Abstract
KEY POINTS
Relative survival, a robust survival measure, favored radioactive iodine (RAI) therapy in several differentiated thyroid cancer subgroups.
Clinically meaningful survival benefits emerged mainly in intermediate- and high-risk papillary thyroid cancer and in follicular thyroid cancer (FTC), including minimally invasive FTC.
No subgroup demonstrated a detrimental effect of RAI on long-term relative survival.
SUMMARY
Background
The role of postoperative radioactive iodine (RAI) therapy in differentiated thyroid cancer (DTC) remains controversial, particularly in patients with low- and intermediate-risk diseases. Although American Thyroid Association (ATA) and European Thyroid Association guidelines have restricted routine RAI use largely to high-risk patients,1,2 real-world practice varies widely across regions. A major limitation for these recommendations is the scarcity of long-term prospective survival data, especially across histologic subtypes and recurrence risk categories. Importantly, prior population-based studies have relied primarily on overall or cancer-specific survival, both of which may be biased by misclassification of cause of death.
Methods
Using the SEER database (2000–2020), Weis et al. 3 analyzed 101,087 adults with papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC), stratified a priori by histologic subtype and recurrence risk category. Patients were categorized as very low risk (pT1aN0), low risk (pT1bN0), intermediate risk (pT3N0, pT1-3N1, or with minimal extrathyroidal extension), or high risk (pT3-4N1, gross extrathyroidal extension, or M1 disease) based on existing criteria. 4 Long-term outcomes were assessed using relative survival, a net survival metric that compares observed survival with expected survival in a cancer-free population. Relative survival was compared between thyroid cancer patients treated with or without RAI at 3, 5, and 10 years using a dedicated z-test designed for this purpose. 5
Results
Across most subgroups, relative survival was higher or trended higher among thyroid cancer patients who were treated with RAI. In patients with PTC, significant benefits were observed in those who had lymph node involvement, larger tumor size, or high-risk disease. The absolute 10-year survival gains ranged from approximately 1% to 2% for patients in intermediate-risk groups to over 10% for patients in the high-risk groups. In the FTC, survival benefits were even more pronounced, reaching up to 30.9% in patients with high-risk disease. Notably, even low-risk, minimally invasive FTC showed a trend toward improved 10-year relative survival (+2.0%, P = 0.055).
Conclusions
In this large population-based analysis, RAI therapy was associated with improved long-term relative survival in selected low-, intermediate-, and high-risk DTC subgroups, without evidence of a negative effect on relative survival in any patient category.
COMMENTARY
This study by Weis et al. represents a methodologically thoughtful population-based analysis addressing the long-debated survival impact of RAI therapy in DTC. By prioritizing relative survival rather than cancer-specific survival, the authors mitigate misclassification of cause of death, which is a critical limitation of registry-based studies and particularly relevant in an indolent disease affecting older patients.
From a clinical standpoint, the findings resonate strongly with scenarios encountered in daily practice. Although the omission of RAI in truly low-risk PTC is increasingly accepted based on high-quality prospective data,6,7 uncertainty often arises in patients with borderline features, such as minimal extrathyroidal extension, limited nodal disease, or follicular histology. The demonstration of consistent, time-dependent survival advantages in intermediate-risk PTC and across multiple FTC categories suggests that the pendulum may have swung too far toward de-escalation in some patient subsets. When applying these data, it is important to consider that the definitions of risk used in this study for the categorization of patients (from very low to high) had particular pathologic definitions, which are not identical to other existing criteria, such as the ATA risk of recurrence.
Particularly compelling is the signal observed in minimally invasive FTC, a condition frequently managed conservatively due to its traditionally favorable prognosis. Although the absolute survival gain appears modest, the delayed divergence of survival curves underscores the importance of long-term follow-up when evaluating therapeutic benefit in DTC. As someone who follows FTC patients for decades, I find these data highly relevant and potentially practice informing.
This study does not advocate indiscriminate RAI use. Instead, it reinforces the concept of individualized risk-adapted therapy, integrating histology, nodal status, tumor burden, and patient age, while acknowledging the long natural history of DTC. In my practice, these results support a more nuanced discussion with intermediate-risk patients, particularly those with FTC or nodal PTC, regarding the potential long-term survival implications of RAI therapy.