# Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial

Sophie Leboulleux, Claire Bournaud, Cecile N Chougnet, Livia Lamartina, Slimane Zerdoud, Christine Do Cao, Bogdan Catargi, Inna Dygai, Antony Kelly, Marie-Luce Barge, et al.

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## ► To cite this version:

Sophie Leboulleux, Claire Bournaud, Cecile N Chougnet, Livia Lamartina, Slimane Zerdoud, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. The Lancet. Diabetes & Endocrinology, 2025, 13 (1), pp.38-46. 10.1016/S2213-8587(24)00276-6. inserm-05062136

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# Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial

Sophie Leboulleux, Claire Bournaud, Cecile N Chougnet, Livia Lamartina, Slimane Zerdoud, Christine Do Cao, Bogdan Catargi, Inna Dygai, Antony Kelly, Marie-Luce Barge, Pierre Vera, Daniela Rusu, Olivier Schneegans, Julie Roux, Perrine Raymond, Danielle Benisvy, Marie-Claude Eberle, Sophie Bidault, Camila Nascimento, Delphine Bastie, Anne-Laure Giraudet, Stéphane Bardet, Nathalie Le Moullec, Nathalie Roudaut, Delphine Drui, Yann Godbert, Mohamad Zalzali, Anne Drutel, Olivier Morel, Fritz-Line Velayoudom, Abir Al Ghuzlan, Martin Schlumberger, Camille Buffet, Isabelle Borget

## Summary

**Background** ESTIMABL2, a multicentre randomised phase 3 trial in patients with low-risk differentiated thyroid cancer (ie, pT1am or pT1b, N0 [no evidence of regional nodal involvement] or Nx [involvement of regional lymph nodes that cannot be assessed in the absence of neck dissection]), showed the non-inferiority of a follow-up strategy without radioactive iodine (131I) administration compared with a postoperative 131I administration at 3 years post-randomisation. Here, we report a pre-specified analysis after 5 years of follow-up.

**Methods** Patients treated with total thyroidectomy with or without prophylactic neck lymph node dissection, without postoperative suspicious findings on neck ultrasonography, were randomly assigned to the no-radioiodine group or to the radioiodine group (1·1 GBq-30 mCi after recombinant human thyrotropin-stimulating hormone). Follow-up consisted of annual thyroglobulin and thyroglobulin antibody determinations during levothyroxine treatment and neck ultrasonography in odd-numbered years. An event was defined as abnormal foci of 131I uptake on the post-treatment whole-body-scan requiring subsequent treatment, abnormal neck ultrasonography, elevated thyroglobulin levels, increasing titres or appearance of thyroglobulin antibody (using the same laboratory assay), or a combination of these definitions. Non-inferiority of the proportion of patients without an event in one group compared with the other at 5 years after randomisation was shown if this proportion and its CI did not differ by more than -5%. This study was registered on ClinicalTrials.gov (NCT01837745) and is completed.

**Findings** Of the 776 patients (n=642 [82·7%] female and n=134 [17·3%] male, median age 52·9 years [IQR 42·6–63·1]) enrolled, 698 were evaluable at 5 years. The proportions of patients without events were 93·2% in the no-radioiodine group and 94·8% in the radioiodine group, for a difference of -1·6% (90% CI -4·5 to 1·4). Events consisted of structural or functional abnormalities (n=11) and biological abnormalities (n=31).

**Interpretation** The non-inferiority of a follow-up strategy compared with postoperative 131I administration in low risk differentiated thyroid cancer was confirmed at 5 years. There is no loss of opportunity in following these patients without postoperative ablation.

**Funding** Programme de Recherche Hospitalier Clinique.

**Copyright** © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

## Introduction

Radioactive iodine (131I) has been used in the treatment of thyroid cancer for decades. The first successful treatment of a patient with metastatic thyroid cancer with 131I was reported in 1946.¹ 131I is administered after total thyroidectomy to destroy normal thyroid remnants (ablation) and to treat suspected (adjuvant) or proven persistent disease with the goal of improving recurrence-free and overall survival. In the 1990s, a large retrospective study including more than 900 patients with a long median follow-up of 15·7 years found an improvement in survival and recurrence-free survival in patients with thyroid cancer larger than 15 mm or

metastatic lymph nodes in the absence of known distant metastases when radioactive iodine was given.² At that time, 131I was widely administered to most, if not all, patients with follicular cell-derived thyroid cancer. Currently, however, most patients have a low-risk follicular-cell derived thyroid cancer with stage I disease with a risk of thyroid cancer-related death of less than 2% and a risk of recurrence of less than 5%.³ Among these patients with low-risk thyroid cancer, there is a broad consensus to avoid 131I administration in the case of intrathyroidal unifocal microcarcinoma (≤10 mm in diameter), but in the other low-risk thyroid cancer, the modalities and use of radioiodine remain controversial.⁴⁻⁶

Lancet Diabetes Endocrinol
2025; 13: 38–46

Published Online
November 22, 2024
https://doi.org/10.1016/
S2213-8587(24)00276-6

See Comment page 5

Department of Nuclear
Medicine and Endocrine
Oncology (Prof S Leboulleux MD,
L Lamartina MD,
Prof M Schlumberger MD),
Department of Radiology
(S Bidault MD), Department of
Medical Biology and Pathology
(A Al Ghzlan MD), Department
of Biostatistics and
Epidemiology
(Prof I Borget PhD), Gustave
Roussy, Paris, France;
University Paris-Saclay, Paris,
France (Prof S Leboulleux,
L Lamartina, A Al Ghzlan,
Prof M Schlumberger,
Prof I Borget); Department of
Endocrinology and
Diabetology, Hôpitaux
Universitaires de Genève,
Geneva, Switzerland
(Prof S Leboulleux); Faculty of
Medicine, University of
Geneva, Geneva, Switzerland
(Prof S Leboulleux); Department
of Nuclear Medicine, Hospices
Civils de Lyon, Groupement
Hospitalier Est, Bron, France
(C Bournaud MD); Department
of Endocrine Oncology,
Assistance Publique-Hôpitaux
de Paris Hôpital Saint-Louis,
Paris, France
(C N Chougnet MD);
Department of Nuclear
Medicine, Nuclear Oncology,
and Thyroid Oncology, IUCT
Oncopole Toulouse-Institut
Claudius Regaud, Toulouse,
France (S Zerdoud MD,
C Nascimento MD); Department
of Endocrinology, CHRU de
Lille-Hôpital Claude Huriez,
Lille, France (C Do Cao MD);
Department of
Endocrinology-Metabolic
Research in context

Evidence before this study

On June 1, 2024, we searched PubMed using the following
terms: "low-risk", "thyroid cancer", "prospective", "randomized
trial", "radioiodine", without language or date restrictions. In
patients with low-risk follicular cell-derived thyroid cancer, a
randomised trial showed that a follow-up without
postoperative radioactive iodine (¹³¹I) administration was not
inferior to a low-activity (1·1 GBq [30 mCi]) of ¹³¹I, administered
to euthyroid patients after injections of recombinant human
thyroid-stimulating hormone in terms of functional, structural,
or biological events during a 3 year-follow-up. Longer-term
follow-up was needed to ensure detection of late recurrences.

Added value of this study

After a 5-year follow-up, among 698 patients evaluable at
5 years, the proportions of patients without events were 93·2%

in the no radioiodine group and 94.8% in the radioiodine
group, for a difference of -1.6% (90% CI -4.5 to 1.4). Events
consisted of structural or functional abnormalities (n=11: five in
the radioiodine group and six in the no radioiodine group) and
biological abnormalities (n=31; 13 in the radioiodine group and
18 in the no radioiodine group). After randomisation and initial
treatment (radioiodine or not), 11 patients in each group
underwent a subsequent treatment (surgery with ¹³¹I). We also
found that a postoperative serum thyroglobulin level of
>1ng/mL measured under thyroid hormone treatment, an age
between 55 and 60 years, a follicular histology, and a larger
tumour size were prognostic for an event.

Implications of all the available evidence

Our study confirms that in patients with low-risk thyroid cancer
there is no need for systematic postoperative ablation.

A meta-analysis concluded that the benefit of ¹³¹I in patients with stage I (which includes patients at low risk of recurrence but also some at intermediate or even at high risk of recurrence) was inconsistent.⁷ Moreover, another review of retrospective studies in patients with thyroid cancer with a low risk of recurrence did not show a benefit of ¹³¹I.⁸

Two large, randomised trials have shown that postoperative administration of a low activity (1·1 GBq) ¹³¹I after administration of recombinant human thyrotropin-stimulating hormone is non-inferior to a high activity (3·7 GBq) ¹³¹I after thyroid hormone treatment withdrawal in terms of ablation success rate and 5-year recurrence rate in patients with follicular cell-derived thyroid cancer with low to intermediate risk of recurrence.⁹⁻¹² These two trials allowed a de-escalation in the ¹³¹I activity administered in these patients with low-risk differentiated thyroid cancer. Although retrospective studies have shown no benefit of radioactive administration in low risk differentiated thyroid cancer, postoperative ¹³¹I is still prescribed or recommended in differentiated thyroid cancer for tumours greater than 10 mm by some experts.¹³,¹⁴

We recently published an open-label, investigator-
initiated, phase 3 randomised trial (ESTIMABL2)
showing that in patients with thyroid cancer with a low
risk of recurrence undergoing thyroidectomy, a follow-up
strategy without postoperative radioiodine admin-
istration was not inferior to an ablation strategy with
1·1 GBq (30 mCi) radioiodine with respect to the occur-
rence of functional, structural, and biological events after
the first 3 years from randomisation.¹⁵ In fact, the rate of
patients without an event was 95·6% in the no radioio-
dine group and 95·9% in the radioiodine group
(a difference of −0·3%; 90% CI −2·7 to 2·2). Most
recurrences of thyroid cancer occur within the first
5 years, so a follow-up of 3 years might be too short given

the indolent nature of most low-risk and intermediate-
risk thyroid cancer.¹¹,¹⁶⁻¹⁸ Therefore, the benefit of
post-operative ¹³¹I still remains controversial for some
clinicians, especially in the field of nuclear medicine.¹⁹

Here, we aim to present the pre-specified secondary
endpoint of the ESTIMABL2 trial, which was to assess
non-inferiority in the percentage of patients free of
events after 5 years following randomisation.

Methods

Study design and participants

Details of the study design and protocol have been
published previously¹⁵ (appendix p 2). The study was
an open-label, randomised phase 3 trial conducted across
35 centres of the French Endocan-TuThyRef network.
From May 2013, to March 2017, patients treated with
total thyroidectomy with or without prophylactic neck
lymph node dissection, without postoperative suspi-
cious findings on neck ultrasonography were randomly
assigned to receive postoperative radioiodine (radioiodine
group) or no postoperative radioiodine (non-radioiodine
group). The primary objective was to assess the non-infe-
riority of the non-radioiodine group compared with the
radioiodine group in terms of the percentage of patients
without a functional, structural, or biological event after
the 3 years following randomisation. The randomisation
process was done centrally at the biostatistics service of
Gustave Roussy using the TenAlea website (created by
the Netherlands Cancer Institute, Amsterdam) by investi-
gators or duly authorised people with a random block
method (block size of four patients). Randomisation was
stratified by study centre and lymph node status (ie, N0 [no evidence of regional nodal involvement] or Nx [involvement of regional lymph nodes that cannot be assessed in the absence of neck dissection]). A secondary
objective was to compare the percentage of patients
without an event after 5 years following randomisation.

Diseases, Hôpital Saint-André,
Centre Hospitalier Universitaire
de Bordeaux, Bordeaux, France
(Prof B Catargi MD);
Department of Nuclear
Medicine, Centre Georges
François Leclerc, Dijon, France
(I Dyrai MD); Department of
Nuclear Medicine, Centre Jean
Perrin, Clermont-Ferrand,
France (A Kelly MD);
Department of Nuclear
Medicine, Centre Eugene
Marquis, Rennes, France
(M-L Barge MD); Centre Henri
Becquerel and Laboratoire
QUANTif, Rouen, France
(Prof P Vera MD); Department
of Nuclear Medicine, Centre
René Gauducheau, Saint
Herblain, France (D Rusu MD);
Department of Nuclear
Medicine, Centre Paul Strauss,
Strasbourg, France
(O Schneegans MD);
Department of Nuclear
Medicine, CHU Grenoble-Alpes,
Grenoble, France (J Roux MD);
Department of Endocrinology,
Centre Hospitalier Régional
Universitaire de Nancy,
Hôpitaux de Brabois,
Vandoeuvre Les Nancy, France
(P Raymond MD); Department
of Nuclear Medicine, Antoine
Lacassagne, Nice, France
(D Benisvy MD); Department of
Nuclear Medicine, Institut du
Cancer de Montpellier, Institut
Régional du Cancer Val
d'Aurelle, Montpellier, France
(M-C Eberle MD); Department
of Nuclear Medicine, Institut
Curie Site Saint-Cloud, Saint-
Cloud, France (C Nascimento);
Department of Nuclear
Medicine, CHU Rangueil
Toulouse, France (D Bastie);
Department of Nuclear
Medicine, Centre Léon Bérard,
Lyon, France (A-L Giraudet MD);
Department of Nuclear
Medicine and Thyroid Unit,
Centre François Baclesse, Caen,
France (S Bardet MD);
Department of Endocrinology,
CHU Saint Pierre, Saint Pierre,
France (N Le Moullec MD);
Department of Endocrinology,
CHU La Cavale Blanche, Brest,
France (N Roudaut MD);
Department of Endocrinology,
L'institut du thorax, CHU de
Nantes-Hopital Laennec Saint-
Herblain, Nantes, France
(D Drui MD); Department of
Thyroid Oncology and Nuclear
Medicine, Institut Bergonié,
Bordeaux, France
(Y Godbert MD); Thyroid Unit,
Institut Jean Godinot, Reims,
France (M Zalzali MD);
Department of Endocrinology,
CHU Dupuytren, Limoges,
France (A Drutel MD);
Department of Nuclear
Medicine, Institut de
Cancérologie de l'Ouest,
Angers, France
(Prof O Morel MD);
Department
of Endocrinology, CHU de
Guadeloupe, Hôpital Ricou,
Les Abymes, France
(F-L Velayoudom MD);
Department of Thyroid and
Endocrine Tumors,
Pitié-Salpêtrière Hospital,
Paris, France (C Buffet MD);
Thyroid Tumors Clinical
Research Group 16, Sorbonne
University, Cancer Institute,
Inserm U1146, CNRS UMR
7371, Paris, France (C Buffet);
Office of Biostatistics and
Epidemiology, Gustave Roussy,
Université Paris-Saclay,
Villejuif, France (Prof I Borget);
Inserm, Université Paris-Saclay,
CESP U1018, Oncostat, labelled
Ligue Contre le Cancer, Villejuif,
France (Prof I Borget)

Correspondence to:
Prof Sophie Leboulleux,
Department of Endocrinology
and Diabetology, Hôpitaux
Universitaires de Genève,
Geneva 1205, Switzerland
sophie.leboulleux@hug.ch

See Online for appendix

The main inclusion criteria were: treatment with total thyroidectomy with or without prophylactic neck lymph node dissection and no postoperative suspicious findings on neck ultrasonography, aged 18 years or older, differentiated thyroid cancer (ie, papillary, follicular, or oncocytic) with multifocal pT1a tumours (diameter of each lesion ≤1 cm and sum of the longest diameters of the lesions ≤2 cm) or pT1b tumours (>1 cm and ≤2 cm), an N0 or Nx lymph node status, and the absence of extra-thyroidal extension. Patients with aggressive histological subtypes (tall cell, clear cell, columnar cell, and diffuse sclerosing variants of papillary thyroid cancer that are poorly differentiated) based on local diagnosis were excluded. A full list of inclusion and exclusion criteria are available in the appendix (p 4). The study was conducted in accordance with the protocol approved by the ethics committee and national authorities and in accordance with the Declaration of Helsinki. All patients provided written informed consent.

## Procedures and outcomes

Patients randomly assigned to the radioiodine group received 1·1 GBq (30 mCi) ¹³¹I under thyroid hormone treatment, 24 h after the second intramuscular injection of recombinant human thyrotropin (Thyrogen, Sanofi, Paris, France) given at a dose of 0·9 mg on 2 consecutive days. Whole-body scanning and single-photon emission CT of the neck were performed 2 to 5 days after radioiodine administration. Follow-up of patients in the radioiodine group consisted of measurement of thyroglobulin under recombinant human thyrotropin-stimulating hormone stimulation with measurement of thyroglobulin antibodies and neck ultrasonography at 10 months after randomisation (appendix p 2). Thereafter, follow-up consisted of measurement of thyroglobulin under thyroid hormone treatment and of thyroglobulin antibody every year, and a neck ultrasonography every other year. Follow-up for patients in the no radioiodine group consisted of measurements of thyroglobulin while on thyroid hormone treatment and of thyroglobulin antibodies every year, and a neck ultrasonography every other year. Diagnostic radioiodine scanning was not performed during follow-up, because it is not considered a standard of care for thyroid cancer surveillance in France and most European countries.

An event was a composite criterion of functional, structural, or biological events. A functional event was defined by the presence of foci of ¹³¹I uptake outside the thyroid bed on the post-therapeutic whole-body scan with subsequent treatment including the administration of another therapeutic activity of ¹³¹I or surgery. A structural event was defined as the presence of a suspicious lymph node on neck ultrasonography with abnormal cytology findings, a thyroglobulin level of more than 10 ng/mL in the aspirate fluid, an abnormal mass in the thyroid bed with abnormal cytology findings, or a combination of these factors. A biological event was defined as an

elevated thyroglobulin level, or the occurrence of an elevated thyroglobulin antibody titre above the upper limit of the normal range or an increase in the thyroglobulin antibody titre by more than 50% in two determinations performed 6 months apart, using the same laboratory assay. The threshold for an elevated serum thyroglobulin for patients in the radioiodine group was a thyroglobulin level greater than 1 ng/mL and less than 5 ng/mL on thyroid hormone treatment in two measurements performed 6 months apart or a thyroglobulin level greater than 5 ng/mL. The threshold for an elevated serum thyroglobulin for patients in the no radioiodine group was a thyroglobulin level greater than 2 ng/mL and less than 5 ng/mL on thyroid hormone treatment on two measurements performed 6 months apart or a thyroglobulin level greater than 5 ng/mL. For the present analysis, for patients with two consecutive events, only the first one was considered.

For the assessment of the appearance of elevated thyroglobulin and for the appearance and increase of serum thyroglobulin and thyroglobulin antibody levels, determinations had to be performed using the same laboratory assay. In contrast to the 3-year evaluation, only local serum thyroglobulin and thyroglobulin antibody determinations were performed at the 5-year follow-up.

A central review was performed for functional events, but only for patients in the radioiodine group. Otherwise, for the two treatment groups, assessment of structural events required confirmation by cytology or elevated thyroglobulin levels in the liquid fluid, and biological events used predefined abnormal thresholds, with investigators not necessarily masked to treatment group.

## Statistical analyses

Descriptive quantitative data were expressed as means (SD) or median (IQR), depending on the distribution, whereas qualitative data were expressed as absolute number, percentage, and 95% CIs (calculated using the Wilson score method).

For the main outcome, we calculated the difference in the observed percentages of patients without an event and those with an event and its 90% two-sided exact CI (the lower limit of the latter being equal to the lower limit of upper one-sided 95% CI). The results are presented without and with adjustment on stratification variables. For the calculation of the 90% CI of the difference of two proportions, the exact method based on a score statistic was used.²⁰ Non-inferiority is declared if the lower limit for the two-sided 90% CI for the proportion of patients without an event in the no radioiodine group minus that in the radioiodine group is more than -5%. Because the rate of adverse events related to radioiodine ablation is very low, we chose a low non-inferiority margin of -5% with the goal of encouraging a change in clinical practice if non-inferiority was shown.
The primary analysis was performed on all evaluable patients in the per-protocol population, ie, patients whose treatment and follow-up were consistent with the study protocol. A sensitivity analysis was performed in the intention-to-treat population (ie, 776 randomly assigned patients) reporting the results in event-free survival at 5 years using a time-to-event analysis and its two-sided 90% CI. Prognostic factors associated with the risk of event were searched using a Poisson approach with a generalised estimating equation estimation to assess the relative risk (RR) and its 95% CI.

A post-hoc analysis was performed to compare between the two groups the percentage of excellent responses according to the American Thyroid Association risk classification, published in 2016 after the start of ESTIMABL2 trial.⁴ SAS software (version 9.4) was used for statistical analyses. The study was registered at ClinicalTrials.gov (NCT01837745).

<table><thead><tr><th></th><th>Radioiodine group (n=389)</th><th>No radioiodine group (n=387)</th></tr></thead><tbody><tr><td>Age, years</td><td>52.2 (42.3-62.7)</td><td>52.9 (42.7-63.9)</td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Female</td><td>319 (82.0%)</td><td>323 (83.5%)</td></tr><tr><td>Male</td><td>70 (18.0%)</td><td>64 (16.5%)</td></tr><tr><td>Days from thyroidectomy to randomisation</td><td>92.1 (23.2)</td><td>91.2 (23.6)</td></tr><tr><td>Histology</td><td></td><td></td></tr><tr><td>Papillary</td><td>372 (95.6%)</td><td>372 (96.1%)</td></tr><tr><td>Follicular</td><td>13 (3.3%)</td><td>11 (2.8%)</td></tr><tr><td>Oncocytic</td><td>4 (1.0%)</td><td>4 (1.0%)</td></tr><tr><td>Largest tumour size, mm</td><td>13 (11-15)</td><td>14 (11-17)</td></tr><tr><td>pTNM stage</td><td></td><td></td></tr><tr><td>pT1amN0</td><td>26 (6.7%)</td><td>23 (5.9%)</td></tr><tr><td>pT1amNx</td><td>56 (14.4%)</td><td>42 (10.9%)</td></tr><tr><td>pT1bN0</td><td>143 (36.8%)</td><td>148 (38.2%)</td></tr><tr><td>pT1bNx</td><td>164 (42.2%)</td><td>174 (45.0%)</td></tr><tr><td>Multifocality</td><td>178 (45.8%)</td><td>156 (40.3%)</td></tr><tr><td>Neck dissection performed</td><td>171 (44.0%)</td><td>171 (44.2%)</td></tr><tr><td>Type of neck dissection performed</td><td></td><td></td></tr><tr><td>Central only</td><td>69 (17.7%)</td><td>77 (19.9%)</td></tr><tr><td>Central and lateral</td><td>74 (19.0%)</td><td>65 (16.8%)</td></tr><tr><td>Lateral only</td><td>26 (6.7%)</td><td>27 (7.0%)</td></tr><tr><td>Unknown</td><td>2 (0.5%)</td><td>2 (0.5%)</td></tr><tr><td>Thyroglobulin levels at randomisation in the 597 patients without thyroglobulin antibodies</td><td>N=304</td><td>N=293</td></tr><tr><td>Median (IQR)</td><td>0.26 (0.10-0.59)</td><td>0.20 (0.10-0.40)</td></tr><tr><td>&lt;0.2 ng/mL</td><td>94 (30.9%)</td><td>104 (35.5%)</td></tr><tr><td>0.2-1.0 ng/mL</td><td>161 (53.0%)</td><td>155 (52.9%)</td></tr><tr><td>&gt;1.0 ng/mL</td><td>32 (10.5%)</td><td>18 (6.1%)</td></tr><tr><td>Missing value</td><td>17 (5.6%)</td><td>16 (5.5%)</td></tr></tbody></table>

Data are n (%), mean (SD), or median (IQR).

<caption>**Table 1: Characteristics of the patients at randomisation**</caption>

## Role of the funding source

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

## Results

From May 2013, to March 2017, 776 patients (642 [82.7%] were female and 134 (17.3%) were male, with a median age of 52.9 years [IQR 42.6-63.1]) were randomly assigned (table 1, figure 1). The tumour histology was predominantly papillary (n=744, 95.9%) and the pTNM stage was mainly pT1b N0 and Nx (n=629, 81.1%). One patient randomly assigned to the no radioiodine group did not meet the inclusion criteria due to the presence of suspicious lymph nodes. 730 patients (94.1%) were evaluable at 3-year post-randomisation and 698 (89.9%) were evaluable at 5-year post-randomisation (figure 1).

The number of patients without an event after 5 years was 330 (93.2%) of 354 (95% CI 90.1 to 95.4) in the no radioiodine group and 326 (94.8%) of 344 (91.9 to 96.7) in the radioiodine group, for a unadjusted difference of -1.6% (90% CI -4.5 to 1.4), indicating that the no post-operative radioiodine strategy remains non-inferior to routine radioiodine administration (table 2, figure 2;

<figure><img src="image_4.png" /><figcaption>**Figure 1: Trial profile**</figcaption></figure>

*Causes of death in the iodine group: pulmonary embolism (n=1), sarcomatoid lung cancer (n=1), aneurysm rupture (n=1), pancreatic cancer (n=1), and heart failure (n=1). Causes of death in the no iodine group: heart failure (n=1), peritoneal cancer (n=1), and lymphoma-related adverse event (n=1).
<table><thead><tr><th></th><th>Radioiodine group (n=344)</th><th>No radioiodine group (n=354)</th></tr></thead><tbody><tr><td>Number of patients without an event during the 5 years, n (%); 95% CI*</td><td>326 (94.8%); 91.9 to 96.7</td><td>330 (93.2%); 90.1 to 95.4</td></tr><tr><td>Difference in the percentage of patients without an event at 5 years (90% CI), in the no-radioiodine group compared with the radioiodine group</td><td>NA</td><td>-1.6% (-4.5 to 1.4);† -1.3% (-3.9 to 0.01)‡</td></tr><tr><td>Number of patients with at least one event during the 5 years, n (%); 95% CI</td><td>18 (5.2%); 3.3 to 8.1</td><td>24 (6.8%); 4.6 to 9.9</td></tr><tr><td>Type of events</td><td></td><td></td></tr><tr><td>Foci of radioactive iodine uptake outside the thyroid bed needing further treatment</td><td>3</td><td>NA</td></tr><tr><td>Abnormal neck ultrasonography with abnormal cytology or elevated thyroglobulin in the liquid fluid</td><td></td><td></td></tr><tr><td>Abnormal lymph node</td><td>2§</td><td>4¶</td></tr><tr><td>Abnormal thyroid mass</td><td>0</td><td>2||</td></tr><tr><td>Biological events</td><td></td><td></td></tr><tr><td>Thyroglobulin after recombinant human thyrotropin-stimulating hormone &gt;5 ng/mL (radioiodine group)</td><td>3</td><td>NA</td></tr><tr><td>Thyroglobulin after recombinant human thyrotropin-stimulating hormone &gt;1 ng/mL and ≤5 ng/mL on two consecutive measurements (radioiodine group)</td><td>6</td><td>NA</td></tr><tr><td>Thyroglobulin level on thyroid hormone treatment &gt;5 ng/mL (both groups)</td><td>0</td><td>4</td></tr><tr><td>Thyroglobulin level on thyroid hormone treatment &gt;1 ng/mL and ≤5 ng/mL on two consecutive measurements (radioiodine group)</td><td>0</td><td>NA</td></tr><tr><td>Thyroglobulin level on thyroid hormone treatment &gt;2 ng/mL and ≤5 ng/mL on two consecutive measurements (no radioiodine group)</td><td>NA</td><td>6</td></tr><tr><td>Appearance of thyroglobulin antibodies</td><td>3</td><td>6</td></tr><tr><td>Increase of thyroglobulin antibody titre over time</td><td>1</td><td>2</td></tr></tbody></table>

NA=not applicable. *CI of the proportion is estimated using the Wilson score method. †CI of the difference of the two proportions is estimated using an exact method based on a score statistic. ‡Adjusted estimate of the difference of two proportions is estimated using a generalised linear model using a binomial distribution and identity link. The adjustment variables are N status (N0 or Nx) and study centre (grouped into three categories regarding the number of patients recruited in the trial: small centre (<20 patients included), intermediate centre (20 to 30 patients included), or large centre (>30 patients included). The 90% CI is obtained via the sandwich variance estimator. §Thyroglobulin or thyroid hormone treatment level of 0.2 ng/mL and <0.1 ng/mL when recurrence was diagnosed. ¶Thyroglobulin or thyroid hormone treatment level of 0.1 ng/mL, 0.7 ng/mL, 2.5 ng/mL and 3.0 ng/mL when recurrence was diagnosed. ||Thyroglobulin or thyroid hormone treatment level of 0.1 ng/mL and 0.2 ng/mL when recurrence was diagnosed.

<figure><img src="image_5.png" /><figcaption>Table 2: Number and type of events occurring during the 5 years following randomisation</figcaption></figure>

**Figure 2:** Proportion of patients without events during the 5 years after randomisation

Circles represent the percentage of patients without an event during the 5 years after randomisation for each group, with error-bars representing their 95% CIs, estimated using the Wilson score method. The last line on the left represents the unadjusted difference of percentages of patients without an event between groups, and its 90% two-sided exact CI, and the non-inferiority margin (ΔL=-5%) defined in the protocol.

appendix p 3). Similar results were obtained both after adjustment and in the intention-to-treat population in terms of 5-years event-free survival (table 2, appendix p 5). Of note, characteristics of the patients not included

in the per-protocol analysis did not differ to those included in the per-protocol population (appendix p 6). Events occurred in 24 (6.8%) of 354 patients (95% CI 4.6 to 9.9) in the no radioiodine group and in 18 (5.2%) of 344 patients (3.3 to 8.1) in the iodine group (table 2).

Compared with the analysis at 3 years, there were eight patients with new events in the no radioiodine group and three patients with new events in the radioiodine group (figure 3). Events consisted of structural or functional abnormalities in 11 patients and biological abnormalities in the remaining 31 patients (table 2, figure 3). Structural or functional events included abnormal ¹³¹I uptake leading to further treatment in three patients (in the radioiodine group), lymph node metastasis in six patients (two in the radioiodine group and four in the no radioiodine group), and thyroid bed mass recurrence in two patients (in the no radioiodine group). Treatment of patients with abnormal iodine uptake consisted of ¹³¹I administration in three patients. Treatment of patients with lymph node metastases consisted of surgery in two patients, ¹³¹I administration in two patients, and both surgery and ¹³¹I administration in the two patients. Treatment of patients with thyroid bed recurrence consisted of surgery and ¹³¹I administration in one patient and follow-up only in one patient.

Thyroglobulin levels under levothyroxine treatment measured at the time of diagnosis of structural recurrence ranged from 0.1 to 3.0 ng/mL in patients in the no radioiodine group and were between <0.1 and 0.2 ng/mL in patients in the radioiodine group. No patients had elevated thyroglobulin antibody (table 2).

Among biological events, elevated thyroglobulin levels (between 1 and 5 ng/mL, between 2 and 5 ng/mL, or >5 ng/mL) were the most frequent events (n=19), followed by the appearance of thyroglobulin antibodies (n=9), and finally increases in thyroglobulin antibody titres (n=3; table 2). Compared with the analysis at the 3-year follow-up, there were three new structural events at the 5 year-follow up (recurrence in the thyroid bed in two patients and in a metastatic lymph node in one patient, all in the no radioiodine group). Overall, the number of subsequent treatments (surgery, ¹³¹I administration, or both) was 11 in the no radioiodine group and 11 in the radioiodine group, while the remaining patients with an event were followed up (seven patients in the no radioiodine group and 13 patients in the radioiodine group).

Of the 19 patients with elevated thyroglobulin levels, ten underwent further treatment, mostly in the patients with the highest thyroglobulin levels. Among the nine patients who did not receive any treatment, two of five patients in the no radioiodine group had a spontaneous decrease in thyroglobulin levels and normalisation of thyroglobulin levels (<2 ng/mL), and the four patients in the radioiodine group had a spontaneous decrease in thyroglobulin levels and
normalisation of thyroglobulin levels (<1 ng/mL; appendix p 7). There was a total of eight deaths, none of which were related to thyroid cancer.

On multivariable univariate analysis in patients without thyroglobulin antibodies, prognostic factors associated with a significantly higher risk of events were an elevated postoperative thyroglobulin level under thyroid hormone treatment (with thresholds of >1 ng/mL), age (especially for patients aged 55-60 years vs those aged <55 years), larger tumour size, and follicular and oncocytic histology (appendix p 8). Non-significant results were observed for ages greater than 60 years, gender, pN status (ie, N0 or Nx), or multifocality. The event rate was 4.0% (n=19) in the 481 patients with a postoperative thyroglobulin level measured under thyroid hormone treatment of 1 ng/mL or less versus 23.9% (n=11) in the 46 patients with a thyroglobulin level of more than 1 ng/mL (RR=6.31, 95% CI 2.83-14.05; appendix p 8). Among patients with postoperative thyroglobulin levels greater than 1 ng/mL without thyroglobulin antibodies measured under levothyroxine treatment at inclusion, events occurred in patients from both groups (appendix p 9). There was one structural or functional event in the no radioiodine group and one in the radioiodine group and six biological events in the no radioiodine group and three in the iodine group (appendix p 9). Among patients without thyroglobulin antibodies, events occurred in 19 (4.0%) of the 481 patients with postoperative thyroglobulin levels of 1 ng/mL or less, in 14 (3.5%) of the 404 patients with postoperative thyroglobulin levels of 0.5 ng/mL or less and in nine (3.2%) of the 277 patients with postoperative thyroglobulin levels of 0.2 ng/mL or less without thyroglobulin antibodies. In all cases, events occurred in both treatment groups (appendix p 9).

Using local thyroglobulin determination, the proportion of patients with an excellent response according to the 2015 American Thyroid Association treatment response definition was higher in the no radioiodine group (295 [83.3%] of 354 patients) than in the radioiodine group (260 [75.6%] of 344 patients), and the proportion of patients with an indeterminate response was higher in the radioiodine group (68 [19.8%]) than in the no radioiodine group (26 [7.3%]; appendix p 10). However, there was no difference in the proportions of patients with structural disease (three [0.9%] in the no radioiodine group and 0 in the radioiodine).

## Discussion

After 5-years of follow-up, we found that a follow-up strategy without a postoperative radioiodine administration is not inferior to a postoperative administration of 1·1 GBq ¹³¹I after recombinant human thyrotropin-stimulating hormone, with an event rate including functional, structural, and biological events of 6·0%. If only structural events are considered, the rate is even lower at 1·1%, and if functional events from the

radioiodine group plus structural events from both groups are considered, the rate of event is 1.6%.

In the literature, the majority of follicular cell-derived thyroid cancer recurrences are consistently reported as being detected within the first 5 years of follow-up.²¹,²² Late recurrences can occur though and the patients from the present study are scheduled for further follow-up. As expected, we observed eight functional or structural events within the first 3 years and three additional structural events during the subsequent 2 years. Similarly, we observed 25 biological events in 23 patients within the first 3 years, and another eight patients had a biological event during the subsequent 2 years. Overall, biological events were more frequent, accounting for 74% of all events. Among the biological events, increases in thyroglobulin levels (61%) were more frequently observed than the appearance or the increase of thyroglobulin antibody titres (31%). Of note, given the high rates of discordance between thyroglobulin and thyroglobulin antibody results from one laboratory assay to another one, clinicians should interpret any thyroglobulin modification or appearance of thyroglobulin antibodies with caution regarding the method used.²³,²⁴ The de novo detection of thyroglobulin antibodies is not always associated with recurrence, whereas the trend of thyroglobulin antibodies usually is.²⁵,²⁶ In the present study we only considered thyroglobulin antibody appearance or increase if generated from the same laboratory assay and confirmed by two consecutive blood tests performed 6 months apart.

The definition of an event including functional or structural events and biological events is the subject of discussion. However, functional or structural events occurred in similar numbers in both groups. Biological events are more difficult to clearly define as recurrent disease. One reason to administer ¹³¹I is to destroy thyroid remnants to facilitate follow-up. We show in the present study that in the absence of ¹³¹I there are no more biological events during the first 5 years of follow-up, that thyroglobulin levels can be reliably interpreted, and that elevation of thyroglobulin antibodies is less

<figure><img src="image_6.png" /><figcaption>Figure 3: Structural or functional and biological events occurring during the 5 years of follow-up</figcaption></figure>
frequent than thyroglobulin elevation. The absence of central thyroglobulin and thyroglobulin antibody determination might have introduced biases but has the advantage of reflecting a real-life assessment. However, the threshold for a thyroglobulin level to be considered as significantly elevated is different whether patients are treated with postoperative ¹³¹I or not. The threshold of 2 ng/mL was chosen in the present study in 2012, based on data that were available at that time on the thyroglobulin levels of patients followed after total thyroidectomy in the absence of postoperative ¹³¹I administration.²⁷,²⁸ In fact, this value is similar to the value derived from a systematic review of the literature.²⁹ This difference in the threshold used explains the difference in the excellent response and the indeterminate response rates according to the American Thyroid Association post-treatment classification.⁴ The main result of the present study is that the rate of incomplete structural response is low and similar in both groups. Thyroglobulin levels at the time of structural disease detection was low (<1 ng/mL) in most patients, which is usually associated to small recurrences with a very good prognosis. Furthermore, the number of subsequent treatments (ie, ¹³¹I or surgery) were similar in both groups. Of note, in an observational study comparing patients submitted to ¹³¹I ablation or not, the rate of biological events (ie, biochemical incomplete or indeterminate response) was higher in patients who did not receive ¹³¹I compared with those who did, but the difference tended to decrease over time.³⁰ We did not take into account the trend of thyroglobulin that could occur during follow-up with a spontaneous decrease of thyroglobulin levels after surgery or after surgery and radioiodine in the absence of any recurrence.²⁸,³¹ We only included fixed thresholds of thyroglobulin levels to define biological recurrence and requested two thyroglobulin measurements 6 months apart in case of thyroglobulin values less than 5ng/mL. Elevation of thyroglobulin levels, in 19 patients (nine in the radioiodine group and ten in the no radioiodine group), was followed by subsequent treatment in ten patients, and among the untreated patients, six (67%) of nine had spontaneous normalisation of serum thyroglobulin levels. This emphasises the fact that when thyroglobulin levels are slightly elevated, there is no emergency to administer empiric activities of radioiodine.²⁸,³¹

Events can occur in patients with low postoperative thyroglobulin levels and even in patients with postoperative thyroglobulin levels less than 0·2 ng/mL, a threshold used for the definition of excellent response for patients treated with ¹³¹I. We confirm that a postoperative thyroglobulin level greater than 1 ng/mL is associated with a higher risk of events. This finding was expected because elevated thyroglobulin levels were included in the definition of an event, similar to the inclusion of thyroglobulin levels in the treatment response classification. Most of the patients that we

treated with ¹³¹I were already cured after surgery, but this has been the standard of care for decades. If we consider the postoperative thyroglobulin level as a parameter to decide for radioiodine administration, which seems reasonable, the number of patients to be treated will decrease drastically.³² Since a thyroglobulin level greater than 1 ng/mL was found to be a prognostic factor for an event in the present study, but the threshold of 2 ng/mL was chosen to monitor the patients without ¹³¹I and to define an event, a cutoff of 2 ng/mL could be used as a threshold to give ¹³¹I to these patients. Persistent disease or uncomplete surgery could then be the reason for ¹³¹I. However, proof that the outcome of these patients will be improved by the ¹³¹I is still needed with prospective studies. In fact, in the present study, among patients with postoperative thyroglobulin levels greater than 1 ng/mL, events occurred both in patients with and without postoperative iodine administration.

Other prognostic factors included age, with a higher risk of an event in patients aged 55–60 years (compared with those aged <55 years), tumour size, with a higher risk of an event in patients with large tumours (compared with small tumours), and histology, with a higher risk of an event in patients with follicular cancers (compared with papillary thyroid cancer). Older age and tumour size are known to be prognostic factors in thyroid cancer. The present multivariate analysis looking at size in a continuous manner showed that size has a prognostic role in the occurrence of events, which is consistent with the literature. Finally, due to the small number of oncocytic cancers, these were included with the follicular cancers, but none of them reported an event. Of note, the pN status was not prognostic for an event, with patients with pNx being treated with total thyroidectomy only and patients with pN0 being treated with total thyroidectomy and neck dissection.

Although per-protocol analysis is considered the primary analysis for a non-inferiority trial compared with an intention-to-treat analysis because of its conservatism, some limitations need to be highlighted even if non-inferiority was observed for both per-protocol and intention-to-treat populations in the present trial. Patients excluded from the per-protocol analysis could have led to selection bias in the per-protocol estimates. These patients (n=78) represented 10% of the intention-to-treat population (n=45 in the experimental group and n=33 in the control group), but patients included or not in the per-protocol population had similar initial characteristics (appendix p 6).

Furthermore, as the definition of an event at 5 years is a composite criterion and differs between groups (eg, functional events are included in the control group but not in the experimental group), a possible measurement bias might exist. Its effect is expected to be low, though, since there were only three functional events observed in the control group. Finally, selection bias due to missing outcomes (missingness) should be discussed.
Missingness is related to the possible effect of missing data on the conclusion. In the present study, 32 patients (4.4% of the cohort; n=19 from the control group and n=13 from the experimental group) had no outcome measurement at 5 years. In most cases, this was due to loss of follow-up before 5 years or due to the absence of the 5-year visit (N=27 patients: n=16 in the control group and n=11 in the experimental group), which occurred in both groups and are not related to the outcome defined by the occurrence of an event or not. Whatever the true value of the outcome (having an event or not) at 5 years should be, the missingness in the outcome data does not depend on its true value.

The conclusions of this study can only apply to patients similar to those included in the study. All patients had total thyroidectomy and even if surgeries were not performed in tertiary centres, one should recognise that many patients were well operated on with thyroglobulin levels being less than 0·2 ng/mL in one third of the patients. Furthermore, not all patients with low-risk thyroid cancer were included in ESTIMABL2, but, all low-risk thyroid cancers have a risk of recurrence of less than 5%, so the impact of postoperative ¹³¹I administration might be difficult to show. Instead, some patients with an intermediate risk of recurrence were enrolled in ESTIMABL2 trial: the inclusion criteria were defined in 2012, before the 2015 American American Thyroid Association risk level definition, and some patients at an intermediate risk of vascular invasion or extra-thyroid extension were enrolled.⁴ The presence of thyroid cancer with vascular invasion and extra thyroid extension was shown in the nested case analysis that was performed, in which among the 90 patients with a central pathology review, 23% had vascular invasion and 15% had minimal extra-thyroid extension.¹⁵ However, reclassifying all patients as being at low or intermediate risk was not possible. We did this in the nested case-control analysis at 3 years of follow-up only for those patients who had a central pathology review.

Notably, our results are consistent with the results of the randomised phase 3 trial, IoN, in which 500 patients with low to intermediate risk differentiated thyroid cancer were randomly assigned to follow-up without postoperative ¹³¹I administration or to postoperative administration of ¹³¹I (ie, 30 mCi after recombinant human thyrotropin-stimulating hormone). Surveillance appeared to be non-inferior to ¹³¹I administration with a 3-year recurrence-free rate of 98·4% in the absence of ¹³¹I and 96·2% in the radioiodine group.¹³ Only structural events were considered in the IoN study.

In conclusion, the non-inferiority of a follow-up strategy compared with the postoperative administration of ¹³¹I in low-risk thyroid cancer already reported at 3 years was confirmed at 5 years. There is no loss of opportunity in following these patients without postoperative ablation.

Contributors

SL, IB, and MS conceived the study and contributed to the study design and protocol development. IB drafted the statistical analysis plan.

IB and SL accessed and verified the underlying data reported in the manuscript. IB did the statistical analyses. SL wrote the first draft of the manuscript. All authors made substantive comments thereon and approved the final version for submission. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Declaration of interests

LL declares consultancy fees from EISAI, IPSEN, and Eli Lilly. SL declares consultancy fees from EISAI, Eli Lilly, and Bayer. All other authors declare no competing interests.

Data sharing

Anonymised data can be requested after publication from the corresponding author to be shared subject to the approval of all institutional review boards.

Acknowledgments

The study was funded by the French Ministry of Health through the National Institute for Cancer (grant obtained in 2012). We thank the patients, their families, all research staff, and investigators involved in this study and Nathalie Bouvet, Catherine Richon, and Thibaud Motreff.

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