European Journal of Nuclear Medicine and Molecular Imaging

https://doi.org/10.1007/s00259-024-06625-w

ORIGINAL ARTICLE

Radioiodine versus radiofrequency ablation to treat autonomously

functioning thyroid nodules: a systematic review and comparative
meta‑analysis
Luca Giovanella1,2 · Maria Luisa Garo3 · Alfredo Campenní4 · Petra Petranović Ovčariček5,6

Received: 7 December 2023 / Accepted: 20 January 2024

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024

Abstract
Purpose Radioiodine (RAI) is a well-established first-line therapy for autonomously functioning thyroid nodules (AFTN).
Radiofrequency ablation (RFA) is a minimally invasive procedure that has been proposed as an alternative treatment option
for hyperthyroidism caused by AFTN. Although RFA has been shown to be useful for reducing nodule volume and improving
TSH levels in AFTN, no comprehensive comparative clinical studies have been proposed to evaluate the overall response to
RFA treatment. The aim of this comparative systematic review and meta-analysis was to evaluate the response of RAI and
RFA treatments in AFTN.
Methods A systematic search strategy was applied in PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTri-
als.gov until July 2023 without time or language restrictions. Studies investigating the response to RAI and/or RFA treatment
in AFTN patients 6 and/or 12 months after treatment were included. The risk of bias was assessed based on the study design.
Random-effect models were used for the meta-analysis.
Results Twenty-three articles (28 reports) met the inclusion criteria and were included in the study. Overall, RAI therapy
was found to have a significantly higher treatment response (94%) than RFA (59%), although the volume of AFTNs was
reduced to a similar extent. In the direct comparison (n = 3 studies), RFA showed a higher risk of non-response than RAI
(RR, 1.24; 95% CI, 0.94–1.63; z = 1.55; p = 0.12).
Conclusions Our results demonstrate the superiority of RAI over RFA in terms of success rates and safety profile and confirm
RAI as the first choice for the treatment of AFTNs.

Keywords Autonomously functioning thyroid nodules · Radioiodine · Radiofrequency · Hyperthyroidism

Introduction

* Luca Giovanella Autonomously functioning thyroid nodules represent the

luca.giovanella.md@gmail.com
1 Graves’ Disease (about 70% of cases) in Europe [1]. AFTNs
Department of Nuclear Medicine, Gruppo Ospedaliero
Moncucco SA, Clinica Moncucco, Via Soldino 10,
6900 Lugano, Switzerland
2
Clinic for Nuclear Medicine, University Hospital of Zurich,
Zurich, Switzerland
3
Biostatistic Unit, Mathsly Research, Rome, Italy
4 appear as regions with higher tracer uptake (“hot” nodules)
Nuclear Medicine Unit, Department of Biomedical
and Dental Sciences and Morpho‑Functional Imaging,
University of Messina, Messina, Italy
5
Department of Oncology and Nuclear Medicine, University
Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia
6
School of Medicine, University of Zagreb, 10000 Zagreb,
Croatia
second cause of hyperthyroidism (about 30% of cases) after
synthesize and secrete thyroid hormones independently from
the hypothalamus-pituitary-thyroid regulatory axis. In par-
ticular, excessive thyroid hormone production firstly induces
suppression of thyroid-stimulating hormone (TSH) and
may lead to overt hyperthyroidism over time [2, 3]. AFTNs
than surrounding thyroid tissue at thyroid scintigraphy [4].
Treatment of hyperthyroidism is indicated to reduce symp-
toms and risk of atrial fibrillation and osteoporosis in both
overt and subclinical hyperthyroid patients [5]. Currently,
AFTNs are treated with radioactive iodine (131I) or alterna-
tively with surgery. Radiofrequency ablation is a minimally

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invasive, ultrasound-guided procedure successfully applied
to decrease volume of non-AFTN and reduce mechanical
complaints from nodular compression [6] and was recently
proposed as a treatment option for hyperthyroidism caused
by AFTN [7, 8]. Currently this option is only considered in
selected cases when surgery and radioiodine are contrain-
dicated. Recently, however, some authors hypothesized the
use of RFA as a first-line therapy of AFTN. Notably, how-
ever, no adequately designed and powered clinical trials,
including extended follow-up periods and comparison with
the gold standard (i.e., radioiodine) are available. Therefore,
our present study aimed to extract more robust evidence by
a comparative systematic review and meta-analysis of the
available literature on either RAI and RFA treatments of
AFTNs.
Methods
Protocol and registration
This comparative systematic review and meta-analysis
was conducted in accordance with the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analy-
ses (PRISMA) guidelines. The methodology was registered
in the PROSPERO (International Prospective Register of
Systematic Review) database under registration number:
CRD42023456752. The components of the PICO question
were (population) patients with autonomously function-
ing thyroid nodules (AFTN), (intervention) radioiodine or
radiofrequency ablation, (comparator): RAI or RFA if a
comparator was present, and (outcome): euthyroid and/or
hypothyroid status.
Eligibility criteria
Articles published in peer-reviewed journals that included
patients with AFTN treated with RAI or RFA and reported
follow-up data at 6 and/or 12 months after treatment were
included. Case reports or case series with less than 10
patients, reviews, letters, editorials, abstracts, or other types
of studies without observational value were excluded.
Search strategy
A systematic search was conducted in PubMed, Web of
Science, Scopus, Cochrane Library, and ClinicalTrial.
gov until July 2023 without time and language restrictions
using the following keywords: ((radiofrequency) OR (radi-
ofrequency ablation) OR (RFA) OR (laser) OR (PLA) OR
(laser ablation) OR (thermal ablation) OR (radioiodine) OR
(radioactive iodine ablation) OR RAI OR I-131 OR 131I))
AND (thyroid) AND ((autonomously functioning thyroid
European Journal of Nuclear Medicine and Molecular Imaging
nodules) OR (hyperfunction) OR (adenoma) OR (hyperthy-
roidism) OR (thyrotoxicosis) OR (AFTN) OR (toxic)). A
backward and forward citation chaining on relevant articles
was performed.
Study selection
After downloading the articles from the databases and
removing duplicates, two independent reviewers (MG and
PP) performed an initial screening by title and abstract.
Potentially relevant articles that met the eligibility criteria
were retrieved and screened independently by the same two
reviewers. Disagreements were discussed by consensus. A
third independent reviewer (AC) screened the potentially
eligible articles using a backward and forward citation chain-
ing approach. The final eligibility of each article was decided
by consensus among all authors. The reasons for exclusion
were recorded. Subsequently, two authors (MLG and LG)
independently conducted a confirmatory search strategy
and screening process. No discrepancy was found with the
implemented screening process.
Data extraction
Two reviewers (MLG and PP) independently extracted data
from each included article and reported them in an Excel
file (Microsoft Corp., Redmond, WA, USA). No additional
data were requested from the authors of the studies. Data
collected included the following:
1. First author’s name
2. Publication year
3. Study design
4. Country
5. Observation period
6. Multicenter study
7. Nodules type
8. Treatment (RAI, RFA, or both)
9. Patient inclusion and exclusion criteria
10. RAI dose or RFA mean power or energy
11. Number of sessions
12. Frequency of visits during follow-up
13. Definition of treatment success
14. Follow-up
15. Sample size
16. Patients’ mean age
17. Gender or male/female ratio
18. Success rate (euthyroid or hypothyroid) at the end of
follow-up
19. Success rate (euthyroid or hypothyroid) between 3 and
6 months
20. Success rate (euthyroid or hypothyroid) between 6 and
12 months
European Journal of Nuclear Medicine and Molecular Imaging
21. Hypothyroid at 12 months
22. Euthyroid at 12 months
23. Hypothyroid at the end of follow-up
24. Euthyroid at the end of follow-up
25. Reduction in nodule volume during the observation
period
26. TSH changes during the observation period
27. Post-treatment complications (adverse events associ-
ated with significant morbidity or disability requiring
hospitalization or a higher level of care)
Risk of bias
The quality of the prospective and retrospective studies was
assessed using the instrument for observational, cohort, and
cross-sectional studies (https://​www.​nhlbi.​nih.​gov/​health-​
topics/​study-​qualit​ y-​asses​sment-​tools). For RCTs, the RoB2
was used according to the Cochrane guidelines.
Outcome
The primary outcome was treatment response (hypothyroid/
euthyroid status vs. hyperthyroid status), as defined in each
individual study. The secondary outcomes were the percent-
age reduction in nodule volume and changes in TSH lev-
els. Response to treatment and secondary outcomes were
measured at three predefined time periods: between 3 and
6 months after treatment, between 6 and 12 months after
treatment, and at the end of the entire follow-up period if it
exceeds 12 months.
Data synthesis and analyses
All data from the included articles were summarized in a
systematic summary. A meta-analytic approach was used
to assess the pooled treatment success at 6 and 12 months
and the end of the follow-up period. First, pooled treatment
success was assessed in a direct comparison between RFA
and RAI, including studies comparing treatment success in
patients treated with RAI or RFA in the same study setting.
An indirect comparison between the two approaches were
then conducted, in which the pooled treatment success of
RAI and RFA was determined separately. Given the large
heterogeneity, likely due to differences in patient character-
istics and inclusion and exclusion criteria, the DerSimonian-
Laird random effects approach was used. Heterogeneity was
also assessed using the Cochrane Q test and the I2 statistic
according to the Cochrane Handbook for Systematic Reviews
of Interventions (Chapter 10—Paragraph 10.9, https://​
train​ing.​cochr​ane.​org/​handb​ook/​curre​nt/​chapt​er-​10#​secti​
on-​10-9). Comparative subgroup analysis was performed
for each treatment, considering study design, sample size
(lower or higher than the median of the sample sizes of the
included studies), and overall follow-up. Meta-analysis was
performed using STATA18 (StataCorp., College Station,
TX, USA). Evaluations about a possible correlation between
percentage nodule volume reduction and an increase in TSH
values were conducted using a narrative approach.
Results
Studies selection
Using the search strategy defined above, 3159 articles were
found in databases (Fig. 1).
After excluding duplicates (n = 2130), 1029 articles were
screened by title and abstract. Fifty-eight articles met the
inclusion criteria; 55 were retrieved and screened in full text.
Of these, 32 were excluded because the sample was unclear
(it was not possible to separate patients with AFTN from
those with Graves’ disease, n = 11), reporting was incom-
plete (missing data on treatment success rate, n = 10), the
sample included fewer than 10 patients (n = 4), and there
were no data on success rate at 6 or 12 months (n = 7).
Twenty-three articles (with a total of 28 reports given that
some studies contained more than one report) met the inclu-
sion criteria and were included. Response to treatment after
RAI was examined in 14 articles (15 reports in total) [9–22],
while response to treatment after RFA was examined in 11
articles (12 reports in total [10, 12, 15, 23–30], three studies
directly compared RAI and RFA [10, 12, 15], and one study
assessed the efficacy of combined RFA (laser ablation) and
RAI treatment in large toxic thyroid nodules [31].
Studies characteristics
RAI studies
Fourteen articles with a total of 15 reports (1042 patients
with AFTN) were included in this review (Table 1). Ten
studies were retrospective, two prospective [13, 21], one
RCT [12], and one study did not specify the study design
[16]. Six studies were conducted in Turkey [9, 11, 13–15,
20], two in Italy [10, 19], two in the UK [16, 18], one each
in Denmark [12], Brazil [17], the USA [22], and India [21].
The time period of the studies ranged from 1968 [22] to
2020 [15]. Six articles did not include explicit inclusion/
exclusion criteria, while the remaining 8 articles showed
great heterogeneity in terms of inclusion/exclusion criteria.
In 8 studies, single RAI sessions were performed, while in
the remaining 6 studies, multiple RAI sessions were per-
formed in case of persistent hyperthyroidism. Response to
treatment was defined in 8 studies and varied consistently in
terms of accuracy of euthyroid or hypothyroid normal range.
Follow-up ranged from 6 months [12, 20] to 6.2 ± 2.9 years

Fig. 1  PRISMA flow-chart
[19]. The patient population was sufficiently homogeneous
in terms of age and gender, with a higher representation of
women (746 women, 282 men). RAI studies characteristics
are reported in Table 1.
RFA studies
Eleven articles with a total of 12 reports (296 patients
with AFTN) were included (Table 2). Four studies were
retrospective [10, 15, 28, 29], four were prospective [24,
25, 27, 30], one was RCT [12], and two studies did not
specify the study design [23, 26]. Seven studies were
conducted in Italy [10, 23–27, 29], one in Austria [30],
Denmark [12], Turkey [15], and the Netherlands [28].
The temporal span ranged from 2004 [26] to 2020 [15,
28]. Three articles did not report inclusion/exclusion
criteria [10, 28, 29]. The remaining 7 articles showed
great heterogeneity in terms of inclusion/exclusion cri-
teria. Single RFA sessions were performed in 8 studies,
while multiple percutaneous laser ablation, interstitial
laser photocoagulation, or microwaves were used in the
remaining 3 studies. Treatment success was defined in
European Journal of Nuclear Medicine and Molecular Imaging
three studies [12, 15, 24]. The follow-up period ranged
from 6 [12, 26] to 24 months [25]. The mean age of the
patients ranged from 31 [23] to 80 years [25, 28]. The
ratio between men and women was 1:3. Complete RFA
studies characteristics are reported in Table 2.
Risk of bias
The risk of bias was low in almost all included studies.
Eleven studies (six for RAI treatment and five for RFA
treatment) raised concerns about the percentage of eli-
gible people included in the study (Table 3). Common
problems in all studies were sample size selection and
blinding of outcome assessors. In 14 studies (6 in the RAI
group, 7 in the RFA group, and one in RAI + RFA vs. RAI)
the response to treatment was not clearly defined. In the
only included RCT, RoB2 indicated a high risk of bias,
mainly due to deviations from the planned intervention
(impossibility to blind patients and those delivering the
intervention) and some concerns about outcome reporting
(Table 4) [12].
Table 1  Radioiodine treatment—studies characteristics
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success defini- Follow-up (mo) Sample Age (years) Sex
criteria tion

Aktas et al. Retrospective Turkey 1996–2006 Toxic nodular (1) Nodule or nod- (1) Pts who Multiple 370–740 MBq Achievement of euthyroid 44.3 ± 26.2 (for 63 103 63 ± 12 (Range: F: 44, M: 59
(2015) [9] goiter (TNG) ules ≤ 4 cm; (2) had thyroid RAI (10–20 mCi) or hypothyroid state with- patients) 21–94)
pts with surgical surgery sessions out ATD medication
controindication before RAI; in case of
(2) pts who persis-
received RAI tence
in a different
center; (3)
pts who
were lost to
follow-up
Cervelli Retrospective Italy 2013–2018 AFTNs NR NR Single RAI 555 MBq NR 12 months 25 57.2 ± 12.8 F: 17, M: 8
et al. session (15 mCi) (20–76)
(2019)
[10]
Demir et al. Retrospective Turkey 2014–2020 TMNG None Pts (1) who Single RAI 15–20 mCi NR Median: 24 mo 133 69 (IQR: 62–75) F: 86, M: 17
(2022) (n = 47) and received session (IQR: 11–38
[11] TA (n = 86) RAI for the mo)
second time,
European Journal of Nuclear Medicine and Molecular Imaging

(2) whose
clinical and
laboratory
recordes
could not be
accessed,
(3) who had
antithyroid
receptor
antibody
positiv-
ity and
remained
hyperthy-
roid with a
follow-up
period of < 6
mo
Døssing RCT​ Denmark NR AFTNs NR NR Single RAI 3.7 MBq/g total Normalization or elevation 6 months 15 54 ± 3 F: 13, M:2
et al. session thyroid mass; of serum TSH at the
(2007) max thera- 6-month evaluation
[12] peutic activity
600 MBq,
(16.2 mCi)
Erdogan Prospective Turkey NR Toxic adenoma NR NR Multiple 740 MBq Euthyroidism (serum TSH NR 39 51.2 (range: F:39, M: 9
et al. RAI (296–1110) level over 0.2 mUI- 35.75)
(2004) sessions mL^ − 1 accompanied by
[13] in case of normal serum FT4 and
persis- FT3 levels)
tence
Table 1  (continued)
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success defini- Follow-up (mo) Sample Age (years) Sex
criteria tion

Erkan et al. Retrospective Turkey 2008–2010 Single toxic Pts diagnosed with NR Single RAI 370–925 MBq Acquisition of normal Up to 24 months 59 69 ± 5 (range: F: 38, M: 21
(2012) nodule TNG session (10–25 mCi) TSH and FT3 levels 60–82)
[14] (n = 29), without the requirement
TMNG of antithyroid therapy.
(n = 30) Hypothyroid status after
RAI at any time within
1 year
Erturk et al. Retrospective Turkey 2017–2020 AFTN Patients with None Single RAI 555 MBq Euthyroid state at 6 months 35 61.43 ± 12.60 F: 24, M:11
(2021) AFTNs session (15 mCi) without antithyroid medi-
[15] cal treatment
Franklyn NR UK NR Toxic nodular None Nodules with Multiple 185 MBq Judgement at 6 and 12 44 60.5 (range: F: 40, M: 4
et al. hyperthy- increased RAI (5 mCi) 12 months—Euthyroid: 20.81)
(1995) roidism risk for sessions FT4 and FT3 concentra-
[16] malignancy in case of tions off antithyroid drug
and malig- persis- therapy within the normal
nant nodules tence range; Persistently hyper-
thyroid: FT4 and/or FT3
elevated; Hypothyroid:
FT4 below the normal
range and TSH elevated
Pereira et al. Retrospective Brazil 2000–2016 Toxic nodular None Pts (1) using Single RAI 1110 MBq Success: Euthyroidism or 12 39 52 (39–62) F: 36, M: 3
(a) (2021) goiter propranolol, session (30 mCi) hypothyroidism without
[17] (TNG)— corticos- the use of antythyroid
uninodular teroids, 1 year after RIT. Failure:
Pereira et al. Retrospective Brazil 2000–2016 Toxic nodular amiodarone, hyperthyroidism not con- 20 63 (56–67) F: 17, M: 3
(b) (2021) goiter or exposed trolled without anthyroid
[17] (TNG)— to iodinated medications
multinodular contrasts up
to 3 months
before evalu-
ation; (2)
heart failure
(class III or
IV), severe
liver disease,
advanced
chronic kid-
ney disease
(stage 4 or
5) or hemo-
dialysis, any
infection,
and those
severely ill
Ratcliffe Retrospective UK NR Solitary NR NR Multiple 550 MBq NR 3.1 years (range: 48 59 (range: 31–85) F: 38, M: 10
et al. functioning RAI (15 mCi) 2–10)
(1986) toxic thyroid sessions
[18] nodules in case of
persis-
tence
European Journal of Nuclear Medicine and Molecular Imaging
Table 1  (continued)
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success defini- Follow-up (mo) Sample Age (years) Sex
criteria tion

Roque et al. Retrospective Italy Toxic mul- Pts with at least Pts (1) treated Single RAI 15 mCi NR 6.2 ± 2.9 years 153 68.7 ± 9.2 F: 116, M: 37
(2020) tinodular one US evalu- surgically session (range:
[19] goiter ation before and exclu- 2–12 years)
(TMNG) and after 131I sively medi-
therapy and with cally; (2)
at least 2 years treated with
of follow-up activities
other than
15 mCi; (3)
pretreated
with human
recombinant-
TSH and
those
without US
follow-up
Ross et al. Retrospective USA 1968–1980 Solitary toxic NR NR Multiple 10.3 mCi NR 4.9 ± 3.2 years 45 57.6 ± 14.7 F: 33, M12
(1984) thyroid RAI (range 0.5–13.5)
[22] nodules sessions
European Journal of Nuclear Medicine and Molecular Imaging

in case of
persis-
tence
Şakı et al. Retrospective Turkey NR Toxic nodular Pts who attended Pts who Single RAI 555–740 MBq 6 months 233 64 ± 10 F: 163, M: 70
(2015) goiter regular follow- received a session
[20] up appointments second dose
during a 1-year of I-131
period after therapy
receiving RAIT during their
and who had follow-up
complete clini- due to
cal and labora- on-going
tory data in the hyperthy-
post-treatment roidism
follow-up period
Sharma Prospective India NR AFTNs NR NR Multiple 10 mCi 4.5 mg/dL < T4 < 13.5 mg/ 12 months 51 57 ± 9 Male/female
et al. RAI dL; 0.25 mUI/ ratio: 1:7.5
(1994) sessions mL < TSH < 5 mUI/mL
[21] in case of
persis-
tence
Table 2  Radio frequency ablation—studies characteristics
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success Follow-up Sample Age (years) Sex
criteria definition (mo)

Barbaro et al. NR Italy NR Single hyper- Refusal of RAI or surgical None Multiple percou- 1600 to NR 12 18 Range: 31–80 F: 10, M: 8
(2007) [23] functioning treatment or the need for quick taneous laser 2000 J per
thyroid nod- restoration of euthyroidism ablation fiber was
ule (n = 8) or with anthyroid treatment used
multinodular
goiter
(n = 10)
Bernardi et al. Prospective Italy 2012– Solitary AFTN (i) Patients over the age of None Single RFA NR Remission: clinical and 12 30 69.1 ± 2.0 F: 20; M: 10
(2017) [24] 2015 18 years; (ii) presence of a session biochemical evidence
solitary AFTN (as assessed of an euthyroid state
by serum TSH and thyroid after methimazole
scintigraphy); (iii) Thy2/Tir2 withdrawal; improve-
(or Bethesda II) cytology; (iv) ment and no response
refusal or contraindications for corresponded to
radioiodine therapy or surgery the situation where
patients needed to
take anti-thyroid
medication in order
to maintain their
euthyroid state
Cappelli et al. Retrospective Italy 2017– Functioning NR NR Single RFA NR NR 12 17 45.3 ± 18.0 F: 11, M: 6
(2020) [29] 2018 thyroid session
nodules
Cervelli et al. Retrospective Italy 2013– AFTN NR NR Single RFA 30–45 W NR 12 22 51.9 ± 13.9 F:20, M:2
(2019) [10] 2018 session (range:26–
72)
Cesareo et al. Prospective Italy 2014– AFTN Presence of a solitary AFTN, Presence of a Single RFA 60 W NR 24 29 52 (28–80) F:18, M:11
(2018) [25] 2015 as assessed by serum thyroid multinodu- session
stimulating hormone (TSH) lar goiter;
and 99 m technetium (Tc) willingness
pertechnetate thyroid to undergo
scintigraphy; age greater radioiodine
than 18 years; Thy2/Tir2 therapy;
(or Bethesda II) cytology on Thy3/Tir3
ultrasound-guided fine-needle (Bethesda
aspiration biopsy; no history III) cytology;
of methimazole treatment; presence of
calcitonin levels within a malignant
normal limits; refusal of or thyroid nod-
contraindications to surgery or ule; history of
radioiodine therapy radioiodine
therapy or
thermal abla-
tion; previous
neck or trunk
external beam
radiotherapy;
pregnancy
European Journal of Nuclear Medicine and Molecular Imaging
Table 2  (continued)
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success Follow-up Sample Age (years) Sex
criteria definition (mo)

Deandrea et al. NR Italy 2004– Hot nodules Pts refused or were ineligible for NR Single RFA NR NR 6 23 66.8 NA
(2008) [26] 2006 (ptz: 22, surgery for benign nodules, session
nodules: 23) causing pressure symptoms
such as difficulty in swallow-
ing, throat constraint or cough,
or refused 131I therapy or
surgery (or were ineligible
for the latter) for hyperfunc-
tioning nodules (whether
compressive or not). Pts were
included only if the nodules
were cytologically benign and
of at least 20 mm diameter
Dobnig et al. Prospective Austria 2014– Toxic nodules NR Pts (1) with ill- Single RFA 60 W NR 6 55 NA NA
(2018) [30] 2017 defined nod- session
ule margins
and far distal
locations;
(2) with
European Journal of Nuclear Medicine and Molecular Imaging

multinodu-
lar goiters
for whom,
despite an
anticipated
significant
volume
reduction fol-
lowing RFA
treatment,
an overall
unsatisfac-
tory outcome
in terms of
improve-
ment of local
symptoms
or thyroid
function was
predictable
or likely; (3)
pregnancy;
(4) presence
of a cardiac
pacemaker;
(5) a history
of neck or
trunk external
beam radia-
tion
Table 2  (continued)
Author Study design Country Period Nodules types Inclusion criteria Exclusion Treatment Dose Treatment success Follow-up Sample Age (years) Sex
criteria definition (mo)

Døssing et al. RCT​ Denmark NR AFTN None Evidence of Interstitial laser 2.5–3.5 W Normalization or 12 14 58 ± 3 F:11, M:3
(2007) [12] thyroid photocoagula- elevation of serum
malignancy, tion (ILP) TSH at the 6-month
compression evaluation
symptom,
regional
lymphad-
enopathy
Erturk et al. Retrospective Turkey 2017– AFTN Patients with AFTNs None Single microwave 30–40 W Euthyroid state at 6 30 52.77 ± 11.13 F:23, M:7
(2021) [15] 2020 6 months without
antithyroid medical
treatment
Faggiano et al. Prospective Italy 2010– AFTN (1) Age above 18 yr; benign TNs Pregnancy and Single RFA NR NR 12 10 NR NR
(2012) [27] 2011 (Thy2); (2) solid or predomi- malignant or
nantly solid (cystic compo- suspicious
nent < 30%) large (> 4.0 mL) TNs
TNs; (3) and refusal and/or
inefficacy of surgery and/or
radioiodine therapy
van der Meeren Retrospective The Neth- 2015– Solitary AFTN NR NR Single RFA > 2.109 kJ 3-, 6-, and 12-months 12 36 55 (22–74) F: 30, M: 6
et al. (a) erlands 2020 (0.5 kCal) post-RFA
(2023) [28] per mL
of nodal
volume
van der Meeren Retrospective The Neth- 2015– Toxic multinod- NR NR Single RFA > 2.109 kJ 3-, 6-, and 12-months 12 12 57 (34–80) F: 11, M: 1
et al. (b) erlands 2020 ular goiter (0.5 kCal) post-RFA
(2023) [28] (TMG) per mL
of nodal
volume
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European Journal of Nuclear Medicine and Molecular Imaging

Table 3  Risk of bias—part I

1 2 3 4 5 6 7 8 9 10 11 12 13 14

RAI
Aktas et al. (2015) [9] No Yes Yes Yes No Yes Yes NA Yes NA Yes CD No NA
Cervelli et al. (2019) [10] Yes Yes Yes Yes No Yes Yes NA Yes NA No CD No NA
Demir et al. (2022) [11] Yes Yes Yes Yes No Yes Yes NA Yes NA No CD No NA
Erdogan et al. (2004) [13] Yes Yes CD Yes No Yes Yes NA Yes NA Yes CD No NA
Erkan et al. (2012) [14] No Yes No Yes No Yes Yes NA Yes NA Yes CD No NA
Erturk et al. (2021) [15] Yes Yes CD Yes No Yes Yes NA Yes NA Yes CD No NA
Franklyn et al. (1995) [16] No Yes No Yes No Yes Yes NA Yes NA Yes CD No NA
Pereira et al. (2021) [17] Yes Yes CD Yes No Yes Yes NA Yes NA Yes CD No NA
Ratcliffe et al. (1986) [18] Yes Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Roque et al. (2020) [19] Yes Yes No Yes No Yes Yes NA Yes NA No CD No NA
Ross et al. (1984) [22] No Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Saki et al. (2015) [20] Yes Yes Yes Yes No Yes Yes NA Yes NA Yes CD No NA
Sharma et al. (1994) [21] No Yes CD Yes No Yes Yes NA Yes NA No CD No NA
RFA
Barbaro et al. (2007) [23] No Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Bernardi et al. (2017) [24] Yes Yes Yes Yes No Yes Yes NA Yes NA Yes CD No NA
Cappelli et al. (2020) [29] Yes Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Cervelli et al. (2019) [10] Yes Yes Yes Yes No Yes Yes NA Yes NA No CD No NA
Cesareo et al. (2018) [25] No Yes Yes Yes No Yes Yes NA Yes NA No CD No NA
Deandrea et al. (2008) [26] Yes Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Dobnig et al. (2018) [30] Yes Yes CD Yes No Yes Yes NA Yes NA No CD No NA
Erturk et al. (2021) [15] Yes Yes CD Yes No Yes Yes NA Yes NA Yes CD No NA
Faggiano et al. (2012) [27] Yes Yes Yes Yes No Yes Yes NA Yes NA No CD No NA
van der Meeren et al. (2023) [28] Yes Yes Yes Yes No Yes Yes NA Yes NA Yes CD No NA
RAI + RFA vs. RAI
Chianelli et al. (2014) [31] Yes Yes Yes Yes No Yes Yes NA Yes NA No CD No NA

1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Was the par-
ticipation rate of eligible persons at least 50%? 4. Were all the subjects selected or recruited from the same or similar populations (including the
same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a
sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of
interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an asso-
ciation between exposure and outcome if it existed? 8. For exposures that can vary in amount or level, did the study examine different levels of
the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure meas-
ures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s)
assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented con-
sistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up
after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship
between exposure(s) and outcome(s)?

Table 4  Risk of bias—part II

Unique ID Experimental Comparator Outcome D1 D2 D3 D4 D5 Overall

Døssing et al. (2007) [12] RFA RAI Response to treatment

! - + + ! -
The risk of bias was assessed using the RoB2 tool for randomized trials. The study was analyzed as a per-protocol analysis. D1 (randomization
process): Some concerns about allocation order concealment until patients were included. D2 (deviations from intended interventions): High risk
of bias given the specific study design, as participants were likely to know which intervention they were allocated to. Certainly, the allocation
was known to the people delivering the intervention. D3 (missing outcome data): low risk. D4 (measurement of outcome): low risk. D5 (selec-
tion of reported result): It was unclear whether the data were analyzed according to a pre-specified analysis plan

Response to treatment
Direct comparison between RAI and RFA In three studies
[10, 12, 15] with a total of 141 patients, the response
to treatment was directly compared between RAI and
RFA. Overall, it was found that 15% and 32% of patients
treated with RAI and RFA, respectively, continued to
have hyperthyroidism after a single treatment ses-
sion. The pooled risk ratio showed a higher, although
not statistically significant, risk of failure in patients
treated with RFA (RR, 1.24; 95%CI, 0.94–1.63; z = 1.55;
p = 0.12) (Fig. 2).
Indirect comparative analysis
Twenty-seven reports on a total of 1338 patients (1042
treated with RAI and 296 treated with RFA) were included
in the meta-analysis of RAI or RFA models. The pooled
success rate for RAI was more than 94% (proportion,
Fig. 2  Forest plot—RFA + RAI vs. RAI
Fig. 3  Forest plots 1 RAI; 2 RFA
European Journal of Nuclear Medicine and Molecular Imaging
0.94; 95%CI, 0.91–0.97; z = 69.59; p < 0.001; I2 = 81.35%)
(Fig. 3(1)), while only 59% of patients treated with RFA
became euthyroid or hypothyroid after RFA treatment
(proportion, 0.59; 95%CI, 0.45–0.73; z = 8.21; p < 0.001;
I2 = 88.03%) (Fig. 3(2)).
Comparing the response to the two treatments, taking into
account different study designs (Fig. 4(1)) and Fig. 4(2)), the
pooled proportion of patients who responded to RAI treat-
ments and were included in prospective studies was 0.96
(95%CI, 0.90–1.02; z = 32.95; p < 0.001), while the propor-
tion of patients treated with RFA who were included in the
same study design did not exceed 0.50 (95%CI, 0.36–0.65;
z = 6.78; p < 0.0001).
The same trend was confirmed when only retrospective
studies were considered with a slight increase in the pooled
proportion for RFA treatment (0.70, 95%CI, 0.51–0.90;
z = 7.04; p < 0.001). Considering the sample size, the pooled
proportion of euthyroid or hypothyroid patients after RAI
treatments was 0.88 (95%CI, 0.81–0.96; z = 22.91; p < 0.001;
European Journal of Nuclear Medicine and Molecular Imaging

Fig. 4  Forest plots subgroup analysis for study design 1 RAI; 2 RFA

I2 = 83.74%) for studies with less than 45 patients (median z = 5.91; p < 0.001; I2 = 87.77%) for studies with fewer
sample size of included studies). The pooled proportion of than 23 patients (median sample size of included studies)
success rate for RFA patients was 0.64 (95%CI, 0.43–0.86; (Fig. 5(1), (2)).

Fig. 5  Forest plots subgroup analysis for sample size 1 RAI; 2 RFA

Fig. 6  Forest plots subgroup analysis for follow-up 1 RAI; 2 RFA
In the first six months after RAI therapy, more than
94% of patients (95%CI, 0.91–0.97; z = 65.34; p < 0.001;
I2 = 0.00%) became euthyroid or hypothyroid, while only
34% (95%CI, 0.07–0.61; z = 2.43, p = 0.02; I2 = 68.38%)
achieved the same success rate with RFA. After the first
12 months, the pooled success rate for patients treated with
RAI was 0.93 (95%CI, 0.88–0.98; z = 34.82; p < 0.001;
I 2 = 81.39%), while the pooled success rate for RFA
patients was 0.63 (95%CI, 0.49–0.78; z = 8.35; p < 0.001;
I2 = 86.72%). Higher pooled success rates for RAI were also
confirmed at 12-month follow-up (Fig. 6(1)), while no infor-
mation was found for RFA treatment (Fig. 6(2)), for which
only one study reported a success rate of 66% at 12 months.
RFA add‑on to RAI
In a pilot study conducted on a sample of 32 patients to
compare thyroid function after treatment with laser abla-
tion in combination with 131I iodine (n = 15) with thyroid
function in patients receiving 131I alone (n = 17), Chianelli
et al. [31] showed a progressive increase in TSH in both
groups with normalization in all patients after 12 months. In
patients treated with RAI and RFA, normalization occurred
in 9 out of 15 after only one month. After a 24-month fol-
low-up, no relapse of hyperthyroidism was reported and
European Journal of Nuclear Medicine and Molecular Imaging
late hypothyroidism was observed in only one patient in the
RAI + RFA group [31].
Volume reduction and TSH changes
Two studies reported data on volume reduction and TSH
changes after RAI treatments. In the RCT by Døssing et al.
[12], which was conducted on a sample of 14 patients, the
authors showed a significant percentage volume reduction
after 6 months (47% ± 8%), which was accompanied by a
significant increase in mean TSH from baseline (0.02 mU/
mL, < 0.001–0.27) to 1.21 mU/mL (0.43–2.58). The same
trend for RAI was also seen in Erturk et al. [15], where
a 45.81% (20.60–45.81) reduction in nodule volume was
associated with an increase in TSH levels from 0.03 ± 0.13
µIU/mL at baseline to 1.20 µIU/mL (0.68–1.95) at 12
months. Six studies investigated the response to treatment
after RFA [12, 15, 24–26, 29]. Three studies examined the
percentage reduction in nodule volume and TSH levels
3 months after RFA treatment [24, 26, 29]: they showed
an increase in TSH levels as the volume of the nodule
decreased. When analyzing the changes 6 and 12 months
after RFA treatment, the correlation between the reduction
in nodule volume and the TSH increase remained almost
unchanged (Table 5).
European Journal of Nuclear Medicine and Molecular Imaging

Discussion
TSH 6–12 months

1.8 ± 0.8 mUI/L

1.41 ± 0.20 µU/
(0.68–1.95)

(0.19–1.55)
1.20 µIU/mL

1.04 µIU/mL
As the main result of our present study, RAI therapy per-
formed significantly better than RFA in treating AFTNs. In

mL
NR

NR
NR
NR
particular, TSH increased slowly and normalized in only
1.21 mU/mL (0.43–2.58)
59% of all patients after thermal ablation compared to a sig-

0.32 mU/mL (< 0.001–

nificantly faster response and higher normalization rate of

0.661 ± 1.233 mUI/L 0.993 ± 2.033 mUI/L

1.15 ± 0.15 µU/mL
TSH in 94% of patients treated with RAI. This occurred
TSH 3–6 months

1.7 ± 0.8 mUI/L

despite a significant reduction of AFTNs’ volume reported
even after thermal ablation in most studies, which is in line

0.82)
with a previous observation of Giovanella and colleagues
NR

NR

NR
in patients with AFTNs treated with high-intensity focused
ultrasound (HIFU) technique [32]. The authors performed
1.91 ± 0.32 µU/mL
TSH 1–3 months

pre- and post-ablation thyroid scintigraphy and observed a

0.4 ± 0.2 mUI/L

shift from overactive to hypoactive/isoactive nodules in most

patients treated with radioiodine, while AFTNs remained
hyperactive, even if reduced in volume, in the majority of
NR

NR

NR

patients treated with HIFU, respectively. Notably, RAI tar-

gets hyperfunctioning cells independently by their locali-
0.02 mU/mL (< 0.001–

0.03 mU/mL (< 0.001–

0.508 ± 0.339 mUI/L
0.03 ± 0.13 µIU/mL

0.04 ± 0.22 µIU/mL

zation within the nodules while thermal ablation cannot

1.01 ± 0.20 µU/mL

0.15 ± 0.17 mUI/L

0.3 ± 0.2 mUI/L

be functionally complete as a percentage of constitutively

TSH baseline

activated thyroid cells remains to avoid thermal damage on

0.27)

0.20)

surrounding tissues (“safety areas”). Additionally, the distri-

bution of the released energy depends on many factors as the
patient’s movements and operator-dependent technique and
Nodule Volume reduction (%)

experience. This phenomenon was also observed in patients

with AFTNs treated with percutaneous ethanol injection
45.81 (20.60–45.81)

54.29 (45.23–59.61)

(PEI). Zingrillo and colleagues evaluated 43 patients with

AFTNs < 40 mm [33]. Twenty-one patients were treated
6–12 months

74.78 ± 3.01

by RAI and 22 by multiple PEI (5–9 sessions). After 36

9.8 ± 8.4

(12–84) months of follow-up, suppressed TSH levels were

75 ± 10
NR

NR
NR

still recorded in 14% of patients after multiple PEI but not in

patients treated with RAI despite a comparable reduction in
Nodule volume

nodules’ volume in the two groups. More recently, Sung and

reduction (%)

69.35 ± 2.97
3–6 months

65.0 ± 17.7

52.6 ± 16.3

colleagues underlined that the amount of the undertreated

68 ± 15
47 ± 8

44 ± 5

portion of AFTNs can be a source of recurrence and it is

Table 5  Correlation between nodule volume reduction and TSH

NR

NR

strictly dependent on the operators’ proficiency [34]. Several

biases in study design and data reporting were identified
Nodule volume
reduction (%)

when analyzing the included studies. First, except for three,

62.63 ± 2.13
1–3 months

39.5 ± 18.9

49.2 ± 20.1

the majority of included studies examined response to RFA

61 ± 10

treatment without including a RAI-treated control group.

NR

NR

While the cohort-based, retrospective approach may be justi-

fied in RAI studies due to the lack of an effective comparison
2007

2021

2016

2019
2018
2008
2007

2021
Year

group, at least in the older studies, it may represent a bias in

the case of RFA. Second, different inclusion/exclusion crite-
ria and the lack of a clear definition of response to treatment
Deandrea et al. (2008) [26]
Bernardi et al. (2017) [24]

Cappelli et al. (2020) [29]

Døssing et al. (2007) [12]

Døssing et al. (2007) [12]

Cesareo et al. (2018) [25]

in some studies prevented further subgroup analyses from

Erturk et al. (2021) [15]

Erturk et al. (2021) [15]

being conducted, so we do not have relevant information on

response to treatment in terms of specific patients’ charac-
teristics and the type of response achieved. Third, little infor-
mation was collected both in RAI and RFA studies, on hypo-
thyroid patients, recurrences, and mean time of occurrence
Author

RFA
RAI

of hypothyroidism or hyperthyroidism recurrences during
follow-up. Fourth, systematic differences in the study set-
tings of both treatments cannot be excluded; however, as the
comparative meta-analyses of RAI and RFA studies were
conducted using the same methodology, the resulting evi-
dence is robust. Fifth, no meta-analytic approach was used
to compare, albeit indirectly, the nodule volume reduction
and TSH between the two treatments. However, from the
narrative summary, a clear correlation between these two
parameters emerged. Overall, current literature demonstrated
a faster and more sustained response in patients with AFTNs
treated with RAI than RFA, respectively. Furthermore, it
is important to emphasize that there is increasing evidence
of the impact of thyroid dysfunction on the incidence and
prognosis of various cancers [35] in addition to well-estab-
lished cardiovascular outcomes. Most studies demonstrate
unfavorable effects of lower TSH and higher thyroid hor-
mone levels, especially in case of prostate and breast cancer
[35–37]. In addition to preventing possible complications
of hyperthyroidism, prompt resolution of euthyroidism can
potentially eliminate the pro-oncogenic effects of hyperthy-
roidism in cancer-free individuals and improve the prognosis
in cancer patients. RAI therapy is a safe and effective option
with superior long-term outcome compared to RFA and a
far more favorable risk profile compared to RFA and sur-
gery. In facts, even if rare, potential side-effects of surgery
(bleeding, laryngeal nerve injuries, hypoparathyroidism,
and infection) and RFA (voice changes/horseness, brachial
plexus nerve injury, Horner’s syndrome, nodule rupture,
needle track seeding, transient thyrotoxicosis, colliquation,
hemorrhage/hematoma, skin burn) are significantly more
relevant than those rarely reported after RAI administration
(transient pain and thyrotoxicosis). Randomized controlled
trials and/or comparative prospective studies between RFA
and RAI are recommended to evaluate, in the same study
setting, the response to treatment, nodule volume reduc-
tion, TSH normalization and time of such normalization as
well as possible side effects, the occurrence of hypothyroid-
ism and possible recurrences of hyperthyroidism. All facts
considered, taking into account available evidence on the
superiority of RAI over RFA in terms of success rates and
safety profile, RAI remains the first-line treatment modality
in patients with AFTN.
Author contribution The study was conceived and designed by Luca
Giovanella. Material preparation and data collection were performed
by all authors. Data analysis was performed by Maria Luisa Garo.
The first draft of the manuscript was written by Luca Giovanella and
Maria Luisa Garo and all authors commented on previous versions of
the manuscript. All authors read and approved the final manuscript.
Data availability The datasets generated during and/or analyzed dur-
ing the current study are available from the corresponding author on
reasonable request.
European Journal of Nuclear Medicine and Molecular Imaging
Declarations
Ethics approval and consent to participate Not applicable.
Competing interests The authors declare no competing interests.
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