Age-Specific Risk of Second Primary Malignant Neoplasm After Radioactive Iodine Treatment for Differentiated Thyroid Cancer

Importance Radioactive iodine treatment for differentiated thyroid cancer has been associated with second primary malignant neoplasms, but age-specific risks remain poorly understood. Objective To evaluate the association of age with increased risk of second primary malignant neoplasm after radioactive iodine treatment for differentiated thyroid cancer (DTC). Design, Setting, and Participants This retrospective cohort study used data from 8 cancer registries in the US National Cancer Institute’s Surveillance, Epidemiology, and End Results Program for 1975 to 2021. Patients who received radioactive iodine treatment for DTC were identified; those with fewer than 2 years of follow-up, missing follow-up data, or distant metastases at diagnosis were excluded. Included patients were categorized into 3 age groups: 15 to 44, 45 to 64, and 65 years or older. Among 5-year survivors, median (IQR) follow-up time was 14.7 (8.6-24.0) years in the 15- to 44-year age group; 8.3 (6.4-11.4) years in the 45- to 64-year group; and 9.3 (6.9-12.7) years in the 65 years or older group. Data were analyzed from May to July 2024. Exposure Radioactive iodine vs no radioactive iodine. Main Outcomes and Measures Relative risks (RR) and 95% CIs for solid and hematologic second primary malignant neoplasms, calculated using multivariable Poisson regression models adjusted for age, sex, and latency. Results The study sample comprised 72 412 patients with nonmetastatic DTC, of whom 28 432 (39%) were age 15 to 44 years; 34 009 (47%), age 45 to 64 years; and 9971 (14%), 65 years or older. In the 15- to 44-year age group, radioactive iodine was associated with an increased risk of hematologic cancers (RR, 1.35; 95% CI, 1.02-1.80), specifically myeloma (RR, 4.22; 95% CI, 1.68-10.62). In the 45- to 64-year age group, the analyses showed increased risks of prostate cancer (RR, 1.61; 95% CI, 1.10-2.37), salivary gland cancer (RR, 10.22; 95% CI, 1.27-82.24), and nodal non-Hodgkin lymphoma (RR, 2.81; 95% CI, 1.34-5.89). The overall risk of a solid second primary malignant neoplasm was not elevated (RR, 0.94; 95% CI, 0.76-1.16), but hematologic second primary malignant neoplasm risk was elevated (RR, 1.73; 95% CI, 1.14-2.60). Patients in the group that was 65 years and older showed elevated risks of stomach (RR, 4.06; 95% CI, 1.05-15.81), esophagus (RR, 11.42; 95% CI, 1.40-93.3), nonepithelial skin cancers (RR, 10.52; 95% CI, 1.09-88.77), and acute myeloid leukemia (RR, 3.26; 95% CI, 1.15-9.24). The overall risk of a solid second primary malignant neoplasm was elevated (RR, 1.88; 95% CI, 1.59-2.21), whereas risk of hematologic malignant neoplasm was not (RR, 1.35; 95% CI, 0.97-1.87). Conclusions and Relevance This cohort study found that the risk of radioactive iodine−associated second primary malignant neoplasm among patients who received radioactive iodine for DTC varies significantly by age group, with distinct patterns in middle-aged compared with older adults. These findings suggest a need for age-specific surveillance strategies in radioactive iodine−treated DTC survivors. Further research is needed to establish optimal screening protocols.