Comparison of Low-Dose and High-Dose Radioactive Iodine Adjuvant Therapy in Intermediate-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study

Comparison of Low-Dose and High-Dose Radioactive Iodine Adjuvant Therapy in Intermediate-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of Low-Dose and High-Dose Radioactive Iodine Adjuvant Therapy in Intermediate-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study Wasit Kanokwongnuwat This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9250941/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background The optimal activity of radioactive iodine (RAI) for adjuvant therapy in intermediate-risk differentiated thyroid cancer (DTC) remains uncertain. This study aimed to compare treatment response and recurrence outcomes between low-dose and high-dose RAI in this population. Methods In this retrospective cohort study, intermediate-risk DTC patients treated with total thyroidectomy followed by adjuvant RAI were included. Patients received either low-dose (30 mCi) or high-dose (≥100 mCi) RAI. Treatment response at 6-8 months was classified according to American Thyroid Association criteria and dichotomized as excellent versus non-excellent response. Structural disease–free survival was analyzed using Kaplan-Meier and Cox regression methods. Results A total of 113 patients were included (low-dose: n=52; high-dose: n=61). Excellent response was observed in 67.3% of the low-dose group and 54.1% of the high-dose group (p=0.15). RAI dose was not associated with excellent response in multivariable analysis (OR 0.65, 95% CI 0.27–1.55, p=0.33). During a median follow-up of 34 months, RAI dose was not associated with recurrence-free survival (HR 1.17, 95% CI 0.38–3.66, p=0.79). Lymph node metastasis and tumor size were independent predictors of both poorer response and recurrence. Conclusions Low-dose RAI provides comparable treatment response and recurrence outcomes to high-dose RAI in intermediate-risk DTC. Disease burden, rather than RAI activity, appears to be the primary determinant of outcome, supporting a risk-adapted approach and consideration of lower RAI activities in appropriately selected patients. Trial registration Registry: https://www.thaiclinicaltrials.org/ Trial registration number: TCTR20260313002 Date of registration: 11 March 2026, retrospectively registered Data of registration: https://www.thaiclinicaltrials.org/export/pdf/TCTR20260313002 Intermediate risk. Thyroid cancer Radioactive iodine (RAI) Low dose High dose Excellent response Response to therapy Figures Figure 1 Figure 2 Introduction Differentiated thyroid cancer (DTC) is the most common endocrine malignancy and generally has an excellent prognosis (1). Standard treatment typically includes total thyroidectomy followed by risk-adapted postoperative management. Radioactive iodine (RAI) therapy has historically been used to ablate remnant thyroid tissue, facilitate long-term surveillance using serum thyroglobulin, and treat microscopic residual disease. Recent guidelines recommend a risk-adapted approach to postoperative RAI therapy. While RAI therapy is routinely used in high-risk patients, its role in intermediate-risk disease remains more controversial (2, 3). In these patients, RAI is often administered as adjuvant therapy, with the goal of reducing recurrence risk by targeting possible microscopic residual disease. Traditionally, relatively high RAI activities, typically 100–150 mCi, have been used for adjuvant therapy. However, growing evidence suggests that lower activities may provide similar therapeutic benefits while reducing radiation exposure and treatment-related adverse effects (4-6). Lower RAI doses may also reduce healthcare costs and minimize radiation exposure to both patients and healthcare personnel. Despite increasing interest in dose reduction strategies, data comparing different RAI activities for adjuvant therapy in intermediate-risk patients remain limited. Therefore, this study aimed to compare treatment response between low-dose and high-dose RAI adjuvant therapy in patients with intermediate-risk differentiated thyroid cancer treated at a tertiary care center. Methods Study Design and Population This retrospective cohort study was conducted at a tertiary care hospital. Medical records of patients with differentiated thyroid cancer who underwent total thyroidectomy followed by radioactive iodine therapy were reviewed from September 2005 to July 2025. We performed this study under the approval of the Ethics Committee of the Phrapokklao Hospital, Chanthaburi, Thailand (Approval No. 031/69). The need of the written informed consent was waived by the ethic committee. Patients were eligible for inclusion if they met the following criteria: (1) histologically confirmed differentiated thyroid cancer, (2) intermediate-risk disease based on clinicopathologic features, (3) total thyroidectomy or completion thyroidectomy, (4) receipt of postoperative RAI therapy, and (5) available clinical follow-up data approximately 6-8 months after therapy. Patients were excluded if they had distant metastasis at diagnosis, prior RAI therapy before the study period, or incomplete clinical data. Radioactive Iodine Adjuvant Therapy Following thyroidectomy, patients received radioactive iodine therapy as adjuvant therapy according to institutional clinical practice. TSH stimulation was achieved through thyroid hormone withdrawal. Patients were categorized according to the administered RAI activity: (1) low-dose RAI: 30 mCi and (2) high-dose RAI: ≥100 mCi. A post-therapy whole-body scan was performed after RAI administration to assess iodine uptake and identify possible residual or metastatic disease. Definition of Intermediate-Risk Disease Intermediate-risk DTC was defined according to the ATA risk stratification system (1). Patients were classified as intermediate risk if they had one or more of the following features: microscopic extrathyroidal extension, cervical lymph node metastasis (<3 cm), aggressive histological variants, vascular invasion, or microscopic positive surgical margins. Microscopic positive margin was defined as the presence of tumor cells at any surgical resection margin on histopathological examination. Margin location was not consistently available and was therefore not analyzed separately. Follow-Up and Response Assessment Patients were followed with periodic clinical evaluation, including serum thyroglobulin measurement, anti-thyroglobulin antibody testing, neck ultrasonography, and additional imaging when clinically indicated. Initial treatment response was assessed at approximately 6–8 months after RAI therapy and classified according to the ATA response-to-therapy system as: (1) excellent response, (2) indeterminate response, (3) biochemical incomplete response, and (4) structural incomplete response. For the primary analysis, treatment response was dichotomized into excellent and non-excellent response, with non-excellent response including indeterminate, biochemical incomplete, and structural incomplete categories. Definitions of Response Treatment response was classified according to the American Thyroid Association (ATA) response-to-therapy system (1). Excellent response was defined as nonstimulated Tg <0.2 or stimulated Tg<1 and negative imaging. Indeterminate response was defined as nonspecific findings on imaging or nonstimulated Tg 0.2-1 or stimulated Tg 1-10 or stable /declining Tg levels. Biochemical incomplete response was defined as nonstimulated Tg >1 or stimulated Tg >10 or increasing TgAb levels and negative imaging. Structural incomplete response was defined as structural evidence of disease (suspicious imaging or biopsy proven local or distant metastasis). Time-to-Event Outcomes For secondary outcome analysis, structural disease–free survival was evaluated. Structural disease was defined as the presence of persistent or recurrent structural disease identified by imaging or histopathological confirmation. Follow-up time was calculated from the date of RAI to the date of detection of structural disease or last clinical follow-up. Patients who developed structural disease during follow-up were considered to have an event, and time-to-event was defined as the interval between surgery and the date of detection of structural disease. Patients with structural incomplete response at initial assessment were considered to have persistent disease and assigned an event at the time of first evaluation (6–8 months). Patients without evidence of structural disease were censored at the date of last follow-up. Data Collection Clinical and pathological data were extracted from electronic medical records. Variables collected included: age at diagnosis, sex, tumor size, multifocality, extrathyroidal extension, lymphovascular invasion, lymph node metastasis, aggressive histological variants (including tall cell, hobnail, columnar cell, solid, and diffuse sclerosing variants), microscopic positive margin, administered RAI activity, and treatment response at 6–8 months. Statistical Analysis Continuous variables were expressed as mean ± standard deviation or median with range, as appropriate. Categorical variables were presented as frequencies and percentages. Baseline characteristics between low-dose and high-dose RAI groups were compared using the independent t-test or Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. Logistic regression analysis was performed to identify factors associated with excellent response. Variables with clinical relevance or p < 0.10 in univariate analysis were included in multivariable models. Odds ratios (OR) with 95% confidence intervals (CI) were reported. Time-to-event outcomes were analyzed using the Kaplan–Meier method to estimate structural disease–free survival, and differences between groups were compared using the log-rank test. Cox proportional hazards regression analysis was performed to identify factors associated with structural disease, with results reported as hazard ratios (HR) and 95% confidence intervals (CI). A two-sided p-value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics (version 30.0). Results Patient Characteristics A total of 113 patients with intermediate-risk differentiated thyroid cancer were included in the analysis. Among them, 52 patients (46%) received low-dose radioactive iodine (RAI) therapy (30 mCi), while 61 patients (54%) received high-dose RAI therapy (≥100 mCi). Baseline characteristics are shown in Table 1. The mean age and sex distribution were comparable between groups. Tumor size, multifocality, T stage, lymphovascular invasion, aggressive histology, and margin status were also similar. However, patients in the high-dose group demonstrated more advanced disease features, including a higher prevalence of lymph node metastasis (34.4% vs. 17.3%, p = 0.04) and extrathyroidal extension (36.1% vs. 13.5%, p = 0.006), suggesting a tendency toward administering higher RAI doses in patients with higher-risk disease. Table 1. Baseline characteristics of patients according to RAI dose Characteristic Low dose (n=52) High dose (n=61) p-value Age (years), mean ± SD Female sex, n (%) Tumor size (cm), median (range) Multifocality, n (%) T stage (T3), n (%) N stage (N1), n (%) Extrathyroidal extension, n (%) Lymphovascular invasion, n (%) Aggressive histology, n (%) Positive margin, n (%) 45.5 ± 12.1 43 (82.7%) 3 (1.5-5) 17 (34%) 23 (46%) 9 (17.3%) 7 (13.5%) 27 (51.9%) 4 (7.7%) 7 (13.5%) 46.2 ± 14.5 54 (88.5%) 3.2 (2.2-4.8) 28 (46.7%) 32 (54.2%) 21 (34.4%) 22 (36.1%) 38 (62.3%) 10 (16.4%) 15 (24.6%) 0.1 0.38 0.64 0.2 0.39 0.040* 0.006* 0.27 0.17 0.14 Continuous variables compared using t-test or Mann–Whitney U; categorical variables using chi-square or Fisher’s exact test Early Treatment Response At 6–8 months following RAI therapy, an excellent response was achieved in 35 patients (67.3%) in the low-dose group and 33 patients (54.1%) in the high-dose group. Non-excellent response was observed in 17 patients (32.7%) and 28 patients (45.9%) in the low-dose and high-dose groups, respectively. There was no statistically significant difference in treatment response between the two groups (p = 0.15) (Table 2). In multivariable logistic regression analysis, RAI dose was not associated with excellent response. However, male sex (OR 0.25, p = 0.03), maximal tumor size (OR 0.76, p = 0.01) and lymph node metastasis (OR 0.18, p < 0.001) were independently associated with a lower likelihood of achieving an excellent response (Table 3.). Table 2. Treatment response at 6-8 months according to RAI dose Response Low dose (n=52) High dose (n=61) p-value Excellent Non-excellent 35 (67.3%) 17 (32.7%) 33 (54.1%) 28 (45.9%) 0.15 Table 3. Multivariate logistic regression for excellent response Variable Adjusted Odds Ratio 95% Confidence Interval p-value RAI dose (high vs low) Sex (male vs female) N stage (N1 vs N0) Maximal tumor size (cm) 0.65 0.25 0.18 0.76 0.27-1.55 0.07-0.86 0.07-0.49 0.61-0.94 0.33 0.028* <0.001* 0.010* Structural Recurrence The median follow-up time was 34 months (IQR 16-72), with longer time in the high-dose group compared with the low-dose group (49 vs 25 months, p = 0.006). During follow-up, structural recurrence occurred in a minority of patients, with a numerically higher rate observed in the high-dose group compared to the low-dose group (Table 4). Table 4. Structural recurrence according to RAI dose Variable Low dose (n=52) High dose (n=61) p-value Structural recurrence No structural recurrence 5 (9.6%) 47 (90.4%) 11 (18%) 50 (82%) 0.2 Time-to-Event Analysis In Cox proportional hazards analysis (Table 5), RAI dose was not associated with recurrence-free survival (HR 1.17, 95% CI 0.38–3.66, p = 0.79). However, lymph node metastasis (HR 3.38, p = 0.03) and tumor size (HR 1.25 per cm, p = 0.047) were independent predictors of recurrence. Kaplan-Meier analysis demonstrated no significant difference in recurrence-free survival between the low-dose and high-dose groups (log-rank p = 0.45) (Figure 1). Table 5. Multivariable Cox proportional hazards model for structural recurrence Variable Adjusted Hazard Ratio 95% Confidence Interval p-value RAI dose (high vs low) N stage (N1 vs N0) Maximal tumor size (cm) 1.17 3.38 1.25 0.38-3.66 1.12-10.15 1.00-1.56 0.79 0.030* 0.047* Early Response and Recurrence Recurrence occurred exclusively in patients with non-excellent response (35.6% vs 0%, p < 0.001) (Table 6). Kaplan–Meier analysis demonstrated a marked difference in recurrence-free survival between groups, with significantly worse outcomes in patients with non-excellent response (log-rank p < 0.001) (Figure 2). Due to complete separation between early response and recurrence outcomes, regression modeling was not stable, indicating a strong prognostic effect of early treatment response. Table 6. Early response vs structural recurrence Response Recurrence (n, %) No recurrence (n, %) p-value Excellent Non-excellent 0 (0%) 16 (35.6%) 68 (100%) 29 (64.4%) <0.001* Percentages represent row percentages (recurrence within response group) Discussion In this retrospective cohort study of intermediate-risk differentiated thyroid cancer, we found that low-dose RAI (30 mCi) achieved comparable outcomes to high-dose RAI (≥100 mCi) in terms of both early treatment response and recurrence-free survival. Importantly, RAI dose was not independently associated with either outcome after adjustment for clinicopathologic factors. These findings support a risk-adapted approach to RAI therapy, as recommended by current guidelines (1). While higher RAI doses have traditionally been used in intermediate-risk patients, our results suggest that increasing administered activity does not necessarily translate into improved clinical outcomes. A key observation in this study is the presence of confounding by indication. Patients receiving high-dose RAI had significantly higher rates of lymph node metastasis and extrathyroidal extension, reflecting real-world clinical decision-making. Despite this higher-risk baseline profile, outcomes in the high-dose group were not superior, suggesting that tumor biology, rather than RAI dose, is the primary determinant of prognosis. Randomized trials such as HiLo and ESTIMABL1 have demonstrated non-inferiority of low-dose RAI for remnant ablation, with similar long-term outcomes (4, 5). Although conducted in low-risk populations, these findings have influenced broader clinical practice. Emerging observational studies in intermediate-risk patients similarly report no significant advantage of higher RAI doses, supporting a trend toward treatment de-escalation in appropriately selected patients. In our study, lymph node metastasis and tumor size were the strongest predictors of both poorer early response and structural recurrence, consistent with prior literature (7-11). Male sex was also associated with a lower likelihood of achieving an excellent response. These findings reinforce that baseline disease burden and tumor characteristics are the key determinants of outcome and should guide risk stratification and management decisions (12, 13). Microscopic positive margin was not significantly associated with treatment response. However, margin location was not analyzed, and its clinical impact may vary depending on anatomical context. Therefore, this finding should be interpreted with caution (14, 15). An important strength of this study is the incorporation of dynamic risk stratification using early treatment response. We observed that recurrence occurred almost exclusively in patients with non-excellent response, confirming that early response is a powerful predictor of long-term outcomes. This finding aligns with previous studies demonstrating that response-to-therapy assessment provides superior prognostic information compared to initial risk stratification alone (16, 17). From a clinical perspective, the lack of benefit associated with higher RAI doses has important implications. Lower RAI activity may reduce radiation exposure, minimize adverse effects such as salivary gland dysfunction, decrease the risk of secondary malignancies, and reduce healthcare costs, without compromising oncologic outcomes (18-21). This study has several limitations. The difference in follow-up duration between groups, with shorter follow-up in the low-dose RAI group, likely reflects evolving clinical practice and increased adoption of lower RAI activities in more recent years. As a result, patients in the low-dose group had less time at risk for recurrence, which may lead to underestimation of recurrence events. Although Kaplan–Meier and Cox regression analyses were used to account for variable follow-up time, residual bias cannot be excluded. In addition, the retrospective design introduces potential selection bias and confounding, and the relatively small number of recurrence events limits statistical power. Longer follow-up is needed to confirm long-term outcomes. Conclusion In patients with intermediate-risk differentiated thyroid cancer, low-dose RAI (30 mCi) provides comparable outcomes to high-dose RAI (≥100 mCi) in both early treatment response and recurrence-free survival. RAI dose was not an independent predictor of recurrence, whereas lymph node metastasis, tumor size, and early treatment response were the primary determinants of outcome. These findings support the use of lower RAI activities in appropriately selected patients, reinforcing a risk-adapted and individualized approach to postoperative management. Abbreviations ATA American Thyroid Association CI Confidence interval DTC Differentiated thyroid cancer ETE Extrathyroidal extension HR Hazard ratio mCi Millicurie OR Odds ratio RAI Radioactive iodine SD Standard deviation TSH Thyroid-stimulating hormone Declarations Acknowledgements None. Author Contributions W.K. designed the study, collected and analysed the data, and wrote the manuscript. Funding This research project is supported by the Medical Education Center, Phrapokklao Hospital. Data availability The data used in this manuscript are subject to local privacy and data protection laws and are not publicly available. Requests for anonymized data review can be directed to the corresponding author. Conflict of interests The author declares no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate declaration This retrospective study was approved by the ethics institutional review board, Chanthaburi Research Ethics Committee/Region 6 of Phrapokklao Hospital (Approval no. 031/69). The requirement for written informed consent was waived due to its retrospective nature. The study was conducted in accordance with the Declaration of Helsinki. Trial registration Registry: https://www.thaiclinicaltrials.org/ Trial registration number: TCTR20260313002 Date of registration: 13 March 2026, retrospectively registered Data of registration: https://www.thaiclinicaltrials.org/export/pdf/TCTR20260313002 References Ringel MD, Sosa JA, Baloch Z, Bischoff L, Bloom G, Brent GA, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid. 2025;35(8):841–985. Lamartina L, Montesano T, Trulli F, Attard M, Torlontano M, Bruno R, et al. 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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):618–26. Abiri A, Nguyen T, Goshtasbi K, Torabi SJ, Kuan EC, Armstrong WB, et al. A comparative analysis of treatment efficacy in intermediate-risk thyroid cancer. Eur Arch Otorhinolaryngol. 2023;280(5):2525–33. Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, et al. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab. 2005;90(10):5723–9. Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. 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Sanabria A, Rojas A, Arevalo J, Kowalski LP, Nixon I. Microscopically positive surgical margins and local recurrence in thyroid cancer. A meta-analysis. Eur J Surg Oncol. 2019;45(8):1310–6. Khan ZF, Kutlu O, Picado O, Lew JI. Margin Positivity and Survival Outcomes: A Review of 14,471 Patients with 1-cm to 4-cm Papillary Thyroid Carcinoma. J Am Coll Surg. 2021;232(4):545–50. Momesso DP, Vaisman F, Yang SP, Bulzico DA, Corbo R, Vaisman M, et al. Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine. J Clin Endocrinol Metab. 2016;101(7):2692–700. Tuttle RM, Alzahrani AS. Risk Stratification in Differentiated Thyroid Cancer: From Detection to Final Follow-Up. J Clin Endocrinol Metab. 2019;104(9):4087–100. Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer. 2003;89(9):1638–44. Piscopo L, Volpe F, Nappi C, Zampella E, Manganelli M, Matrisciano F, et al. Second Primary Malignancies in Patients with Differentiated Thyroid Cancer after Radionuclide Therapy: A Retrospective Single-Centre Study. Curr Oncol. 2022;30(1):37–44. Fard-Esfahani A, Emami-Ardekani A, Fallahi B, Fard-Esfahani P, Beiki D, Hassanzadeh-Rad A, et al. Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma. Nucl Med Commun. 2014;35(8):808–17. Van Nostrand D. Sialoadenitis secondary to (1)(3)(1)I therapy for well-differentiated thyroid cancer. Oral Dis. 2011;17(2):154–61. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 17 May, 2026 Reviewers agreed at journal 11 May, 2026 Reviewers invited by journal 29 Apr, 2026 Editor invited by journal 06 Apr, 2026 Editor assigned by journal 30 Mar, 2026 Submission checks completed at journal 29 Mar, 2026 First submitted to journal 29 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9250941","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":635764159,"identity":"cbe81448-6fbc-46b5-bd30-c3b99d3494cf","order_by":0,"name":"Wasit Kanokwongnuwat","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYJCCAwwMCXIMEgyMByB8HiK0HGBIMAZqYYBoYSNCC1BpQmID0VoMjh9/ePgDQ1p6/+wegwM/GOzkGeR7D+DXcibHAOiwnNwZd84YHOxhSDZsYONLwKvF7EAOyC8VuRskgHp5GJgTgA4zwK/l/PMHIC3pBkAtB/8w1BOh5UYC2GEJIC2HeRgOE9Zif+ONwYEzBmmGM26kFRyWMThu2MaWg1+LZH/64w8VFcny/DOSNz58U1Etz898Br8WCDBAYrARoX4UjIJRMApGAQEAACabRrBLPUGoAAAAAElFTkSuQmCC","orcid":"","institution":"Phrapokklao Hospital","correspondingAuthor":true,"prefix":"","firstName":"Wasit","middleName":"","lastName":"Kanokwongnuwat","suffix":""}],"badges":[],"createdAt":"2026-03-28 08:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9250941/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9250941/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108957065,"identity":"65398c98-bce3-4491-aa19-dc9f679bdc84","added_by":"auto","created_at":"2026-05-11 08:16:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25554,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Curve by RAI dose\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"28Mar14.15KM1.png","url":"https://assets-eu.researchsquare.com/files/rs-9250941/v1/328b51b8e3d4e9fe3f471e78.png"},{"id":108957086,"identity":"951466e8-41c4-49cf-b049-1c26ea70a8f0","added_by":"auto","created_at":"2026-05-11 08:16:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24775,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Curve by Early Response\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"28MarKM2.png","url":"https://assets-eu.researchsquare.com/files/rs-9250941/v1/0688a0a960e7d12500cd4a13.png"},{"id":108957166,"identity":"22db82d1-b7a8-4f72-95f4-da5fb579fe91","added_by":"auto","created_at":"2026-05-11 08:17:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":265495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9250941/v1/113abe4d-a0a4-40e6-a14b-91652255349e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Low-Dose and High-Dose Radioactive Iodine Adjuvant Therapy in Intermediate-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDifferentiated thyroid cancer (DTC) is the most common endocrine malignancy and generally has an excellent prognosis (1). Standard treatment typically includes total thyroidectomy followed by risk-adapted postoperative management. Radioactive iodine (RAI) therapy has historically been used to ablate remnant thyroid tissue, facilitate long-term surveillance using serum thyroglobulin, and treat microscopic residual disease.\u003c/p\u003e\n\u003cp\u003eRecent guidelines recommend a risk-adapted approach to postoperative RAI therapy. While RAI therapy is routinely used in high-risk patients, its role in intermediate-risk disease remains more controversial (2, 3). In these patients, RAI is often administered as adjuvant therapy, with the goal of reducing recurrence risk by targeting possible microscopic residual disease.\u003c/p\u003e\n\u003cp\u003eTraditionally, relatively high RAI activities, typically 100\u0026ndash;150 mCi, have been used for adjuvant therapy. However, growing evidence suggests that lower activities may provide similar therapeutic benefits while reducing radiation exposure and treatment-related adverse effects (4-6). Lower RAI doses may also reduce healthcare costs and minimize radiation exposure to both patients and healthcare personnel.\u003c/p\u003e\n\u003cp\u003eDespite increasing interest in dose reduction strategies, data comparing different RAI activities for adjuvant therapy in intermediate-risk patients remain limited. Therefore, this study aimed to compare treatment response between low-dose and high-dose RAI adjuvant therapy in patients with intermediate-risk differentiated thyroid cancer treated at a tertiary care center.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study was conducted at a tertiary care hospital. Medical records of patients with differentiated thyroid cancer who underwent total thyroidectomy followed by radioactive iodine therapy were reviewed from September 2005 to July 2025. We performed this study under the approval of the Ethics Committee of the Phrapokklao Hospital, Chanthaburi, Thailand (Approval No.\u0026nbsp;031/69). The need of the written informed consent was waived by the ethic committee.\u003c/p\u003e\n\u003cp\u003ePatients were eligible for inclusion if they met the following criteria: (1) histologically confirmed differentiated thyroid cancer, (2) intermediate-risk disease based on clinicopathologic features, (3) total thyroidectomy or completion thyroidectomy, (4) receipt of postoperative RAI therapy, and (5) available clinical follow-up data approximately 6-8 months after therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients were excluded if they had distant metastasis at diagnosis, prior RAI therapy before the study period, or incomplete clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadioactive Iodine Adjuvant Therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing thyroidectomy, patients received radioactive iodine therapy as adjuvant therapy according to institutional clinical practice. TSH stimulation was achieved through thyroid hormone withdrawal. Patients were categorized according to the administered RAI activity: (1) low-dose RAI: 30 mCi and (2) high-dose RAI: \u0026ge;100 mCi. A post-therapy whole-body scan was performed after RAI administration to assess iodine uptake and identify possible residual or metastatic disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of Intermediate-Risk Disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntermediate-risk DTC was defined according to the ATA risk stratification system (1). Patients were classified as intermediate risk if they had one or more of the following features: microscopic extrathyroidal extension, cervical lymph node metastasis (\u0026lt;3 cm), aggressive histological variants, vascular invasion, or microscopic positive surgical margins.\u003c/p\u003e\n\u003cp\u003eMicroscopic positive margin was defined as the presence of tumor cells at any surgical resection margin on histopathological examination. Margin location was not consistently available and was therefore not analyzed separately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-Up and Response Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were followed with periodic clinical evaluation, including serum thyroglobulin measurement, anti-thyroglobulin antibody testing, neck ultrasonography, and additional imaging when clinically indicated.\u003c/p\u003e\n\u003cp\u003eInitial treatment response was assessed at approximately 6\u0026ndash;8 months after RAI therapy and classified according to the ATA response-to-therapy system as: (1) excellent response, (2) indeterminate response, (3) biochemical incomplete response, and (4) structural incomplete response.\u003c/p\u003e\n\u003cp\u003eFor the primary analysis, treatment response was dichotomized into excellent and non-excellent response, with non-excellent response including indeterminate, biochemical incomplete, and structural incomplete categories.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinitions of Response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment response was classified according to the American Thyroid Association (ATA) response-to-therapy system (1).\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eExcellent response was defined as nonstimulated Tg \u0026lt;0.2 or stimulated Tg\u0026lt;1 and negative imaging.\u003c/li\u003e\n \u003cli\u003eIndeterminate response was defined as nonspecific findings on imaging or nonstimulated Tg 0.2-1 or stimulated Tg 1-10 or stable /declining Tg levels.\u003c/li\u003e\n \u003cli\u003eBiochemical incomplete response was defined as nonstimulated Tg \u0026gt;1 or stimulated Tg \u0026gt;10 or increasing TgAb levels and negative imaging.\u003c/li\u003e\n \u003cli\u003eStructural incomplete response was defined as structural evidence of disease (suspicious imaging or biopsy proven local or distant metastasis).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eTime-to-Event Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor secondary outcome analysis, structural disease\u0026ndash;free survival was evaluated. Structural disease was defined as the presence of persistent or recurrent structural disease identified by imaging or histopathological confirmation.\u003c/p\u003e\n\u003cp\u003eFollow-up time was calculated from the date of RAI to the date of detection of structural disease or last clinical follow-up. Patients who developed structural disease during follow-up were considered to have an event, and time-to-event was defined as the interval between surgery and the date of detection of structural disease.\u003c/p\u003e\n\u003cp\u003ePatients with structural incomplete response at initial assessment were considered to have persistent disease and assigned an event at the time of first evaluation (6\u0026ndash;8 months). Patients without evidence of structural disease were censored at the date of last follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical and pathological data were extracted from electronic medical records. Variables collected included: age at diagnosis, sex, tumor size, multifocality, extrathyroidal extension, lymphovascular invasion, lymph node metastasis, aggressive histological variants (including tall cell, hobnail, columnar cell, solid, and diffuse sclerosing variants), microscopic positive margin, administered RAI activity, and treatment response at 6\u0026ndash;8 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were expressed as mean \u0026plusmn; standard deviation or median with range, as appropriate. Categorical variables were presented as frequencies and percentages.\u003c/p\u003e\n\u003cp\u003eBaseline characteristics between low-dose and high-dose RAI groups were compared using the independent t-test or Mann\u0026ndash;Whitney U test for continuous variables and the chi-square test or Fisher\u0026rsquo;s exact test for categorical variables, as appropriate.\u003c/p\u003e\n\u003cp\u003eLogistic regression analysis was performed to identify factors associated with excellent response. Variables with clinical relevance or p \u0026lt; 0.10 in univariate analysis were included in multivariable models. Odds ratios (OR) with 95% confidence intervals (CI) were reported.\u003c/p\u003e\n\u003cp\u003eTime-to-event outcomes were analyzed using the Kaplan\u0026ndash;Meier method to estimate structural disease\u0026ndash;free survival, and differences between groups were compared using the log-rank test. Cox proportional hazards regression analysis was performed to identify factors associated with structural disease, with results reported as hazard ratios (HR) and 95% confidence intervals (CI).\u003c/p\u003e\n\u003cp\u003eA two-sided p-value \u0026lt; 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics (version 30.0).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 113 patients with intermediate-risk differentiated thyroid cancer were included in the analysis. Among them, 52 patients (46%) received low-dose radioactive iodine (RAI) therapy (30 mCi), while 61 patients (54%) received high-dose RAI therapy (\u0026ge;100 mCi).\u003c/p\u003e\n\u003cp\u003eBaseline characteristics are shown in Table 1. The mean age and sex distribution were comparable between groups. Tumor size, multifocality, T stage, lymphovascular invasion, aggressive histology, and margin status were also similar.\u003c/p\u003e\n\u003cp\u003eHowever, patients in the high-dose group demonstrated more advanced disease features, including a higher prevalence of lymph node metastasis (34.4% vs. 17.3%, p = 0.04) and extrathyroidal extension (36.1% vs. 13.5%, p = 0.006), suggesting a tendency toward administering higher RAI doses in patients with higher-risk disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of patients according to RAI dose\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLow dose (n=52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh dose (n=61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge (years), mean\u0026nbsp;\u0026plusmn;\u0026nbsp;SD\u003c/p\u003e\n \u003cp\u003eFemale sex, n (%)\u003c/p\u003e\n \u003cp\u003eTumor size (cm), median\u0026nbsp;(range)\u003c/p\u003e\n \u003cp\u003eMultifocality, n (%)\u003c/p\u003e\n \u003cp\u003eT stage (T3), n (%)\u003c/p\u003e\n \u003cp\u003eN stage (N1), n (%)\u003c/p\u003e\n \u003cp\u003eExtrathyroidal extension, n (%)\u003c/p\u003e\n \u003cp\u003eLymphovascular invasion, n (%)\u003c/p\u003e\n \u003cp\u003eAggressive histology, n (%)\u003c/p\u003e\n \u003cp\u003ePositive margin, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e45.5\u0026nbsp;\u0026plusmn; 12.1\u003c/p\u003e\n \u003cp\u003e43 (82.7%)\u003c/p\u003e\n \u003cp\u003e3 (1.5-5)\u003c/p\u003e\n \u003cp\u003e17 (34%)\u003c/p\u003e\n \u003cp\u003e23 (46%)\u003c/p\u003e\n \u003cp\u003e9 (17.3%)\u003c/p\u003e\n \u003cp\u003e7 (13.5%)\u003c/p\u003e\n \u003cp\u003e27 (51.9%)\u003c/p\u003e\n \u003cp\u003e4 (7.7%)\u003c/p\u003e\n \u003cp\u003e7 (13.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46.2\u0026nbsp;\u0026plusmn; 14.5\u003c/p\u003e\n \u003cp\u003e54 (88.5%)\u003c/p\u003e\n \u003cp\u003e3.2 (2.2-4.8)\u003c/p\u003e\n \u003cp\u003e28 (46.7%)\u003c/p\u003e\n \u003cp\u003e32 (54.2%)\u003c/p\u003e\n \u003cp\u003e21 (34.4%)\u003c/p\u003e\n \u003cp\u003e22 (36.1%)\u003c/p\u003e\n \u003cp\u003e38 (62.3%)\u003c/p\u003e\n \u003cp\u003e10 (16.4%)\u003c/p\u003e\n \u003cp\u003e15 (24.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003cp\u003e0.040*\u003c/p\u003e\n \u003cp\u003e0.006*\u003c/p\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eContinuous variables compared using t-test or Mann\u0026ndash;Whitney U; categorical variables using chi-square or Fisher\u0026rsquo;s exact test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEarly Treatment Response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 6\u0026ndash;8 months following RAI therapy, an excellent response was achieved in 35 patients (67.3%) in the low-dose group and 33 patients (54.1%) in the high-dose group. Non-excellent response was observed in 17 patients (32.7%) and 28 patients (45.9%) in the low-dose and high-dose groups, respectively. There was no statistically significant difference in treatment response between the two groups (p = 0.15) (Table 2).\u003c/p\u003e\n\u003cp\u003eIn multivariable logistic regression analysis, RAI dose was not associated with excellent response. However, male sex (OR 0.25, p = 0.03), maximal tumor size (OR 0.76, p = 0.01) and lymph node metastasis (OR 0.18, p \u0026lt; 0.001) were independently associated with a lower likelihood of achieving an excellent response (Table 3.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Treatment response at 6-8 months according to RAI dose\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLow dose (n=52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh dose (n=61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eExcellent\u003c/p\u003e\n \u003cp\u003eNon-excellent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35 (67.3%)\u003c/p\u003e\n \u003cp\u003e17 (32.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33 (54.1%)\u003c/p\u003e\n \u003cp\u003e28 (45.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Multivariate logistic regression for excellent response\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdjusted\u003c/p\u003e\n \u003cp\u003eOdds Ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e95% Confidence\u003c/p\u003e\n \u003cp\u003eInterval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRAI dose (high vs low)\u003c/p\u003e\n \u003cp\u003eSex (male vs female)\u003c/p\u003e\n \u003cp\u003eN stage (N1 vs N0)\u003c/p\u003e\n \u003cp\u003eMaximal tumor size (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.27-1.55\u003c/p\u003e\n \u003cp\u003e0.07-0.86\u003c/p\u003e\n \u003cp\u003e0.07-0.49\u003c/p\u003e\n \u003cp\u003e0.61-0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e0.028*\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n \u003cp\u003e0.010*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eStructural Recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up time was 34 months (IQR 16-72), with longer time in the high-dose group compared with the low-dose group (49 vs 25 months, p = 0.006). During follow-up, structural recurrence occurred in a minority of patients, with a numerically higher rate observed in the high-dose group compared to the low-dose group (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Structural recurrence according to RAI dose\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLow dose (n=52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eHigh dose (n=61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStructural recurrence\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo structural recurrence\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (9.6%)\u003c/p\u003e\n \u003cp\u003e47 (90.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (18%)\u003c/p\u003e\n \u003cp\u003e50 (82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTime-to-Event Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn Cox proportional hazards analysis (Table 5), RAI dose was not associated with recurrence-free survival (HR 1.17, 95% CI 0.38\u0026ndash;3.66, p = 0.79).\u003c/p\u003e\n\u003cp\u003eHowever, lymph node metastasis (HR 3.38, p = 0.03) and tumor size (HR 1.25 per cm, p = 0.047) were independent predictors of recurrence.\u003c/p\u003e\n\u003cp\u003eKaplan-Meier analysis demonstrated no significant difference in recurrence-free survival between the low-dose and high-dose groups (log-rank p = 0.45) (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Multivariable Cox proportional hazards model for structural recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdjusted\u003c/p\u003e\n \u003cp\u003eHazard Ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e95% Confidence Interval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRAI dose (high vs low)\u003c/p\u003e\n \u003cp\u003eN stage (N1 vs N0)\u003c/p\u003e\n \u003cp\u003eMaximal tumor size (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.17\u003c/p\u003e\n \u003cp\u003e3.38\u003c/p\u003e\n \u003cp\u003e1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.38-3.66\u003c/p\u003e\n \u003cp\u003e1.12-10.15\u003c/p\u003e\n \u003cp\u003e1.00-1.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003cp\u003e0.030*\u003c/p\u003e\n \u003cp\u003e0.047*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eEarly Response and Recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecurrence occurred exclusively in patients with non-excellent response (35.6% vs 0%, p \u0026lt; 0.001)\u0026nbsp;(Table 6). Kaplan\u0026ndash;Meier analysis demonstrated a marked difference in recurrence-free survival between groups, with significantly worse outcomes in patients with non-excellent response (log-rank p \u0026lt; 0.001) (Figure 2).\u0026nbsp;Due to complete separation between early response and recurrence outcomes, regression modeling was not stable, indicating a strong prognostic effect of early treatment response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6. Early response vs structural recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRecurrence (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNo recurrence (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eExcellent\u003c/p\u003e\n \u003cp\u003eNon-excellent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e16 (35.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68 (100%)\u003c/p\u003e\n \u003cp\u003e29 (64.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePercentages represent row percentages (recurrence within response group)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort study of intermediate-risk differentiated thyroid cancer, we found that low-dose RAI (30 mCi) achieved comparable outcomes to high-dose RAI (\u0026ge;100 mCi) in terms of both early treatment response and recurrence-free survival. Importantly, RAI dose was not independently associated with either outcome after adjustment for clinicopathologic factors.\u003c/p\u003e\n\u003cp\u003eThese findings support a risk-adapted approach to RAI therapy, as recommended by current guidelines (1). While higher RAI doses have traditionally been used in intermediate-risk patients, our results suggest that increasing administered activity does not necessarily translate into improved clinical outcomes.\u003c/p\u003e\n\u003cp\u003eA key observation in this study is the presence of confounding by indication. Patients receiving high-dose RAI had significantly higher rates of lymph node metastasis and extrathyroidal extension, reflecting real-world clinical decision-making. Despite this higher-risk baseline profile, outcomes in the high-dose group were not superior, suggesting that tumor biology, rather than RAI dose, is the primary determinant of prognosis.\u003c/p\u003e\n\u003cp\u003eRandomized trials such as HiLo and ESTIMABL1 have demonstrated non-inferiority of low-dose RAI for remnant ablation, with similar long-term outcomes (4, 5). Although conducted in low-risk populations, these findings have influenced broader clinical practice. Emerging observational studies in intermediate-risk patients similarly report no significant advantage of higher RAI doses, supporting a trend toward treatment de-escalation in appropriately selected patients.\u003c/p\u003e\n\u003cp\u003eIn our study, lymph node metastasis and tumor size were the strongest predictors of both poorer early response and structural recurrence, consistent with prior literature (7-11). Male sex was also associated with a lower likelihood of achieving an excellent response. These findings reinforce that baseline disease burden and tumor characteristics are the key determinants of outcome and should guide risk stratification and management decisions (12, 13).\u003c/p\u003e\n\u003cp\u003eMicroscopic positive margin was not significantly associated with treatment response. However, margin location was not analyzed, and its clinical impact may vary depending on anatomical context. Therefore, this finding should be interpreted with caution (14, 15).\u003c/p\u003e\n\u003cp\u003eAn important strength of this study is the incorporation of dynamic risk stratification using early treatment response. We observed that recurrence occurred almost exclusively in patients with non-excellent response, confirming that early response is a powerful predictor of long-term outcomes. This finding aligns with previous studies demonstrating that response-to-therapy assessment provides superior prognostic information compared to initial risk stratification alone (16, 17).\u003c/p\u003e\n\u003cp\u003eFrom a clinical perspective, the lack of benefit associated with higher RAI doses has important implications. Lower RAI activity may reduce radiation exposure, minimize adverse effects such as salivary gland dysfunction, decrease the risk of secondary malignancies, and reduce healthcare costs, without compromising oncologic outcomes (18-21).\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. The difference in follow-up duration between groups, with shorter follow-up in the low-dose RAI group, likely reflects evolving clinical practice and increased adoption of lower RAI activities in more recent years. As a result, patients in the low-dose group had less time at risk for recurrence, which may lead to underestimation of recurrence events. Although Kaplan\u0026ndash;Meier and Cox regression analyses were used to account for variable follow-up time, residual bias cannot be excluded. In addition, the retrospective design introduces potential selection bias and confounding, and the relatively small number of recurrence events limits statistical power. Longer follow-up is needed to confirm long-term outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with intermediate-risk differentiated thyroid cancer, low-dose RAI (30 mCi) provides comparable outcomes to high-dose RAI (\u0026ge;100 mCi) in both early treatment response and recurrence-free survival. RAI dose was not an independent predictor of recurrence, whereas lymph node metastasis, tumor size, and early treatment response were the primary determinants of outcome. These findings support the use of lower RAI activities in appropriately selected patients, reinforcing a risk-adapted and individualized approach to postoperative management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eATA American Thyroid Association\u003c/p\u003e\n\u003cp\u003eCI Confidence interval\u003c/p\u003e\n\u003cp\u003eDTC Differentiated thyroid cancer\u003c/p\u003e\n\u003cp\u003eETE Extrathyroidal extension\u003c/p\u003e\n\u003cp\u003eHR Hazard ratio\u003c/p\u003e\n\u003cp\u003emCi Millicurie\u003c/p\u003e\n\u003cp\u003eOR Odds ratio\u003c/p\u003e\n\u003cp\u003eRAI Radioactive iodine\u003c/p\u003e\n\u003cp\u003eSD Standard deviation\u003c/p\u003e\n\u003cp\u003eTSH Thyroid-stimulating hormone\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.K. designed the study, collected and analysed the data, and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research project is supported by the Medical Education Center, Phrapokklao Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this manuscript are subject to local privacy and data protection laws and are not publicly available. Requests for anonymized data review can be directed to the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was approved by the ethics institutional review board, Chanthaburi Research Ethics Committee/Region 6 of Phrapokklao Hospital (Approval no. 031/69). The requirement for written informed consent was waived due to its retrospective nature. The study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegistry: https://www.thaiclinicaltrials.org/\u003c/p\u003e\n\u003cp\u003eTrial registration number: TCTR20260313002\u003c/p\u003e\n\u003cp\u003eDate of registration: 13 March 2026, retrospectively registered\u003c/p\u003e\n\u003cp\u003eData of registration: https://www.thaiclinicaltrials.org/export/pdf/TCTR20260313002\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRingel MD, Sosa JA, Baloch Z, Bischoff L, Bloom G, Brent GA, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid. 2025;35(8):841\u0026ndash;985.\u003c/li\u003e\n\u003cli\u003eLamartina L, Montesano T, Trulli F, Attard M, Torlontano M, Bruno R, et al. Papillary thyroid carcinomas with biochemical incomplete or indeterminate responses to initial treatment: repeat stimulated thyroglobulin assay to identify disease-free patients. Endocrine. 2016;54(2):467\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eVerburg FA, Flux G, Giovanella L, van Nostrand D, Muylle K, Luster M. Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade. Eur J Nucl Med Mol Imaging. 2020;47(1):78\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eDehbi HM, Mallick U, Wadsley J, Newbold K, Harmer C, Hackshaw A. Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(1):44\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eSchlumberger M, Leboulleux S, Catargi B, Deandreis D, Zerdoud S, Bardet S, 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\u0026ndash;26.\u003c/li\u003e\n\u003cli\u003eAbiri A, Nguyen T, Goshtasbi K, Torabi SJ, Kuan EC, Armstrong WB, et al. A comparative analysis of treatment efficacy in intermediate-risk thyroid cancer. Eur Arch Otorhinolaryngol. 2023;280(5):2525\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eLeboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, et al. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab. 2005;90(10):5723\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eRandolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012;22(11):1144\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eYwata de Carvalho A, Kohler HF, Gomes CC, Vartanian JG, Kowalski LP. Predictive factors for recurrence of papillary thyroid carcinoma: analysis of 4,085 patients. Acta Otorhinolaryngol Ital. 2021;41(3):236\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eNguyen XV, Roy Choudhury K, Tessler FN, Hoang JK. Effect of Tumor Size on Risk of Metastatic Disease and Survival for Thyroid Cancer: Implications for Biopsy Guidelines. Thyroid. 2018;28(3):295\u0026ndash;300.\u003c/li\u003e\n\u003cli\u003eGinzberg SP, Sharpe J, Passman JE, Amjad W, Wirtalla CJ, Soegaard Ballester JM, et al. Revisiting the Relationship Between Tumor Size and Risk in Well-Differentiated Thyroid Cancer. Thyroid. 2024;34(8):980\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eGlikson E, Alon E, Bedrin L, Talmi YP. Prognostic Factors in Differentiated Thyroid Cancer Revisited. Isr Med Assoc J. 2017;19(2):114\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eJukkola A, Bloigu R, Ebeling T, Salmela P, Blanco G. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr Relat Cancer. 2004;11(3):571\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eSanabria A, Rojas A, Arevalo J, Kowalski LP, Nixon I. Microscopically positive surgical margins and local recurrence in thyroid cancer. A meta-analysis. Eur J Surg Oncol. 2019;45(8):1310\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eKhan ZF, Kutlu O, Picado O, Lew JI. Margin Positivity and Survival Outcomes: A Review of 14,471 Patients with 1-cm to 4-cm Papillary Thyroid Carcinoma. J Am Coll Surg. 2021;232(4):545\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eMomesso DP, Vaisman F, Yang SP, Bulzico DA, Corbo R, Vaisman M, et al. Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine. J Clin Endocrinol Metab. 2016;101(7):2692\u0026ndash;700.\u003c/li\u003e\n\u003cli\u003eTuttle RM, Alzahrani AS. Risk Stratification in Differentiated Thyroid Cancer: From Detection to Final Follow-Up. J Clin Endocrinol Metab. 2019;104(9):4087\u0026ndash;100.\u003c/li\u003e\n\u003cli\u003eRubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer. 2003;89(9):1638\u0026ndash;44.\u003c/li\u003e\n\u003cli\u003ePiscopo L, Volpe F, Nappi C, Zampella E, Manganelli M, Matrisciano F, et al. Second Primary Malignancies in Patients with Differentiated Thyroid Cancer after Radionuclide Therapy: A Retrospective Single-Centre Study. Curr Oncol. 2022;30(1):37\u0026ndash;44.\u003c/li\u003e\n\u003cli\u003eFard-Esfahani A, Emami-Ardekani A, Fallahi B, Fard-Esfahani P, Beiki D, Hassanzadeh-Rad A, et al. Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma. Nucl Med Commun. 2014;35(8):808\u0026ndash;17.\u003c/li\u003e\n\u003cli\u003eVan Nostrand D. Sialoadenitis secondary to (1)(3)(1)I therapy for well-differentiated thyroid cancer. Oral Dis. 2011;17(2):154\u0026ndash;61.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intermediate risk. Thyroid cancer, Radioactive iodine (RAI), Low dose, High dose, Excellent response, Response to therapy","lastPublishedDoi":"10.21203/rs.3.rs-9250941/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9250941/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe optimal activity of radioactive iodine (RAI) for adjuvant therapy in intermediate-risk differentiated thyroid cancer (DTC) remains uncertain. This study aimed to compare treatment response and recurrence outcomes between low-dose and high-dose RAI in this population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, intermediate-risk DTC patients treated with total thyroidectomy followed by adjuvant RAI were included. Patients received either low-dose (30 mCi) or high-dose (≥100 mCi) RAI. Treatment response at 6-8 months was classified according to American Thyroid Association criteria and dichotomized as excellent versus non-excellent response. Structural disease–free survival was analyzed using Kaplan-Meier and Cox regression methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 113 patients were included (low-dose: n=52; high-dose: n=61). Excellent response was observed in 67.3% of the low-dose group and 54.1% of the high-dose group (p=0.15). RAI dose was not associated with excellent response in multivariable analysis (OR 0.65, 95% CI 0.27–1.55, p=0.33). During a median follow-up of 34 months, RAI dose was not associated with recurrence-free survival (HR 1.17, 95% CI 0.38–3.66, p=0.79). Lymph node metastasis and tumor size were independent predictors of both poorer response and recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow-dose RAI provides comparable treatment response and recurrence outcomes to high-dose RAI in intermediate-risk DTC. Disease burden, rather than RAI activity, appears to be the primary determinant of outcome, supporting a risk-adapted approach and consideration of lower RAI activities in appropriately selected patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegistry: https://www.thaiclinicaltrials.org/\u003c/p\u003e\n\u003cp\u003eTrial registration number: TCTR20260313002\u003c/p\u003e\n\u003cp\u003eDate of registration: 11 March 2026, retrospectively registered\u003c/p\u003e\n\u003cp\u003eData of registration: https://www.thaiclinicaltrials.org/export/pdf/TCTR20260313002\u003c/p\u003e","manuscriptTitle":"Comparison of Low-Dose and High-Dose Radioactive Iodine Adjuvant Therapy in Intermediate-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 08:16:26","doi":"10.21203/rs.3.rs-9250941/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-18T02:35:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315265668296522907835427948150322252033","date":"2026-05-12T03:39:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-29T12:50:17+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-06T15:24:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-30T04:22:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-30T01:42:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2026-03-30T01:39:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"56117905-36e2-4ed1-a65b-ba26af73864f","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-18T02:35:57+00:00","index":65,"fulltext":""},{"type":"reviewerAgreed","content":"315265668296522907835427948150322252033","date":"2026-05-12T03:39:43+00:00","index":64,"fulltext":""},{"type":"reviewersInvited","content":"30","date":"2026-04-29T12:50:17+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T08:16:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 08:16:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9250941","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9250941","identity":"rs-9250941","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}