PubMed, Scopus, and ScienceDirect databases were used as a comprehensive literature search database, from inception to March 2025, to identify studies that evaluate the risk of SPMs following RAI therapy in patients with TC. A search strategy was employed using a mix of keywords and MeSH (Medical Subject Headings) terms pertinent to thyroid cancer, radioactive iodine, and secondary primary malignancies. The specific search terms included: (“thyroid cancer” OR “thyroid carcinoma” OR “differentiated thyroid carcinoma”) AND (“radioactive iodine” OR “radioiodine” OR “I-131”) AND (“second primary malignancy” OR “second cancer” OR “second primary neoplasm”). Additionally, the reference lists of eligible articles and relevant reviews were manually screened to identify further studies.

Studies were considered eligible in this study if they fulfilled inclusion criteria: (1) original observational articles; (2) enrolled patients with histologically confirmed TC; (3) compared patients who received RAI with those who did not; (4) reported the number of SPM events and total patients in each group or provided effect estimates (risk ratio [RR], hazard ratio [HR], or odds ratio [OR]) with 95% confidence intervals (CI); and (5) reported a minimum follow-up duration of at least 2 years after thyroid cancer diagnosis. Studies were excluded under the following criteria: (1) they reported only synchronous malignancies, recurrences, or metastases; (2) lacked a non-RAI comparison group; and (3) were case reports, editorials, reviews, or conference abstracts.

Two independent reviewers were responsible for screening the titles, abstracts, and full texts of the literature to determine eligibility and for extracting relevant data from the included studies. A third party resolved any discrepancies. The extracted data comprised the following elements: the first author, year of publication, country of study, study design, population size, number of patients who received RAI, number of patients who did not receive RAI, the number of SPM events in each group, and the mean or median duration of follow-up.

The primary objective of the study was to evaluate the likelihood of patients diagnosed with TC developing non-thyroidal SPMs following treatment with RAI. This was compared to the risk faced by patients who did not receive RAI as part of their treatment regimen. The effect measure was the natural logarithm of the RR (logRR), which was pooled across studies and then back-transformed to RR for interpretability. Secondary outcomes included pooled RR estimates stratified by tumor site and the predefined subgroup variables.

The methodological quality of the studies included in the analysis was assessed using the Newcastle-Ottawa Scale (NOS), which evaluates three key domains: selection, comparability, and assessment of outcome/exposure. Studies that received a score of 7 points or higher were categorized as high-quality, while those scoring between 5 and 6 points were classified as moderate-quality. Studies with scores below 5 points were regarded as low quality. Two authors independently evaluated the risk of bias, and a third-party adjudicator resolved any discrepancies that emerged.

All statistical analyses were performed using Stata version 17.0 (StataCorp LLC, College Station, TX, USA). LogRRs and SEs were calculated for each study, and pooled using a random-effects model (DerSimonian–Laird method) to account for between-study heterogeneity. Results were presented as pooled RRs with 95% CIs. Statistical heterogeneity was evaluated using Cochran’s Q test (p < 0.10 indicating significant heterogeneity) and quantified with the I ² statistic, with values of 25%, 50%, and 75% considered low, moderate, and high heterogeneity, respectively.

Leave-one-out sensitivity analyses were conducted to evaluate the influence of individual studies on the overall pooled effect. Subgroup analyses were performed in Stata to explore differences in effect estimates across predefined study-level variables, including publication year, follow-up duration, and population size. A two-sided p-value of <0.05 was considered statistically significant.

A total of 2,361 records were identified from electronic databases. After removing duplicates and ineligible records, followed by screening and full-text assessment, 18 articles were included in this study. ^{10– 27} Subsequent citation searching yielded two articles that were included in the current analysis. The complete screening process is outlined in the PRISMA flowchart ( Figure 1).

A total of 1,189,992 patients diagnosed with thyroid cancer were included in this analysis, drawn from eighteen studies. Among these patients, 638,275 received treatment with RAI, whereas 551,717 did not undergo this treatment. The studies, published between 2003 and 2023, primarily utilized retrospective or population-based cohort designs and were conducted in various countries, including South Korea, the United States, several European nations, China, Taiwan, Israel, Saudi Arabia, and Brazil. Follow-up durations ranged from 2 to 16.2 years, with the majority of studies focusing on papillary or follicular thyroid carcinoma. Comprehensive baseline characteristics are presented in Table 1.

The evaluation of the study quality revealed that 11 studies were rated as of good quality, with scores ranging from 7 to 9; six were considered of fair quality, receiving scores of 5 to 6; and one was identified as of poor quality, earning a score of 3 ( Table 2). Most population-based studies (e.g., Rubino et al. 2003; Bhattacharyya & Chien, 2006; Kim et al., 2023; Pasqual et al., 2022) demonstrated clear cohort selection, strong outcome ascertainment through cancer registries, and adequate follow-up durations. In contrast, several institutional studies faced challenges due to limited sample sizes and insufficient adjustment for confounding variables.

The pooled analysis revealed no statistically significant elevation in the risk of SPMs among the RAI-treated cohort. The pooled RR was calculated to be 1.07 (95% confidence interval: 0.96–1.21; p = 0.23), with substantial heterogeneity noted (I ² = 95.96%; see Figure 2). Leave-one-out sensitivity analysis yielded a robust result, as the sequential omission of each study resulted in a pooled logRR that remained consistent with all comparable p-values ( Figure 3).

Subgroup analyses were performed to investigate potential factors contributing to the heterogeneity in the relationship between RAI therapy and the incidence of SPMs among TC survivors, as detailed in Table 3. No significant differences were observed by publication year (≤2015: logRR = 0.08; >2015: 0.07), follow-up duration (≤10 years: 0.08; >10 years: –0.03), or population size (≤10,000: 0.17; >10,000: 0.04). Similarly, site-specific analyses showed no significant increase in risk for any tumor group, including breast (–0.09), genitourinary (0.36), gastrointestinal/hepatobiliary (–0.15), respiratory (–0.22), skin (–0.02), hematologic (–0.16), central nervous system (0.03), and head and neck (0.15). Overall, none of the predefined subgroups significantly modified the association between RAI therapy and SPM risk.

The evaluation of publication bias was conducted by creating a funnel plot and performing Egger’s regression test. The funnel plot indicated an approximately symmetrical distribution of effect sizes around the pooled estimate, with only minor deviations among studies that had larger standard errors, suggesting the absence of significant asymmetry (see Figure 4). Furthermore, Egger’s regression test did not indicate any evidence of small-study effects, with a bias coefficient of -0.53 (95% CI: -2.66 to 1.60; p = 0.609).

Zenodo: Risk of second primary malignancies following radioactive iodine therapy in thyroid cancer: A meta-analysis of 1,189,992 patients. Doi: https://doi.org/10.5281/zenodo.17350685 ³¹

This project contains the following underlying data: •

PRISMA_2020_checklist.pdf

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Zenodo: Risk of second primary malignancies following radioactive iodine therapy in thyroid cancer: A meta-analysis of 1,189,992 patients, Doi: https://doi.org/10.5281/zenodo.17361573 ³²

The Project contains the following reporting guidelines: •

PRISMA Flow.jpg

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Zenodo: Risk of second primary malignancies following radioactive iodine therapy in thyroid cancer: A meta-analysis of 1,189,992 patients, Doi: https://doi.org/10.5281/zenodo.17361311 ³³

The Project contains the following reporting guidelines: •

PRISMA Checklist Updated.docx

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).