Comparing therapeutic outcomes: radioactive iodine therapy versus non-radioactive iodine therapy in differentiated thyroid cancer.

Introduction: Radioactive iodine (RAI) has been utilized for nearly 80 years in treating both hyperthyroidism and thyroid cancer, and it continues to play a central role in the management of differentiated thyroid cancer (DTC) today. Recently, the use of RAI therapy for indolent, low-risk DTC has generated considerable debate. This case-control study evaluated the therapeutic response in DTC patients, comparing outcomes between those who received RAI therapy and those who did not. Methods: The study included individuals diagnosed with either indolent or aggressive histological types of DTC who either underwent RAI therapy or did not. For each patient, information regarding demographics (age, sex, background), clinical data, laboratory parameters, pathological exam, history of RAI therapy, thyroid ultrasound findings, and loco-regional or distant metastasis was extracted. All group comparisons were made using a two-sided test at an α level of 5%. Results: Out of 104 patients diagnosed with DTC, 76 met the inclusion criteria and were subsequently divided into two primary groups based on their history of RAI ablation. The majority of patients underwent RAI therapy (76.3%). Most patients had a good biochemical (68.4%, p = 0.246) and structural control (72.4%, p = 0.366), without a significant difference between the two groups. RAI therapy significantly protected against incomplete biochemical control in the overall population (p = 0.019) and in patients with histological indolent DTC (p = 0.030). Predictive factors for incomplete biochemical control included male sex (p = 0.008) and incomplete structural control (p = 0.002) across all patients, regardless of the histological type. Discussions: While RAI therapy has traditionally been used to manage DTC, our study found no significant difference in biochemical and structural responses between patients who received RAI therapy and those who did not. However, RAI therapy emerged as a protective factor against incomplete biochemical control, even in histological indolent DTC cases. These findings suggest that while RAI therapy may not be universally necessary, it could be beneficial in reducing the risk of biochemical recurrence in select patient subgroups, such as those with incomplete structural control or male patients. Thus, a personalized approach to RAI therapy, tailored to individual risk factors, may improve patient outcomes without overtreatment.

Therapeutic efficacies of remnant ablation and radioiodine adjuvant therapy in differentiated thyroid cancer.

BACKGROUND: Successful ablation in 131I therapy for differentiated thyroid cancer (DTC) includes both remnant ablation (RA) and radioiodine adjuvant therapy (RAT). This study aimed to differentiate between the therapeutic efficacies of RA and RAT, investigate the factors associated with their effectiveness, and assess their impact on prognosis. METHODS: This retrospective study included patients with DTC who underwent initial 131I therapy at our tertiary center. The successful RA (SRA) and successful RAT (SRAT) was determined based on the 131I-diagnostic whole-body scan (Dx-WBS), TSH-stimulated thyroglobulin (sTg) levels, and neck ultrasound at the 6th month after 131I therapy. The patients were divided into complete response and persistent/recurrent disease groups during the follow-up period. RESULTS: A total of 232 patients were included, 91.8% (213/232) of patients achieved SRA, only 8.1% (19/232) failed RA (FRA). Among the 213 patients in the SRA group, 70.4% (150/213) achieved SRAT and 29.6% (63/213) failed RAT (FRAT). Only pre-ablation sTg >10 ng/mL (OR = 46.968, 95% CI 9.731-226.699, P < 0.001) was an independent risk factor predicting the failure of RAT. The prognostic analysis included 215 patients, and 6.1% (13/215) were classified as persistent/recurrent disease at the last follow-up. Both pre-ablation sTg >10 ng/mL (HR = 4.765, 95% CI 1.371-16.566, P = 0.014) and FRAT (HR = 10.104, 95% CI 1.071-95.304, P = 0.043) independently predicted persistent/recurrent disease. CONCLUSIONS: RA is easy to achieve successfully, whereas RAT evaluation provides greater value than RA for prognosis prediction. For patients with low Tg levels and no imaging evidence of disease, routine Dx-WBS during follow-up has minimal significance.

TERT promoter mutations contribute to adverse clinical outcomes and poor prognosis in radioiodine refractory differentiated thyroid cancer.

Telomerase reverse transcriptase promoter (TERTp) mutations are associated with non-radioiodine avidity. However, the role of these mutations in the clinical outcomes of patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) remains unknown. Herein, we aim to analyze gene mutations and clinical manifestations to verify TERTp's role in driving disease progression to RAIR-DTC and clinical outcomes. Next-generation sequencing data and clinical data were obtained from 243 patients with DTC. Of the 25 patients with TERTp mutations, 80% (20/25) had RAIR-DTC. RAIR-DTC was significantly less prevalent in patients with BRAFV600E (9/143, 6.3%) than those with both BRAFV600E and TERTp mutations (14/17, 82.4%). Patients with RAIR-DTC harboring both BRAFV600E and TERTp mutations were more likely to have > 3 distant metastatic sites (85.7%, 12/14) than those with BRAFV600E alone (33.3%, 3/9). Only one patient with both BRAFV600E and TERTp mutations had non-RAIR-DTC. The time from initial radioactive iodine therapy to RAIR-DTC diagnosis was significantly shorter in patients with TERTp mutations than in those without. Patients with BRAFV600E and TERTp mutations progressed faster to RAIR-DTC than those with BRAFV600E alone (p < 0.01). Our findings suggest that molecular testing for TERTp and other mutations like BRAFV600E may inform early diagnosis, prognosis, and treatment strategies before progression to RAIR-DTC.

Analysis of the ideal cutoff age as a predictor of differentiated thyroid cancer using the Surveillance, Epidemiology, and End Results database.

Background: It has been discovered that the prognosis of patients with differentiated thyroid cancer (DTC) correlates with age at initial diagnosis. However, there are disagreements over the optimal cutoff age among the numerous staging and risk stratification criteria, which make it inconsistent to predict the clinical prognosis of specific DTC patients. This study aimed to determine the optimum cutoff age for diagnosis in relation to the clinical outcomes of DTC using data from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The best age cutoff value was determined by the X-tile software. The link between clinical characteristics and cancer-specific survival (CSS) was examined using univariate and multivariate Cox regression models. An additional application of the independent prognostic criteria, such as age stratifications, was applied to construct a nomogram model for predicting the chances of patient survival. Results: The most accurate diagnosis cutoff age for DTC patients was suggested to be 67 years old. The multivariate analysis, using factors determined by univariate analysis, showed that age [>67 years, hazard rate (HR) =5.049, 95% confidence interval (CI): 4.509-5.653, P<0.001], sex (female, HR =0.651, 95% CI: 0.584-0.727, P<0.001), tumor size (>20 and ≤40 mm, HR =2.296, 95% CI: 1.983-2.658, P<0.001; >40 mm, HR =4.976, 95% CI: 4.304-5.752, P<0.001), lymphadenectomy (HR =1.337, 95% CI: 1.186-1.506, P<0.001), distant metastasis (HR =12.166, 95% CI: 10.749-13.769, P<0.001) and surgical treatment (HR =0.173, 95% CI: 0.144-0.210, P<0.001) were independent factors for CSS. Patients in the high-risk group had worse survival rates, and the C-index for the CSS prediction model with age (cutoff of 67) and other independent clinicopathological variables was 0.906. Conclusions: Accordingly, the optimal cutoff age for predicting death from DTC specifically is 67 years old at the time of the initial diagnosis. It might be a more suitable factor when used in risk stratification for patients with DTC.

Efficacy of color Doppler ultrasound signs combined with serum tumor-specific growth factor in the diagnosis of differentiated thyroid cancer.

OBJECTIVE: To construct a diagnostic model for follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC), both subtypes of differentiated thyroid carcinoma (DTC), using color Doppler ultrasound signs in conjunction with serum laboratory markers. METHODS: We conducted a retrospective analysis of patients with thyroid nodules who underwent ultrasonography at Yulin Hospital from February 2021 to March 2023. The cohort included 269 subjects: 105 with benign nodules and 164 with DTC (59 with FTC and 105 with PTC). We compared baseline demographics and laboratory indices between the groups. Diagnostic values of ultrasound features and laboratory markers were assessed using receiver operating characteristic (ROC) curves, and logistic regression was employed to pinpoint independent diagnostic factors for FTC. A predictive nomogram was subsequently developed based on these factors. RESULTS: There were significant differences between the benign and malignant groups regarding ultrasound signs (including border, morphology, echogenicity, calcification, blood flow, lymph node zoning) and laboratory indices (free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), vascular endothelial growth factor (VEGF), tumor-specific growth factor (TSGF)), with all P-values <0.05. The areas under the curve (AUCs) for FT3, FT4, Tg, TSH, VEGF, and TSGF were all above 0.75, with Tg achieving the highest at 0.91. Logistic regression identified borders, morphology, echogenicity, VEGF, and TSGF as independent diagnostic factors for distinguishing between FTC and PTC, with significant P-values. The constructed nomogram demonstrated an AUC of 0.853, indicating high diagnostic accuracy. Both calibration and decision curve analysis (DCA) validated the model's stability and clinical utility. CONCLUSION: We successfully developed a nomogram combining ultrasound features and serum markers that enhances the diagnostic precision for FTC. This model offers a valuable tool for clinical diagnostics in differentiated thyroid cancer.

Changes in Thyroglobulin Antibody Levels in Differentiated Thyroid Cancer Patients After Thyroidectomy: A Retrospective Study in Basrah, Iraq.

INTRODUCTION: Differentiated thyroid cancer (DTC), the most common endocrine malignancy is subdivided into papillary (the most common) and follicular type. Generally, DTC has a good prognosis with standard treatments such as surgery and, in some cases, radioactive iodine (RAI). Post-treatment follow-up includes thyroglobulin (Tg) and anti-thyroglobulin antibody (TgAb) measurement and imaging to assess treatment success and detect recurrence. However, TgAb can interfere with Tg measurements, making it essential to measure TgAb at different times (months).  Aim of the study: The aim of this study was to evaluate the changes in TgAb level in DTC patients after thyroidectomy and its association with recurrence. METHODS: This was a retrospective cohort study done at the Faiha Specialized Diabetes, Endocrine, and Metabolism Center (FDEMC), Basrah, Iraq, for individuals diagnosed with DTC between 2008 and 2023. The data collected were analyzed using IBM SPSS Statistics for Windows, Version 21.0 (Released 2012; IBM Corp., Armonk, New York, United States). The categories were classified according to the TgAb level as: (i) elevated (>115 IU/ml) and (ii) normal (<115 IU/ml), where TgAb levels measured at 0-6 months, 6-12 months, 24-36 months, 36-48 months, and beyond 48 months. RESULTS: The mean age at diagnosis of the study population (n=108) was 40.15 years with a female-to-male ratio of 4:1. Among these individuals, 52.8% (n=57) were found to be obese. Total thyroidectomy was performed on 84.3% (n=91). Papillary thyroid cancer was diagnosed in 69.5% (n=75). TgAb levels were influenced by body mass index (BMI); higher BMI (>30kg/m2) was associated with less consistent TgAb normalization, particularly beyond 48 months (P = 0.04). The study found no significant differences in TgAb normalization based on gender, age, BMI, type of surgery, type of cancer, American Thyroid Association (ATA) risk of recurrence, or radioactive iodine (RAI) treatment. CONCLUSION:  Factors including gender, age, type of surgery, type of cancer, ATA risk of recurrence, and RAI treatment did not significantly affect TgAb normalization in DTC individuals over the study period. However, higher BMI is associated with less consistent TgAb normalization in the long term.

A predictive model for L-T4 dose in postoperative DTC after RAI therapy and its clinical validation in two institutions.

Purpose: To develop a predictive model using machine learning for levothyroxine (L-T4) dose selection in patients with differentiated thyroid cancer (DTC) after resection and radioactive iodine (RAI) therapy and to prospectively validate the accuracy of the model in two institutions. Methods: A total of 266 DTC patients who received RAI therapy after thyroidectomy and achieved target thyroid stimulating hormone (TSH) level were included in this retrospective study. Sixteen clinical and biochemical characteristics that could potentially influence the L-T4 dose were collected; Significant features correlated with L-T4 dose were selected using machine learning random forest method, and a total of eight regression models were established to assess their performance in prediction of L-T4 dose after RAI therapy; The optimal model was validated through a two-center prospective study (n=263). Results: Six significant clinical and biochemical features were selected, including body surface area (BSA), weight, hemoglobin (HB), height, body mass index (BMI), and age. Cross-validation showed that the support vector regression (SVR) model was with the highest accuracy (53.4%) for prediction of L-T4 dose among the established eight models. In the two-center prospective validation study, a total of 263 patients were included. The TSH targeting rate based on constructed SVR model were dramatically higher than that based on empirical administration (Rate 1 (first rate): 52.09% (137/263) vs 10.53% (28/266); Rate 2 (cumulative rate): 85.55% (225/263) vs 53.38% (142/266)). Furthermore, the model significantly shortens the time (days) to achieve target TSH level (62.61 ± 58.78 vs 115.50 ± 71.40). Conclusions: The constructed SVR model can effectively predict the L-T4 dose for postoperative DTC after RAI therapy, thus shortening the time to achieve TSH target level and improving the quality of life for DTC patients.

Impact of extrathyroidal autoimmune diseases on clinical features and the efficacy of Iodine-131 therapy in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of this study is to assess the impact of extrathyroidal autoimmune diseases (ADs) on the clinical characteristics and efficacy of iodine-131 (131I) therapy in patients with differentiated thyroid cancer (DTC). METHODS: Patients with DTC who were received 131I therapy simultaneously were classified into the combination group (n = 35) and noncombination group (n = 146) depending on the presence of ADs. The clinical characteristics, such as gender, age, tumor lesions, lymph node metastasis, distant metastasis, 131I therapy efficacy, and use of levothyroxine, were compared between the two groups. Statistical analysis was conducted using SPSS 26.0 and R 4.0.3. RESULTS: There was a statistically significant difference in age between the combination and noncombination groups (t = -2.872, p < .01), and the optimal cutoff value was 50.5 years. Propensity score matching was completed effectively on a total of 121 patients, using age as the matching factor, comprising 32 cases in the combination group and 80 cases in the noncombination group. The baseline demographic features of the two groups were equivalent after matching (p > .05), and there was no significant difference in the therapeutic efficacy of 131I between the two groups (p > .05). In the subgroup analysis involving patients aged great than 50.5 years, the levothyroxine/weight (µg/kg) was increased in the combination group, and the difference was statistically significant (p < .05). CONCLUSION: While extrathyroidal ADs may enhance the detection of DTC among elderly women, they have no impact on the clinical characteristics of thyroid cancer or the efficacy of 131I therapy. ADs may necessitate higher per-unit dosages of levothyroxine in patients with DTC, regardless of the clinical status. Consequently, it is not essential for nuclear medicine physicians to consider the presence of ADs when designing treatment plans for patients with DTC.

Single-Institution Experience of Larotrectinib Therapy for Patients With NTRK Fusion-Positive Thyroid Carcinoma.

Context: The real world efficacy and tolerabiltiy of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results. Objective: We report a retrospective analysis of patients with thyroid cancer harboring NTRK fusions who underwent treatment with larotrectinib. Methods: A single-institution, retrospective case series of patients with NTRK fusion-positive thyroid cancers treated with neurotrophic tyrosine receptor kinase (NTRK) inhibitors from January 1, 2007, to January 1, 2023, was performed. This study was conducted at a single academic tertiary referral center. Patients with confirmed NTRK-fusion thyroid cancer who received larotrectinib were included. Larotrectinib was administered in accordance with clinical judgment from oncology providers. The primary end point was progression-free survival (PFS). Results: Eight patients with NTRK fusion-positive thyroid cancer treated with larotrectinib were identified: 4 with papillary thyroid cancer (PTC) (50%), 3 with poorly differentiated thyroid cancer (PDTC) (38%), and 1 with anaplastic thyroid cancer (ATC) (12%). The median PFS (mPFS) for all patients was 24.7 months (95% CI, 11.3-38.1). mPFS in PTC was higher than PDTC (34.6 months [24.7-48.7 months] vs 17.5 [7.1-21.1 months]; P = .017). The median overall survival (OS) was 43.8 months (29.8-56.8 months) overall. The single patient with ATC had a PFS and OS of 23 months. Two patients remained on treatment/alive at data cutoff, with a duration of response of 33.5 months and a median follow-up of 52 months. Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%). Conclusion: In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

Differentiated thyroid cancer and adverse pregnancy outcomes: a propensity score-matched retrospective cohort study.

Background: Differentiated thyroid cancer (DTC) has been increasingly common in women of reproductive age. However, the evidence remains mixed regarding the association of DTC with adverse pregnancy outcomes in pregnant women previously diagnosed with DTC. Methods: We conducted a retrospective cohort study in the Peking University Third Hospital in Beijing, China between January 2012 and December 2022. We included singleton-pregnancy women with a pre-pregnancy DTC managed by surgical treatment (after-surgery DTC) or active surveillance (under-surveillance DTC). To reduce the confounding effects, we adopted a propensity score to match the after-surgery and under-surveillance DTC groups with the non-DTC group, respectively, on age, parity, gravidity, pre-pregnancy weight, height, and Hashimoto's thyroiditis. We used conditional logistics regressions, separately for the after-surgery and under-surveillance DTC groups, to estimate the adjusted associations of DTC with both the composite of adverse pregnancy outcomes and the specific mother-, neonate-, and placenta-related pregnancy outcomes. Results: After the propensity-score matching, the DTC and non-DTC groups were comparable in the measured confounders. In the after-surgery DTC group (n = 204), the risk of the composite or specific adverse pregnancy outcomes was not significantly different from that of the matched, non-DTC groups (n = 816; P > 0.05), and the results showed no evidence of difference across different maternal thyroid dysfunctions, gestational thyrotropin levels, and other pre-specified subgroup variables. We observed broadly similar results in the under-surveillance DTC group (n = 37), except that the risk of preterm birth, preeclampsia, and delivering the low-birth-weight births was higher than that of the matched, non-DTC group [n = 148; OR (95% CI): 4.79 (1.31, 17.59); 4.00 (1.16, 13.82); 6.67 (1.59, 27.90)]. Conclusions: DTC was not associated with adverse pregnancy outcomes in pregnant women previously treated for DTC. However, more evidence is urgently needed for pregnant women with under-surveillance DTC, which finding will be clinically significant in individualizing prenatal care.

Mental Health and Quality of Life of Patients with Differentiated Thyroid Cancer Pre and Post Radioactive Iodine Treatment: A Prospective Study.

Background: Although patients with differentiated thyroid cancer (DTC) have a good prognosis, their long-term clinical course can influence their mental health and their health-related quality of life (HRQoL). However, few studies have evaluated the psychological factors that influence subsequent HRQoL in this population, particularly during the initial treatment stage. Methods: In this 1-month cohort study, we evaluated depressive and anxiety symptoms and HRQoL of patients with DTC and examined possible predictors of further HRQoL impairment. Results: In total, 181 patients completed questionnaires where they self-rated their psychological status (the Chinese Health Questionnaire [CHQ], Taiwanese Depression Questionnaire [TDQ]) and HRQoL (the 36-item Short Form Health Survey [SF-36]) at baseline and 1 month after radioactive iodine (RAI) therapy. Compared with the general Taiwanese population, patients with DTC reported a worse HRQoL in all dimensions of the SF-36. Multivariate regression models indicated that anxiety and depressive symptoms were inversely correlated with some dimensions (physical functioning, bodily pain, and general health perceptions for the CHQ; role limitations due to physical problems and social functioning for the TDQ). However, psychiatric follow-up and treatment history were significantly associated with physical functioning and role limitations owing to the physical problem dimensions of HRQoL. Conclusions: In conclusion, although anxiety and depressive symptoms may negatively affect certain HRQoL domains, psychiatric follow-up can improve the physical dimensions.

Vitamin D receptor polymorphisms associate with the efficacy and toxicity of radioiodine-131 therapy in patients with differentiated thyroid cancer.

BACKGROUND: Radioiodine-131 (I-131) therapy is the common postoperative adjuvant therapy for differentiated thyroid cancer (DTC) However, methods to evaluate the efficacy and toxicity of I-131 on DTC are still lacking. OBJECTIVE: To evaluate the association between vitamin D receptor (VDR) gene polymorphisms and the efficacy and toxicity of I-131 in DTC patients. METHODS: A total of 256 DTC patients who received I-131 therapy were enrolled. The patients were divided into effective group and ineffective group. 4 single nucleotide polymorphisms (SNPs) (rs7975232, rs731236, rs1544410 and rs10735810) of VDR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) Cell counting kit-8 (CCK-8) and flow cytometry were used to detect the proliferation and apoptosis of thyroid cancer cells. RESULTS: Patients in effective group had more CC genotype of rs7975232 and GG genotype of rs10735810 compared with patients in ineffective group They were also independent factors for influencing the efficacy of I-131. PTC-1 and FTC-133 cells transfected with CC genotype of rs7975232 showed lower proliferative activity and higher apoptosis rate after being treated with I-131 In addition, patients with CC genotype at rs7975232 had fewer adverse reactions after I-131 treatment. CONCLUSIONS: VDR gene polymorphisms may be associated with the efficacy and toxicity of I-131 in DTC patients, which will help to personalize the treatment for patients.

Reducing noise in radioactive iodine activity selection: the utility of an online clinical calculator.

Background: Noise, an unwanted variability in judgment, is ubiquitous in medicine, including in the prescription of radioactive iodine (RAI). Building upon our recently developed predictive risk model, we created an online clinical support tool to facilitate the translation of our model into clinical practice. The aim of this study is to assess the utility of an online clinical support tool to reduce noise in the treatment for patients with differentiated thyroid cancer (DTC). Methods: The tool was accessible via weblink or a QR code. Activity recommendations were applied to the calculator's four risk categories: 0 GBq for very low risk, 1 GBq for low risk, 4 GBq for intermediate risk, and 6 GBq for high risk. The tool was applied prospectively to 103 patients who received RAI at Royal North Shore Hospital between 2021 and 2022 and retrospectively to 393 patients treated with RAI between 2017 and 2021. Results: A significant difference was observed in administered activity between the 2021-2022 and 2017-2021 cohorts in patients stratified as intermediate risk (median activity 3.95 GBq, interquartile range 2.03-4.04 vs 4 GBq, 4-4) and high risk (4.07 GBq, 3.95-5.7 vs 6 GBq, 6-6) with P-values of 0.01 and <0.01, respectively. No difference was seen in low-risk patients (2.01 GBq, 1.03-3.98 vs 1 GBq, 1-4, P = 0.30). Additionally, no clinically significant recurrence was observed between the two cohorts (6.6% vs 4.5%; P = 0.628). Conclusion: Optimal risk classification and activity recommendation continue to be established. Our data suggest that providing risk stratification and activity recommendation in an easy-to-access online tool can reduce noise and variability in activity prescription for patients with DTC.

Predicting excellent response to radioiodine in differentiated thyroid cancer using machine learning.

Objective: If excellent response (ER) occurs after radioactive iodine (RAI) treatment in patients with differentiated thyroid carcinoma (DTC), the recurrence rate is low. Our study aims to predict ER at 6-24 months after RAI by using machine learning (ML) methods in which clinicopathological parameters are included in patients with DTC without distant metastasis. Methods: Treatment response of 151 patients with DTC without distant metastasis and who received RAI treatment was determined (ER/nonER). Thyroidectomy ± neck dissection pathology data, laboratory, and imaging findings before and after RAI treatment were introduced to ML models. Results: After RAI treatment, 118 patients had ER and 33 had nonER. Before RAI treatment, TgAb was positive in 29% of patients with ER and 55% of patients with nonER (p = 0.007). Eight of the ML models predicted ER with high area under the ROC curve (AUC) values (> 0.700). The model with the highest AUC value was extreme gradient boosting (AUC = 0.871), the highest accuracy shown by gradient boosting (81%). Conclusions: ML models may be used to predict ER in patients with DTC without distant metastasis.

Is second 131I treatment necessary for differentiated thyroid cancer patients and who could not benefit from it? A real-world retrospective study in China.

BACKGROUND: The efficacy of a second radioactive iodine-131 (131I) treatment in patients with differentiated thyroid cancer (DTC) who did not achieve an excellent response (ER) following initial 131I therapy remains controversy and the population that would derive limited benefit from it is currently unclear. OBJECTIVES: The aim of this retrospective study was to assess the efficacy of the second 131I treatment in DTC patients with non-ER after the initial 131I therapy, and to identify potential risk factors associated with non-benefit of the second 131I treatment. METHODS: 127 DTC patients who underwent two 131I treatments following thyroidectomy were included in this study, and the therapeutic response was evaluated after each 131I treatment. Beneficial treatment was defined as an improvement in therapy response grade (e.g. from indeterminate response to ER) after the second 131I treatment, while unbeneficial treatment was defined as no change or a downgrade in therapy response grade. The potential risk factors associated with the non-benefit of the second 131I treatment were identified using univariate and multivariate logistic regression models. RESULTS: Following the second 131I treatment, therapy responses of 55.12% (70/127) of patients were reclassified to a better grade indicating treatment benefit, while 44.88% (57/127) showed no change or were reclassified to a worse grade suggesting no benefit from treatment. The non-benefit of the second 131I treatment was significantly associated with potential risk factors including stimulated thyroglobulin (sTg) level ≥ 11.46 ng/mL before the second 131I treatment, primary tumor size > 2 cm, status T2 or higher, N1b status and ATA high risk. CONCLUSIONS: The study results demonstrated that more than half of DTC patients could potentially benefit from a second 131I therapy. However, over 40% of patients exhibited no benefit in response to the second 131I treatment, suggesting potential overtreatment for this subgroup. Therefore, clinicians should exercise meticulous and precise decision-making based on identified risk factors when considering the necessity of a second 131I treatment.

Efficacy and safety of targeted therapy for radioiodine-refractory differentiated thyroid cancer: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of current targeted drug therapies for radioiodine-refractory differentiated thyroid cancer (RR-DTC). METHODS: This was a meta-analysis of relevant randomized controlled trials (RCTs) and single-arm studies searched across PubMed, Embase, Cochranes, and Web of Sciences up to September 12, 2023. Stata15.0 software was used to assess overall survival (OS), progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and adverse effects (AEs). The Cochrane Bias Risk tool was used to assess literature quality and trial bias and RevMan 5.4 was used to generate a quality assessment map. RESULTS: A total of 8 RCTs and 17 single-arm studies with 3,270 patients on 7 drugs-vandetanib, sorafenib, lenvatinib, cabozantinib, apatinib, donafenib, and anlotinib-were included. Targeted therapy with these drugs effectively prolonged PFS and OS in patients with RR-DTC with overall HRs of 0.35 (95% CI 0.23-0.53, P < 0.00001) and 0.53 (95% CI 0.32-0.86, P < 0.00001), respectively. ORR and DCR were also prolonged, with overall RRs of 27.63 (95% CI 12.39-61.61, P<0.00001) and 1.66 (95% CI 1.48-1.86, P<0.00001), respectively. The subgroup analysis using Effect Size (ES) showed that apatinib had the best effect on ORR with an ES of 0.66 (95% CI 0.49-0.83, P<0.00001) and DCR with a ES of 0.95 (95% CI 0.91-1.00, P<0.00001). Common drug adverse effects included hypertension, diarrhea, proteinuria, and fatigue. CONCLUSION: The currently used targeted drug therapies for RR-DTC can significantly improve clinical outcomes and the new drug apatinib demonstrates promise for potentially superior performance.

Changing Clinical Presentation of Pediatric Differentiated Thyroid Cancer in Poland: A Retrospective Cohort Study Spanning 45 Years.

Background: Differentiated thyroid carcinoma (DTC) in children is uncommon; clinical presentation over recent decades is incompletely characterized. Methods: This retrospective cohort study analyzed demographic and disease characteristics of consecutive juveniles with DTC treated from 1970 to 2015 at Poland's largest pediatric DTC referral center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, who had available records. Sex, age, histopathological characteristics, and DTC stage were documented. We aimed to identify changes in these variables over time and independent risk factors for lymph node or distant metastases. Trends in these variables were assessed using the Cochran-Armitage test and Spearman correlation. Multivariable logistic regression was performed to identify risk factors associated with lymph node or distant metastases. Results: 475 of 479 patients (99.2%) were included in the analysis; roughly half were age ≥15 years, 10%, <10 years. Papillary thyroid carcinoma (PTC) represented 88% of cases and follicular thyroid carcinoma (FTC) 11%. Tumors ≤2 cm constituted 56% of cases with relevant data; those >4 cm accounted for 12%. Multifocality was observed in 37% and extrathyroidal invasion in 22%. Lymph node metastases were noted in 59% and distant metastases in 16%. Over the observation period, significant trends among new cases included: increased proportion of adolescents >15 years; increased frequency of tumors ≤2 cm, decreased multifocality rates, and increased proportion of PTC versus FTC. Extrathyroidal invasion rates remained appreciable throughout, ranging from 17 to 28% during the 5-year study subperiods after 1990. Lymph node metastases significantly increased in frequency in the central neck, remaining consistently common in lateral sites; presence of distant metastases significantly decreased. In multivariable analysis, multifocality, extrathyroidal invasion, and tumor size were independently associated with lateral lymph node metastases and multifocality, larger tumor size, and N1b metastases with distant spread. Conclusions: Our observations of a rising proportion of diagnoses in adolescence, reductions in primary tumor size, and decreased frequency of multifocality and distant metastases may reflect increased detection of patients with less aggressive DTC at earlier disease stages. Nonetheless, we found persistently substantial rates of locoregionally advanced disease features (multifocality, extrathyroidal invasion, and lymph node metastases), which multivariable analyses suggested have significant associations with lateral lymph node and/or distant metastases.

Recent advances in the use of tyrosine kinase inhibitors against thyroid cancer.

INTRODUCTION: Oncogenic tyrosine kinases (TK) are enzymes that play a key role in cell growth and proliferation and their mutations can lead to uncontrolled cell growth and development of aggressive cancer. This knowledge has led to the development of new classes of drugs, Tyrosine kinase inhibitors (TKI). They target oncogenic kinases who are associated with advanced radioactive iodine (RAI) refractory TC, which is not able to uptake RAI anymore and/or still grows between consecutive treatments with Iodine 131 (I131). AREAS COVERED: Since Lenvatinib and Sorafenib approval, several other molecular inhibitors have been studied and then introduced for the treatment of aggressive and refractory thyroid cancer (TC), and, although the development of adverse effects or tumor resistance mechanisms, more and more compounds are still under investigation. The literature search was executed in PubMed and ClinicalTrials.gov to identify relevant articles and clinical trials published until December 2023. EXPERT OPINION: In the context of clinical trials, driven by the presence of specific molecular mutations or even in the absence of both conditions, systemic therapy TKIs are valuable weapons to be used in patients affected by aggressive forms of TC, waiting for further expansion of the treatment landscape with more efficacious and safer drugs.

Cabozantinib plus ipilimumab/nivolumab in patients with previously treated advanced differentiated thyroid cancer.

BACKGROUND: This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) (NCT03914300). METHODS: Eligible patients with RAI-refractory DTC who progressed on 1 prior line of VEGFR-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. RESULTS: Among 11 patients enrolled, the median age was 69 years. Prior VEGFR-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months [95% CI: 3.0, not reached] and median overall survival was 19.2 months [(95% CI: 4.6, not reached]. Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. CONCLUSION: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. CLINICAL TRIAL REGISTRATION: NCT03914300.

Effects of Iodinated Contrast-enhanced CT on Urinary Iodine Levels in Postoperative Patients with Differentiated Thyroid Cancer.

AIMS: This study aims to observe the fluctuating urine iodine levels in patients with differentiated thyroid cancer (DTC) following iodinated contrastenhanced computed tomography (eCT) scans. BACKGROUND: The presence of iodine in iodinated contrast agents (ICAs) can impede the effectiveness of radioactive iodine treatment (RAIT) and diagnostic scans in individuals diagnosed with DTC, as it can engage in competitive interactions with 131I. According to established guidelines, it is recommended to postpone RAIT for a period of three to four months in individuals who have had prior exposure to ICAS. The measurement of spot urine iodine concentration is a valuable indicator for assessing the overall iodine content throughout the body. OBJECTIVE: The objective is to identify the optimal timing for administering postoperative RAIT in DTC patients. METHODS: At various time points after surgery, a cohort of 467 random urine samples (126 male samples, 341 female samples, age (45±12 years)) was obtained from 269 DTC patients. The samples were analyzed for urinary iodine and urinary creatinine levels, and the urinary iodine/urine creatinine ratio (I/Cr) was computed. All samples were divided into two groups according to whether eCT before operation: the non-enhanced CT (eCT-) group and the enhanced CT (eCT+) group. The urine samples in the eCT- group were categorized into four subgroups according to the duration of strict low iodine diet (LID): (eCT-I+) no LID; (eCT-I-2W) 2 weeks of LID; (eCT-I-4W) 4 weeks of LID; and (eCT-I-6W) 6 weeks of LID. The last three groups were merged into the eCT- and effective LID group (eCT- I-). The urine samples from the eCT+ group were categorized into five subgroups: (0.5M eCT+)0.5 month after eCT+; (1M eCT+)1 month after eCT+; (2M eCT+) 2 months after eCT+; (3M eCT+) 3 months after eCT+; (≥4M eCT+) ≥4 months after eCT+. In addition, the patients within 2 months after eCT+ were divided into 2 groups according to their LID: no effective LID group (eCT+ I+) and effective LID group (eCT+ I-). Utilizing the Kruskal-Wallis and Mann-Whitney U rank sum tests, the differences in I/Cr between groups were compared. RESULTS: In the eCT-group, the I/Cr ratios of eCT-I-2W, eCT-I-4W, and eCT-I-6W were significantly lower than those of eCT-I+ (χ2 values: 4.607.99, all P 0.05). However, there was no significant difference in I/Cr between eCT-I-2W, eCT- I-4W, and eCT-I-6W (2 values: 0.591.31, all P > 0.05). Significantly higher I/Cr values were observed in 0.5M eCT+ and 1M eCT+ than in eCT-I+ (χ2 values: 3.22 and 2.18, respectively, all P<0.05). There was no significant difference in I/Cr between 2M eCT+ and eCT-I+ (χ2 = 0.76, P = 0.447). The I/Cr rations of 3M eCT+, ≥4M eCT+ were not significantly different with eCT-I- (χ2 values: 1.76; 0.58; all P > 0.05). However, they were considerably lower than eCT-I+ (χ2 values: 7.03; 5.22; all P<0.05). The I/Cr for patients who underwent eCT within two months (eCT+ I-, eCT+ I+) did not differ significantly (χ2 = 1.79, P = 0.073). CONCLUSION: For patients who are considering receiving radioactive iodine therapy (RAIT) following a diagnosis of differentiated thyroid cancer (DTC), it is recommended that the interval between RAIT treatment and enhanced computed tomography [eCT] scans be conducted at least three months.