Dropping Radioiodine Doesn’t Drop Outcomes in Low-Risk Thyroid Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. Lancet Diabetes Endocrinol, 2025;13(1):38-46; doi: 10.1016/S2213-8587(24)00276-6. PMID: 39586309.
  • Background:
    • Radioiodine (RAI) has historically been used as an adjuvant therapy after total thyroidectomy for differentiated thyroid cancer (DTC) to ablate remnant thyroid tissue and reduce recurrence risk
    • However, for low-risk DTC, characterized by:
      • Tumors ≤ 2 cm without extrathyroidal extension or lymph node or distant metastases:
        • The benefit of routine RAI remains uncertain
    • Recent guidelines, including those from the American Thyroid Association (ATA):
      • Suggest that RAI may be safely omitted in select low-risk cases:
        • But prospective data confirming this approach have been limited
  • Methods:
    • This was a multicenter, prospective, randomized, phase 3 study designed to assess whether omitting RAI affects oncologic outcomes in patients with low-risk DTC
    • Eligible patients were 18 to 75 years old, had undergone total thyroidectomy, and had pT1a-pT2N0 / NxM0 disease with no aggressive histologic features
    • Participants were randomly assigned (1:1) to either thyroidectomy alone (no RAI) or thyroidectomy followed by low-dose RAI (1.1 GBq, approximately 30 mCi)
    • Both groups received thyroid stimulating hormone (TSH) suppression therapy according to guidelines
    • The primary outcome was disease-free survival (DFS) at 5 years:
      • Assessed by determination of a structural disease event based on serial neck ultrasonography, a biochemical event based on thyroglobulin (Tg) and Tg antibody monitoring, or a functional event based on posttherapeutic RAI whole-body scanning (WBS)
    • Diagnostic WBS during surveillance was not performed, since it is not considered standard for low-risk DTC
    • Secondary outcomes included recurrence rate, quality of life (QoL), and adverse effects related to RAI
    • Statistical analysis was conducted using an intention-to-treat (ITT) approach, with Kaplan–Meier estimates for DFS and Cox proportional-hazards models for recurrence risk
    • This study aimed to provide high-level evidence guiding de-escalation strategies in low-risk DTC management
  • Results:
    • The study included 730 patients with low-risk DTC who were randomly assigned to thyroidectomy alone (n = 365) or thyroidectomy followed by low-dose RAI therapy (1.1 GBq, n = 365)
    • Among 698 patients evaluable at 5 years, the proportions without an event were 93.2% in the no-RAI group and 94.8% in the RAI group, a difference of –1.6% (90% CI, –4.5 to 1.4)
    • Event occurrences were structural or functional abnormalities (n = 11: five in the RAI group and six in the no RAI group) and biologic abnormalities (n = 31; 13 in the RAI group and 18 in the no-RAI group)
    • After randomization and initial treatment (RAI or not), 11 patients in each group underwent a subsequent treatment consisting of additional surgery and / or RAI (131I) therapy
    • Postoperative serum thyroglobulin level of > 1 ng/ml measured during TSH suppression, patient age between 55 and 60 years, follicular histology, and larger tumor size were predictive of an event
    • The recurrence rate remained low and comparable between groups
    • No significant differences were observed in overall survival, and there were no cases of distant metastases in either group
    • Patients in the no-RAI group reported better QoL scores, with lower rates of fatigue, salivary gland dysfunction, and dry mouth, consistent with prior reports on RAI-related adverse effects
  • Conclusions:
    • These findings support a de-escalation strategy in the postoperative management of low-risk DTC, reinforcing that thyroidectomy alone is sufficient in appropriately selected patients
    • This trial provides high-level evidence to guide modern risk-adapted treatment strategies and aligns with evolving guidelines recommending a more conservative approach while maintaining oncologic outcomes and improving QoL scores
  • De-escalation trends for low-risk DTC have been suggested and even recommended in guidelines for many years; however, these recommendations lacked the backing of data from sufficiently large randomized controlled trials, which was the aim of this study
  • The group published their initial 3-year findings in the New England Journal of Medicine in 2022, showing noninferiority at 3 years of surveillance alone after initial surgical treatment in over 700 randomly assigned patients
  • Numerous retrospective studies and systematic reviews have also pointed to the safety of omitting radioiodine ablation for low-risk DTC
  • The strengths of the study include its prospective, randomized, multicenter design, which reduces selection bias and enhances the reliability of the data
  • The study also had clinically relevant, comprehensive, and patient-centered end points, including its primary end point of disease-free survival, and secondary outcomes, including recurrence rates and, importantly, quality of life
  • The inclusion of patients from several centers and adherence to ATA low-risk criteria make the study findings more generalizable and directly applicable in clinical practice
  • The study does have several shortcomings:
    • It focuses strictly on low-risk DTC, excluding intermediate-risk patients, thus limiting the ability to extrapolate findings to patients with larger tumors or minimal lymph node involvement
    • Additionally, the study included only T1Nx or T1N0 tumors, which were overwhelmingly of papillary histology, with only 3% follicular and 1% oncocytic, making it difficult to confidently apply the findings to these other thyroid cancer types
    • In our current era, it is also unfortunate that the authors do not report molecular profiles for the tumors that recurred and those that did not
    • Lastly, despite 5 years being a reasonable time frame for follow-up, given the indolent nature of DTC, it is possible that a longer follow-up (10 to 20 years) is needed to confirm sustained low recurrence rates
    • I found most astonishing was to see that patients enrolled in this study routinely underwent total thyroidectomy for T1 disease and that many of these patients also underwent central and even lateral neck dissections for clinically N0 disease
  • It is important to have rigorous studies to prove the safety and efficacy of our treatment paradigms
  • This study supports reducing overtreatment of low-risk thyroid cancer without compromising patient outcomes and shows improvement in patients’ quality of life with treatment de-escalation
  • Key points of the study
    • Omitting RAI does not compromise oncologic outcomes:
      • At 5-years, disease-free survival and recurrence rates were not significantly different between those who received RAI and those who did not
    • Patients in the non-RAI group reported better quality-of-life scores with less fatigue and fewer salivary gland complications
  • The ESTIMABL2 trial findings validate de-escalation strategies and align with dynamic risk assessment to identify individualized treatment considering risk-adapted management
  • References:
    • Schlumberger M, Leboulleux S, Catargi B, et al. Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial. Lancet Diabetes Endocrinol 2018;6(8):618-626.
    • Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.
    • Lamartina L, Durante C, Filetti S, Cooper DS. Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review of the literature. J Clin Endocrinol Metab 2015;100(5):1748-1761.
    • Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. Lancet Diabetes Endocrinol 2025;13(1):38-46.
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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