide the initial treatment as well as
establish the follow-up strategy to be followed. However, this strat-
egy may have to be changed along the course of the disease, and
this will be determined by dynamic stratification of risk.20
1. Teaching point
The stratification of risk classifies patients with DTC as hav-
ing low, intermediate or high risk and can decide the initial
treatment to be administered and establish the follow-up strat-
egy.
2.4. Dynamic stratification of risk
During follow-up patients are reclassified into one of the fol-
lowing clinical categories, and imaging studies and treatments,
if necessary, are adapted to the classification since it has been
• Excellent response: no clinical, biochemical or structural evi-
dence of disease.
• Incomplete biochemical response: detectable Tg or increased
TgAb.
• Incomplete structural response: persistence or new locoregional
or distant tumor tumoral lesions.
• Indeterminate response: biochemical or structural finidings that
can not rule out malignancy or persistence of TgAb with no evi-
dence of structural disease.
During the first year, follow-up is made by cervical ultrasonogra-
phy and determination of plasma TSH and Tg levels under hormone
suppression treatment at 6 or 12 months depending on the ini-
tial risk. Tg is determined by stimulation with rhTSH in patients
with intermediate or high risk with undectable basal Tg (to confirm
excellent response) or to identify persistent/recurrent disease. The
use of imaging or histological studies, if needed, also depends on the
initial risk or whether the patient shows biochemical or incomplete
structural response.
After the first year, plasma TSH levels are determined annu-
ally to adjust the dose or LT4 or to determine that these levels are
maintained at <0.1–0.5 mU/l in patients with incomplete structural
response.
Likewise, according to dynamic stratification of risk, imaging
studies are performed according to the case: cervical ultrasonogra-
phy on suspicion of locoregional disease, whole body scan with 131 I
and/or 18 F-FDG PET/CT in cases suspected of having locoregional or
distant disease, 18 F-FDG PET/CT with contrast in iodine refractory
198 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203
disease or magnetic resonance in patients suspected of presenting
brain disease.
1. Teaching point
Dynamic stratification of risk classifies patients with DTC
during follow-up as having:
• Excellent response.
• Incomplete biochemical response.
• Incomplete structural response.
• Indeterminate response.
3. Treatment with radioiodine
The first treatment with 131 I for DTC was administered in 1945.
However, at present the management of DTC is still controver-
sial due to the lack of prospective randomized clinical trials, and
therefore, the recommendations of the experts are based on ret-
rospective observational data and may be influenced by multiple
factors related to the course of the disease according to their inter-
pretation of the literature as well as their clinical perspective and
experience.21–23
Treatment with 131 I is based on the fact that tumoral thyroid
tissue has the capacity to incorporate iodine from the blood by the
sodium/iodine transporter membrane. Compared with normal tis-
sue, the expression of this transporter is reduced in tumoral tissue,
and thus, the uptake of 131 I may be reduced. Nonetheless, the beta
radiation of 131 I leads to the formation of free radicals at an intracel-
lular level, DNA lesion, and finally, cell death, which is the objective
of the treatment.
Treatment with 131 I in DTC is administered: to eliminate
residual healthy thyroid tissue post-thyroidectomy presenting
great avidity for the iodine (ablative treatment); to treat recur-
rence/persistence of lymph node involvement showing less avidity
for the iodine (adjuvant treatment) or to treat macroscopic or
metastatic disease.
Apart from destroying healthy thyroid tissue post-
thyroidectomy, the objective of ablative treatment is to destroy
possible microscopic foci, minimize the risk of recurrence in
patients with predisposition (i.e. history of cervical irradiation),
increase the specificity of Tg as a tumoral marker and increase the
specificity of the scan with 131 I for the detection of recurrent or
metastatic disease. On the other hand, the objective of adjuvant
treatment with 131 I in recurrence/persistence of lymph node
involvement and metastatic disease is to destroy all micro- and
macroscopic disease that cannot be treated with surgery, thereby
reducing the risk of recurrence and death.
1. Teaching point
In DTC treatment with 131 I may be:
• Ablative: to eliminate healthy residual thyroid tissue post-
thyroidectomy.
• Adjuvant: to treat residual microscopic disease.
• To treat macroscopic or metastatic disease.
3.1. Indications
The administration of 131 I after thyroidectomy depends on the
clinical–pathological characteristics of each tumor (Table 1) as well
as the initial stratification of risk (Table 2). The introduction of the
8th edition of the AJCC TNM classification of DTC raised the limit of
age of risk from ≥45 to ≥55 years. This has led to reclassification of
23–35% of the patients with DTC to lower stages than previously,
with an increase in stages I and II and an increase in the proba-
bility of recurrence in stage II patients ≥55 years of age. On the
other hand, stage III includes patients with more aggressive cervi-
cal disease without distant metastasis, with the vital prognosis in
stages III and IV being worse than in the 7th edition of the AJCC
TNM classification (Table 3). At present, the 2015 ATA guidelines
are the most widely used and have the greatest following among
specialists involved in the treatment of DTC.4 Except in tumors of
low risk ≤1 cm (T1a) and in those of high risk (T4), the 2015 ATA
recommendations on ablative treatment are ambiguous and open
to different interpretations in relation to local factors (Table 4):
• Low risk: 131 I not routinely administered when the tumor is
≤1 cm, even in the presence of affected regional lymph nodes (<5
lymph nodes of <2 mm), of multifocal tumor (all foci <1 cm) and
intrathyroid tumor >1 and ≤4 cm. Low doses can be administered
(1.1 GBq/30 mCi) in a selected group of patients. The decision to
administer 131 I or not can be based on local factors such as the
experience of the ultrasonographer, the surgeon or the method
of Tg measurement.
The decision to not administer 131 I in low risk cases is based
on retrospective studies, systematic reviews and metaanalyses
which have shown no benefits of this treatment with respect to
the rate of recurrence or mortality.24,25 To the contrary, other
retrospective studies have shown benefits in terms of overall
survival and recurrence-free interval in tumors >1 cm11 with the
administration of 131 I. In a retrospective study including 574
patients, Tran et al.26 recently reported that tumors >2 cm are
associated with a 5-fold greater risk of recurrence in patients
≥55 years of age. Three prospective randomized, multicenter,
clinical trials are currently ongoing (ESTIMABL2, IoN and CLERAD-
PROBE). The 5- and 10-year follow-up results of these studies are
expected at the beginning of 2022 and 2027, respectively.27–29
The position of the European Society of Nuclear Medicine (EANM)
is to administer 131 I in all tumors >1 cm.6 Therefore, while await-
ing the results of the previously mentioned ongoing trials, the
administration or not of 131 I remains controversial.22
• Intermediate risk: 131 I is administered according to the character-
istics of the tumor, presence of significant lymph node metastasis,
vascular invasion or aggressive histology, combined with patient
age (≥55 years). The decision to treat or not should be made
by a multidisciplinary committee. The data in the literature are
limited in this group of patients, although they do indicate bene-
fits with respect to overall survival.4,30,31
• High risk: 131 I is routinely administered, having shown benefits
in overall survival.31,32
3.2. Patient preparation
The 131 I uptake depends on adequate cellular stimulation by an
elevation of plasma TSH levels as well as stable low iodine levels in
blood. The first is achieved by withdrawing hormone treatment or
by administering rhTSH. The second can be achieved by instructing
the patient to follow a diet low in iodine and to avoid any exogenous
source of iodine (special care with iodized salt, amiodarone and
radiological contrasts).
 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203 199

Table 3
Comparison between the 7th and 8th edition of the TNM Classification of the AJCC for differentiated thyroid cancer.

7th edition 8th edition

<45 years Survival at 10 years <55 years Survival at 10 years

I Any T and N M0 97–100% I Any T and N M0 98–100%

II Any T and N M1 95–99% II Any T and N M1 85–95%

≥45 years ≥55 years

I T1 N0 M0 97–100% I T1 or 2 N0 M0 98–100%
II T2 N0 M0 97–100% II T1 or 2 N1a/b M0 85–95%
T3a/b any N
III T1 or 2 N1a M0 88–95% III T4a Any N M0 60–70%
T3 N0 or 1a
IVA T1or 2 or 3 N1b M0 50–75% IVA T4b Any N M0 <50%
T4a Any N
IVB T4b Any N M0 IVB any T and N M1
IVC Any T and N M1

AJCC: American Joint Committee on Cancer; TNM: tumor/node/metastasis.

Table 4
Ablative treatment with 131 I according to the ATA 2015.

ATA risk Description Is there evience that 131 I Is there evidence that 131 I Is ablation with 131 I
(TNM) increases survival? increases disease-free indicated?
survival?

ATA low risk ≤1 cm No No No

T1a Uni or multifocal
N0, Nx
M0, Mx
ATA low risk >1 cm No Conflictive observational Not routine usea
T1b, T2 ≤4 cm data Consider in aggressive
N0, Nx histology or
M0, Mx vascular invasion
ATA low/intermediate risk >4 cm Conflictive data Conflictive observational Considera
T3 data According to whether
N0, Nx adverse
M0, Nx characteristics or patient
age
ATA low/intermediate risk Microscopic EET (any T) No Conflictive observational Considera
T3 data Small tumors with
N0, Nx microscopic EET
M0, Mx can avoid 131 I
ATA low/intermediate risk Lymph node metastasis in No, except age ≥55 Conflictive observational Considerara
T1–T3 central compartment (NTCTCSG stage III) data - Yes 131 I for risk of
N1a persistence/
M0, Mx Recurrence by size,
Lymph node metastasis or
EET
- No 131 I if <5 lymph node
metstasis
In central compartment
ATA low/intermediate risk Laterocervical or No, except age ≥55 Conflictive observational Considera
T1–T3 mediastinic lymph node data In general favorable to 131 I
N1b metastasis for risk of
M0, Mx persistence/recurrence
ATA high risk Any T Yes Yes Yes
T4
Any N Macroscopic EET
Any M
ATA high risk Distant metastasis Yes Yes Yes
M1
Any T
Any N

ATA: American Thyroid Association; EET: extrathyroid extension; NTCTCSG: National Thyroid Cancer Treatment Cooperative Study Group; TNM: tumor/node/metastasis;
131
I: radioiodine.
a
In addition to the clinical pathological characteristics, the experience of the ultrasonographer, the surgeon, the multidisciplinary committee and the method of thyroglob-
ulin measurement should also be taken into account.
Source: Haugen et al.4

Suspension of hormone treatment: LT4 is withdrawn 3–4 weeks during 1–2 weeks (25 ␮g × 3/day) to reduce the symptoms of
before the administration of 131 I, and plasma TSH levels should hypothyroidism.
be determined to ensure that they are >30 mU/l prior to its rhTSH: an intramuscular injection of 0.9 mg of rhTSH is made
administration.33 Pre-treatment with LT3 can also be carried out on 2 consecutive days, administering the 131 I on the third day. The
200 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203
1. Teaching point
Indications for treatment with 131 I:
• Low risk: 131 I is not routinely administered when the tumor
is ≤1 cm.
There is controversy as to whether to treat or not tumors
>1 and ≤4 cm (while awaiting the results of ongoing prospec-
tive, randomized, multicenter studies). The decision to
administer or not 131 I is based on local factors such as
the experience of the ultrasonographer, the surgeon, or the
method of Tg measurement. The EANM recommends the
administration of 131 I in tumors >1 cm.
• Intermediate risk: 131 I is administered according to the char-
acteristics of the tumor, the presence of significant lymph
node metastasis, vascular invasion or aggressive histology,
combined with patient age (≥55 years). The decision to treat
or not should be made by a multidisciplinary committee.
• High risk: 131 I is routinely administered.
determination of Tg is made 72 h after the injection of rhTSH; that
is, on the fifth day.
3.2.1. What stimulation method should be used?
Suspension of hormonal treatment is the method of choice for
the treatment of local metastatic (recurrence/persistence of lymph
node involvement) or metastatic disease. However, it is not advised
in elderly patients or in those with comorbidities which may be
aggravated in a maintained state of hypothyroidism (i.e. depres-
sion, heart failure or severe sleep apnea).
rhTSH should be used in ablative treatment with 131 I (destruc-
tion of normal thyroid tissue) and for the preparation of follow-up
scans. It should also be used in the treatment with 131 I of residual
microscopic disease in patients with low or intermediate risk.
Randomized studies and metaanalyses have shown a simi-
lar short-term ablative efficacy with the two methods.34–38 In a
multicenter study including 752 patients with low risk DTC ran-
domly treated with low or high doses of 131 I (1.1 vs. 3.7 GBq/30
vs. 100 mCi) and hormone suspension vs. rhTSH, similar rates of
ablation were found at 6–10 months with both doses and meth-
ods of preparation (rhTSH 89.1% and hormone suspension 88.9%).
Later, after a follow-up of 5.4 years, 98% of these patients did not
present disease persistence or recurrence; structural disease was
identified in 0.6% and biochemical disease in 0.7% and was not asso-
ciated with either the dose of 131 I administered or the method of
preparation (ESTIMABL1 trial36,37 ). Mallick et al.38 published the
results of the HiLo trial and also reported that in patients with low
risk DTC randomly treated with low or high doses of 131 I (1.1 vs.
3.7 GBq/30 vs. 100 mCi) and also prepared with both methods, the
ablation was similar with both doses and methods (rhTSH 87% and
hormone suspension 87%).
Few studies have evaluated the two preparation methods in
the long term. One prospective study with a 10-year follow-
up described similar results for both methods of preparation in
patients treated with 1.1 GBq of 131 I, and another retrospective
study with a 9-year follow-up reported the same, but this latter
study also included patients with intermediate and high risk.39,40
In a retrospective review including 84 patients, Tuttle et al.41 con-
cluded that rhTSH is effective for the treatment of lymph node
and pulmonary micrometastases shown by ablative treatment with
131 I. On the other hand, in a retrospective study including 175
patients with a follow-up of 5 years, Tala et al.42 described a similar
effectiveness with rhTSH and hormone suspension in patients with
macroscopic metastasis with iodine uptake.
1. Teaching point
What stimulation method should be used?
• Suspension of hormonal treatment in local metastatic dis-
ease (recurrence/persistence of lymph node involvement)
and distant metastasis (not in elderly patients and those with
important comorbidity).
• rhTSH in the treatment for ablative purposes and in the treat-
ment of residual microscopic disease with 131 I (patients with
low or intermediate risk).
4. Dose (activity) of radioiodine
• Ablative treatment: this is administered to patients considered as
having low risk who are candidates for ablation.4,5 The optimal
dose of 131 I to administer is based on achieving good ablation,
which is the objective of the treatment, and on the risk of recur-
rence/mortality (Table 4). Several studies have evaluated the
optimal dose.36,37,43,44 However, to date, the lack of uniformity
in relation to the patients, method and even the definition of
ablation have impeded establishing the most optimal dose. The
proposal of 1.1 GBq (30 mCi) as the ablative dose of 131 I is based
on results obtained in studies aimed at evaluating the short
term effectiveness of ablative treatment but not at evaluating its
effectiveness to avoid recurrence, which requires a longer follow-
up. Although 2 retrospective studies45,46 did not find any
differences in regard to recurrence at 5 and 14.7 years of follow-
up in patients treated with low vs. high doses of 131 I, it is the
results of prospective, randomized, multicenter, clinical studies
that will indicate the optimal dose of 131 I to be administered for
ablative purposes.
• Adjuvant treatment: after thyroidectomy, patients with DTC of
intermediate risk are treated with 131 I with 2 objectives: abla-
tion and treatment of residual microscopic disease post-surgery.
A dose of 131 I of between 2.8 and 3.7 GBq (75–100 mCi) has been
proposed. Two retrospective studies performed in patients with
DTC of intermediate risk treated with a low (1.1 GBq/30 mCi) vs.
a high dose (3.7–5.5 GBq/100–15 mCi) of 131 I found no signifi-
cant differences in regard to the rate of ablation.47,48 In another
retrospective study comparing doses of 100, 150 and 200 mCi
of 131 I, Sabra et al.49 concluded that the administration of more
than 100 mCi in N1b patients, especially in younger patients, does
not improve initial response to treatment. In a study including
1298 patients with low and high risk DTC divided into two age
groups(<45 and ≥45 years), Verburg et al.50 concluded that the
high dose was associated with a greater survival in patients ≥45
years of age and that the low dose should be used with caution
in this age group. At present, and as mentioned previously, the
change in the age limt of risk to ≥55 years represents an increase
in patients in stages I and II with a greater probability of recur-
rence in stage II, since in this stage the patient is no longer of low
risk and the low dose should not be considered.
• Treatment of residual macroscopic and local and/or distant
metastatic disease: high empiric doses of 131 I are administered:
– 5.6 GBq (150 mCi): cervical and mediastinic lymph nodes.
– 5.6–7.5 GBq (150–200 mCi): pulmonary metastases.
– 7.5 GBq (200 mCi): bone metastasis or other distant metastasis.
– The administration of higher doses requires a dosimetric study.
 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203
– The dose should not be greater than 5.6 GBq (150 mCi) in
patients with pulmonary metastases over the age of 70 due
to a greater risk of bone marrow toxicity.
– Patients with renal insufficiency or on hemodialysis can be
treated by decreasing the dose of 131 I with posterior dialysis
according to the usual protocol or administer the standard dose
of 131 I followed by more frequent dialysis.51
The treatment is repeated when there is evidence of iodine
uptake disease in a follow-up scan with 131 I. At 6–12 months after
treatment, a scan with 131 I is made in patients with intermediate-
high risk and those with low risk with detectable maintained or
increased Tg. The scan should be done with a low dose of 131 I
(185 MBq/5 mCi) and preparation with rhTSH or with suspension
of hormone treatment which induces hypothyroidism. If the scan
shows evidence of significant cervical uptake, a second treatment
is given with 3.7–5.6 GBq (100–150 mCi) of 131 I to complete the
ablation. If cervical uptake is not significant or there is no evidence
of disease by other imaging techniques, treatment is not admin-
istered. If there is evidence of disease in other localizations, the
corresponding dose of 131 I is administered.
1. Teaching point
Dose (activity) of 131 I:
• Ablative treatment: 1.1 GBq (30 mCi) (low risk, candidates
for ablation). This dose is based on the results obtained in
short-term studies aimed at evaluating its effectiveness with
respect to ablation. Although the premise is that the opti-
mal dose of 131 I to administer should not only achieve good
ablation but also reduce the risk of recurrence/mortality, the
results of long-term studies are still needed to evaluate the
effectiveness of this dose in relation to the risk of recurrence.
• Adjuvant treatment: 2.8–3.7 GBq (75–100 mCi) (intermediate
risk with residual microscopic disease post-surgery).
• Treatment of residual macroscopic and local and/or distant
metastatic disease:
– 150 mCi (5.6 GBq): infiltrated cervical and mediastinic
lymph nodes.
– 150–200 mCi (5.6–7.5 GBq): pulmonary metastasis.
– 200 mCi (7.5 GBq): bone metastasis or other distant metas-
tases.
1. Teaching point
In intermediate-high and low risk DTC with detectable main-
tained or increased Tg levels, a scan with 131 I is made at 6–12
months after treatment and if the following is shown:
• Significant cervical uptake, 3.7–5.6 GBq (100–150 mCi) of 131 I
is administered to complete the ablation.
• Non significant cervical uptake, or no evidence of disease by
other imaging techniques, treatment is not administered.
• Disease in other localizations, the corresponding empiric
dose of 131 I is administered.
201
4.1. Persistent, recurrent or distant disease
During the first 2 years the treatment interval with 131 I is 4–8
months according to the guidelines of the European and American
Societies of Nuclear Medicine7,8 and 6–12 months according to the
2015 ATA and British guidelines4,5 :
• Cervical disease: Cervical tumor recurrence can be detected by
clinical examination or an increase in plasma Tg levels, with cer-
vical ultrasonography being the method of choice for localization.
Surgical resection in the central and laterocervical compartment
is the first treatment when the disease is of low volume. How-
ever, on occasions aggressive surgical resection in stable, low
volume disease is difficult to justify, especially when its bene-
fits in relation to an increase in the overall survival have not been
demonstrated. In these cases surgery is avoided, and the patients
are followed to ensure that they continue to be at low risk and a
wait and see approach is taken.
The extension of recurrence beyond the thyroid bed (larynx,
trachea, esophagus or soft tissue) implies the need for wider
surgical resection based on CT study with contrast or magnetic
resonance.
If disease persists following surgery a scan with 131 I with rhTSH
stimulation is indicated. If this is positive, treatment with 131 I
in the same conditions is carried out. To the contrary, if dis-
ease persists but 131 I uptake is not observed, a 18 F-FDG PET/CT
is performed to localize dedifferentiated disease (not presenting
iodine uptake). In this case, positive results with 18 F-FDG PET/CT
are considered to be an independent indicator of bad progno-
sis, being correlated with global mortality when disease with no
iodine uptake is shown.52
• Distant disease: patients who develop distant disease during
follow-up should be treated with the same dose of 131 I that
would have been given if they had presented metastasis at the
onset. However, in these cases the treatment with 131 I is less
effective.53 The efficacy of treatment with 131 I is related to the
radiosensitivity of the tumoral tissue, which is greater in young
patients with small-sized metastasis and with an elevated uptake
of 131 I. In general, the therapeutic efficacy is achieved with accu-
mulated activity less than 22.2 GBq (600 mCi). Recently, 22.2 GBq
was arbitrarily established as the limit of accumulated activity for
treatment with radioiodine.4 However, to date there is no exten-
sive experience with greater activities without the development
of significant toxicity. Nonetheless, the decision should be made
by a multidisciplinary committee and should always consider
that the objective is to achieve benefits.
When 131 I does not control the disease, the disease is con-
sidered to be iodine refractory. The most frequent scenarios of
refractoriness to 131 I are: evident structural disease which has
no avidity for 131 I from the onset, loss of avidity by 131 I in a
structural disease which showed previous uptake of 131 I and
structural disease which progresses despite 131 I uptake. In these
scenarios treatment with local therapies (percutaneous injection
of ethanol, radiofrequency, embolization or radiotherapy) may
be considered, with surgery in single metastasis and the admin-
istration of systemic treatments (i.e. kinase inhibitors).
Distant disease is treated with the same dose of 131 I that would
have been given if metastasis had been presented at the beginning.
4.2. Elevated thyroglobulin and negative 131 I scan (TENIS
syndrome)
It is not infrequent for a patient to present elevated Tg lev-
els with a negative 131 I scan (Thyroglobulin Elevation/Negative
Iodine Scintigraphy Syndrome – TENIS syndrome). After ruling out
202 M. Estorch, M. Mitjavila, M.A. Muros, et al. / Rev Esp Med Nucl Imagen Mol. 2019;38(3):195–203
1. Teaching point
Cervical tumoral recurrence is treated with:
• Surgical resection whenever possible (evaluate the aggres-
siveness of the procedure with respect to the expected
benefits).
• 5.5 GBq (150 mCi) of 131 I after surgery if disease showing
iodine uptake persists.
• If disease not showing iodine uptake persists after surgery,
18 F-FDG PET/CT is performed.
the possible cause for false negative scan results (inadequate TSH
stimulation, elevated plasma iodine levels due to excess exoge-
nous iodine or very small disease volume), this situation reflects
the loss of the capacity of the tumoral tissue to take up iodine, or in
other words, dedifferentiation. The management of these patients
is complicated and there are very few data to determine the optimal
treatment to follow.54 The management of these patients is based
on:
• Ruling out an excess of exogenous iodine by the 24 h measure-
ment of urinary iodine excretion.
• Performing ultrasonography of the neck and a CT of the neck and
thorax (without contrast).
• Performing 18 F-FDG PET/CT in patients with high risk of non stim-
ulated Tg ≥10 ng/ml.
• Treatment with radiotherapy (i.e. single bone metastasis) or sys-
temic therapy (disease in progression without response to 131 I).
• Treatment with 131 I: 42–72% of patients with a negative 131 I
scan empirically treated with high doses, present 131 I uptake in
the post-treatment scan, especially at a cervical and mediastinic
level, more frequently identifying distant metastasis when the
plasma Tg level is >200 ng/ml.55 However, the benefits of this
treatment are limited, with 44% of stable disease and 56% of pro-
gression after radioiodine treatment.56 Although some studies
have shown a reduction in Tg levels after treatment with 131 I,
this reduction has not been shown to change the prognosis of the
disease. However, despite not seeming to achieve clinical ben-
efits beyond localizing the disease, it does enable restaging and
reclassifying the disease as biochemical persistence or as iodine
refractory.55,57
1. Teaching point
The benefits of empiric treatment with 131 I in the TENIS syn-
drome are questionable, since this treatment has not shown
to have an impact on the prognosis of the disease. However, it
does enable reclassification of the patients.
5. Conclusion
The treatment of DTC with 131 I is controversial in some aspects
due to the lack of prospective, randomized, clinical studies. In
DTC, treatment with 131 I is administered with ablative objec-
tives to eliminate healthy residual microscopic thyroid tissue or
to treat macroscopic or metastatic disease. Apart from destroying
healthy thyroid tissue post-thyroidectomy, the objective of ablative
treatment is to destroy possible microscopic foci, minimize the risk
of recurrence in patients with predisposition, increase the speci-
ficity of Tg as a tumoral marker and increase the specificity of scans
with 131 I for the detection of recurrent or metastatic disease. On the
other hand, the objective of treatment of residual and/or metastatic
disease with 131 I is to destroy all macroscopic disease that cannot
be treated with surgery, thereby reducing the risk of recurrence
and mortality. While awaiting the results of ongoing prospective
trials, the use of 131 I seems to be justified not only in patients with
high risk but also in those with intermediate risk and those with
low risk associated with other factors.
6. Conflict of interest
The authors declare no conflict of interest.
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