The association of radioactive iodine (RAI) with disease-specific survival (DSS) is controversial in N1b papillary thyroid carcinoma (PTC). We aimed to evaluate whether RAI is associated with DSS in low-to-intermediate-risk N1b PTC. The Surveillance, Epidemiology, and End Results database was queried for pT1-3, N1b, M0/Mx classic PTC treated with total thyroidectomy. Multivariable Cox regression was performed to identify predictors of DSS. Subanalyses were conducted for age, intermediate-risk versus otherwise low-risk features, and positive lymph node ratio (LNR) > 0.17. Radioactive iodine recipients were younger (43.0 vs. 44.0 years, p = 0.036) with increased capsular or local invasion (49.2% vs. 41.9%, p < 0.001) and median LNR (0.37 vs. 0.33, p = 0.001). Worse DSS was associated with age (adjusted-HR = 1.09, p < 0.001), tumor size (adjusted-HR = 1.02, p < 0.001), and local invasion (adjusted-HR = 1.86, p = 0.003). Radioactive iodine was associated with improved DSS in the whole cohort (adjusted-HR = 0.61, p = 0.014), in patients ≥ 55 years (adjusted-HR = 0.48, p = 0.001) and in patients ≥55 years with LNR > 0.17 (adjusted-HR = 0.45, p = 0.001) but not LNR ≤ 0.17. Radioactive iodine was not associated with a DSS benefit in patients < 55 years even when stratified by LNR 0.17. Radioactive iodine administered to patients with at least one intermediate-risk feature (> 5 pathologic LNs or any local invasion) was associated with improved DSS (adjusted-HR = 0.60, p = 0.019) but not those with otherwise low-risk features (adjusted-HR = 0.71, p = 0.502). Radioactive iodine is associated with improved DSS in N1b PTC patients with intermediate-risk features, age ≥ 55 years, and LNR > 0.17 in older patients, but not in patients with otherwise low-risk features. These factors could help guide RAI utilization in N1b PTC.
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