Assessment of levothyroxine therapy adequacy in low-risk differentiated thyroid carcinoma: a multicenter cohort study

Objective: This study aimed to evaluate the adequacy of levothyroxine therapy, assessed by serum thyrotropin (TSH) levels, in patients with low-risk differentiated thyroid carcinoma (DTC).

Methods: We conducted a multicenter, retrospective cohort study including patients with low-risk DTC. Dynamic risk stratification was performed 12 months after initial treatment and at the last follow-up visit according to the 2015 American Thyroid Association (ATA) guidelines. Patients were categorized based on treatment response as excellent, indeterminate, biochemical incomplete, and structural incomplete. Levothyroxine adequacy was determined according to ATA-recommended TSH target values.

Results: A total of 1016 patients (median age, 48 years; 80.7% women; 91.4% papillary thyroid carcinoma) were followed for a median of 6.6 years. Total thyroidectomy was performed in 935 (92.0%) (plus radioiodine in 667), while 81 (8.0%) underwent lobectomy. An excellent response was observed in 633 (62.3%) at 12 months and in 761 (77.8%) at the last follow-up. Treatment adequacy increased from 264 (26.0%) at 12 months to 387 (39.5%) at the final visit (P<0.001). Among patients with excellent response, treatment adequacy rose from 25.8% to 44.3% (P<0.001). At the last visit, inadequacy was primarily due to excessive levothyroxine in patients with excellent response (30.5%), and insufficient dosing in those with indeterminate or biochemical incomplete response (62.2% and 50.0%, respectively). Levothyroxine dose instability correlated significantly with treatment inadequacy (P<0.001).

Conclusion: The low rate of treatment adequacy highlights the need of personalized levothyroxine dosing to optimize therapeutic outcomes and minimize the risks of under- or overdosing in patients with low-risk DTC.

Introduction

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. Its incidence has increased in recent years across all countries, reaching rates as high as 13 to 15 per 100,000 inhabitants per year (1, 2). The main causes of DTC, which includes papillary and follicular carcinoma, are genetic alterations that activate the MAPK pathway, especially mutations in BRAF (V600E) and RAS, as well as gene fusions such as RET and NTRK. Exposure to ionizing radiation in childhood is a well-established risk factor, and there are familial forms associated with genetic syndromes such as Cowden syndrome and familial adenomatous polyposis (3). Obesity and certain environmental exposures have been identified as potential risk factors, although their causal relationship requires further study (4).

Most DTCs display indolent behavior, with low mortality and excellent prognosis. Progression to more aggressive forms (poorly differentiated or anaplastic carcinoma) occurs through the accumulation of additional mutations (e.g., TP53, TERT, PI3K/AKT) that promote cellular immortalization and loss of differentiation (3, 5). The risk of recurrence and mortality is associated with variables such as age, tumor size, invasiveness, lymph node or distant metastasis, and specific molecular features (6). Most of these DTCs are classified as low risk. This group includes intrathyroidal tumors ≤4 cm in size, without aggressive histology, extrathyroidal invasion, or local or distant metastases (7, 8). In these tumors, progression is minimal and the prognosis is excellent, with a five-year survival rate of 98% (1, 9). Many of these tumors do not require aggressive treatment or intensive follow-up (10, 11).

For decades, treatment of DTC has been based on three main pillars: surgery, radioiodine (RAI), and inhibition of thyrotropin (TSH) secretion (12). The rationale for the latter is that most DTCs express TSH receptors, and therefore, the use of supraphysiological doses of thyroid hormone inhibits pituitary TSH release and is thought to suppress the proliferation and function of residual thyroid cells, both normal and cancerous (8). However, sustained suppression of TSH secretion is not harmless. Subclinical thyrotoxicosis resulting from excessive levothyroxine has been associated with an increased risk of atrial fibrillation, cardiovascular disease, osteoporosis, and fractures (12, 13).

The 2015 American Thyroid Association (ATA) clinical guideline (14) gives precise recommendations for TSH suppression in low-, intermediate-, and high-risk patients during the first year following initial treatment. One year after initial therapy, and at subsequent follow-up visits, patients should undergo re-stratification using dynamic risk stratification (DRS) and be classified according to their response to therapy (14–16). TSH should be maintained within the range of 0.5-2, between 0.1-0.5 and < 0.1 mcU/ml in the case of low risk patients who achieve an excellent, indeterminate or biochemical incomplete and structural incomplete response, respectively. Real-life studies show that the frequency of TSH suppression in patients with low-risk DTC is much higher than expected (17). A recent survey (18) of 448 North American endocrinologists and surgeons revealed that 48.8% of respondents strongly favored TSH suppression in patients with low-risk papillary thyroid cancer. However, multicenter studies specifically targeting patients at low risk of recurrence, who are the most common in clinical practice, are currently lacking. To give insight into the real-world approach of Spanish endocrinologists on this topic, we designed this study to assess the adequacy of levothyroxine therapy, evaluated by serum TSH levels, in patients with low-risk DTC both 12 months after initial treatment and at their final follow-up visit.

Methods

Subjects

This multicenter, retrospective study analyzed the adequacy of levothyroxine treatment in patients older than 18 years with a histologic diagnosis of low-risk DTC as defined by the ATA risk stratification system (14). To be included in the study, patients had to meet all of the following criteria: (a) surgical treatment by lobectomy or total/near total thyroidectomy, with or without lymph node dissection, followed or not by radioiodine (RAI) treatment, (b) availability of a histological report, (c) follow-up at the same hospital for at least 12 months, and (d) documentation of DRS at both 12 months and at the last clinical visit. Patients with incomplete follow-up data preventing the assessment of DRS were excluded.

Study design

This project was disseminated through the Thyroid Task Force of the Spanish Society of Endocrinology and Nutrition (Sociedad Española de Endocrinología y Nutrición, SEEN) composed of endocrinologists with special expertise and dedicate ghion to thyroid disease. Seventeen investigators from fifteen hospital centers agreed to participate. Each investigator included adult patients with low-risk DTC who attended their outpatient clinics between January 1 and December 31, 2024.

Data collection encompassed clinical and demographic characteristics, initial surgery, RAI treatment when applicable, pathological findings, initial patient risk classification, and follow-up data, with particular attention on DRS assessment and serum TSH level obtained both at 12 months and at the last clinical visit. At the end of follow-up, additional data were collected on the presence of permanent postoperative hypoparathyroidism and any health conditions affecting levothyroxine dosage or TSH suppression. In particular, we consider the presence of osteoporosis, osteopenia, previous fracture, atrial fibrillation, tachycardia or other arrhythmias and fragility, since all these conditions can determine the degree of TSH suppression. For patients with a follow-up period exceeding two years, levothyroxine dose stability was assessed. Patients whose levothyroxine dose remained unchanged over the past year were classified stable, whereas those who had undergone one or more dose adjustments during that period were considered unstable. In patients considered unstable, various causal factors of variability in TSH determination were considered, such as lack of adherence to medication, pharmacological interferences, diseases that produce alterations in thyroxine absorption, significant changes in weight and other factors.

All patients’ data were obtained under the standard medical care conditions. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The patient’s confidential information was protected according to national law, and the study was approved by the local ethics committee of the Hospital Universitario Puerta de Hierro Majadahonda (Madrid, Spain) (PI 157/24).

Initial classification of patients

For the classification of patients at the time of diagnosis, the tumor, node, metastases (TNM) staging system was used according to the criteria of the American Joint Committee on Cancer (AJCC/UICC), 8th edition (19). The initial risk of recurrence was classified according to the 2009 American Thyroid Association (ATA) criteria, with the modifications proposed in 2015 (14).

Laboratory procedures

Serum thyroglobulin (Tg), Tg antibodies (TgAb) and TSH measurements were performed using standard procedures of each hospital. The instruments used for Tg and TSH quantification, along with the number of investigators and patients involved, are summarized in Supplementary Tables S1 and S2 (Supplementary Material). These tables also include the Tg detection limits for each of the assays used and the reference intervals for TSH provided by the manufacturers of the different analytical methods. TSH and other laboratory parameters were measured at participating centers in the morning, regardless of fasting status. The lower limit of the TSH reference interval ranged from 0.25 to 0.55 mcU/ml, while the upper limit was between 4.2 and 5.3 mcU/ml. All participating clinical laboratories used standardized methods and complied with established quality standards.

Dynamic risk stratification

For the assessment of DRS, we considered biochemical data (Tg and TgAb) and imaging tests (ultrasound and others if necessary), as well as the treatment received by each patient (thyroidectomy plus RAI ablation, thyroidectomy without ablation and lobectomy) (14–16, 20, 21).

Tg determination was considered valid only when the TgAb titer was negative. Tg values were stratified into three groups as specified in Supplementary Table S3 (Supplementary Material). In patients who underwent thyroidectomy plus RAI ablation, Tg levels were classified as follows: excellent response (Tg EX group) for values <0.20 ng/ml (<0.50 ng/ml for Immulite 2000); indeterminate response (Tg IN group) for values ​​between 0.20 and 0.99 ng/ml (0.5 to 0.99 ng/ml for Immulite 2000); and biochemical incomplete response (Tg BI group) for values ≥1 ng/ml. In patients who underwent thyroidectomy without ablation, the Tg EX, Tg IN and Tg BI groups were defined by Tg values ​​of <0.20, 0.20 to 4.99 and ≥5.0 ng/ml, respectively (<0.50, 0.50 to 4.99 and ≥5.0 ng/ml, respectively for Immulite 2000). For patients who underwent lobectomy, only two groups were defined: Tg EX (<30 ng/ml) and Tg BI (≥30 ng/ml). Thyroid ultrasound results were classified as negative (normal ultrasound), indeterminate (non-specific findings that cannot be classified as normal or suspicious) or suspicious (findings indicative of malignancy).

DRS was performed at 12 months and at the last follow-up visit. In both cases, patients were classified into four categories (15) based on the following criteria: excellent response (Tg EX, negative TgAb, and negative imaging), indeterminate response (Tg IN or non-rising positive TgAb, or indeterminate or suspicious imaging), biochemical incomplete response (Tg BI or rising TgAb), and structural incomplete response (evidence of structural or functional disease regardless of Tg or TgAb levels).

Adequacy of levothyroxine treatment

The adequacy of levothyroxine treatment was assessed based on the TSH level at 12 months and at the last follow-up visit. In cases of structural incomplete response, a TSH level <0.1 mcU/ml was considered appropriate. In patients with an indeterminate or biochemical incomplete response, TSH values ​​between 0.1 and 0.5 mcU/ml were considered adequate. For patients with an excellent response, control was considered adequate when their serum TSH level was between 0.5 and 2.0 mcU/ml. When TSH levels were above the appropriate control range, it was considered that there was an insufficient dose of levothyroxine. TSH levels above the target range indicate insufficient levothyroxine dosing, whereas levels below the range indicated overtreatment.

Statistical analysis

Quantitative variables are expressed as median (interquartile range, IQR). Categorical variables are described using absolute values, ratios, or percentages. Proportions were compared using the chi-square test or Fisher’s exact test. Comparisons of quantitative variables between two groups were conducting using the Mann–Whitney U-test. The McNemar test was used to compare treatment adequacy at 12 months and the last follow-up visit (paired data). Several univariate and multivariable logistic regression models were applied to identify factors influencing levothyroxine therapy adequacy at 12 months and at the last follow-up visit. We used variables that are generally associated with the prognosis of patients with DTC (gender, age, time of follow-up, histology, tumor size and incidental tumor), as well as variables that were significant in the comparative statistical analysis between patients with adequate and inadequate control (type of thyroidectomy, radioiodine, hypoparathyroidism, health problems and dose instability). All statistical tests were two-sided, and differences were considered significant when P <0.05.

Results

Patients’ characteristics

Of the 1168 patients with low-risk DTC selected for the study, 152 were excluded due to the lack of sufficient clinical information for DRS. The final cohort comprised 1016 patients (820 women, 80.7%) with median (IQR) age of 48 (38–59) years. Papillary thyroid carcinoma was diagnosed in 929 patients (91.4%), while 87 (8.6%) had follicular thyroid cancer. Surgical treatment included lobectomy in 81 patients (8.0%), total thyroidectomy in 610 cases (60.0%), and total thyroidectomy plus lymph node dissection in 325 (32.0%). RAI remnant ablation was administered to 667 patients (65.6%) postoperatively after initial surgery. Based on TNM staging, 94.7% (962) were classified as T1-T2 and 90.7% (922) as N0-Nx (Table 1).

Table 1

Table 1. Clinical, pathological and therapeutic characteristics of the studied patients with low-risk differentiated thyroid carcinoma.

Follow-up and dynamic risk stratification

The median follow-up time was 79 (42–142) months. Health conditions potentially affecting levothyroxine dosing were identify in 88 patients (8.7%), including osteoporosis (51), atrial fibrillation (14), frailty (12), arrhythmia (7), and fractures (3). Among 898 patients with at least two years of follow-up, 310 (34.5%) exhibits dose instability. Identifiable causes were present in 194 cases, including weight changes (74), non-adherence (41), risk category change (24), poor tolerance or comorbidities (19), drug interactions (14), malabsorption (13), medication error (2) and other (7). No cause was identified in 116 patients. At the last visit evaluation, there were 83 patients (8.2%) with chronic hypoparathyroidism.

DRS outcomes at 12 months after initial treatment were as follows: excellent response, 62.3%; indeterminate response, 34.0%; incomplete biochemical response, 3.0%; and incomplete structural response, 0.8%. Final DRS outcomes were: excellent response, 77.8%; indeterminate response, 19.7%; incomplete biochemical response, 2.0%; and incomplete structural, 0.4% (Table 2).

Table 2

Table 2. Dynamic risk stratification at 12 months after initial treatment and at the last visit.

Adequacy of levothyroxine treatment

Twelve months after initial therapy, 264 patients (26.0%) had TSH levels within the target for their DRS status, indicating adequate control. At the final evaluation, this proportion increased significantly to 39.6% (387/978; P <0.001; McNemar test). The adequacy of treatment across DRS categories is summarized in Table 3.

Table 3

Table 3. Number and proportion of patients with adequate and inadequate control at 12 months and at the last visit.

For comparative analysis, two groups of patients were examined: those with excellent response versus those with indeterminate or incomplete biochemical response. Patients with structural incomplete response were excluded due to their distinct characteristics and small number. Among patients with excellent response, treatment adequacy increased significantly from 25.8% at 12 months to 44.3% at the last visit (P<0.001; Figure 1). However, no significant changes in adequacy were observed over time in the indeterminate or incomplete biochemical response group (26.1% vs 23.0%; P = 0.515).

Figure 1

Figure 1. Percentage of patients with adequate and inadequate control at 12 months after initial treatment and at the final visit. Patients are classified according to response type (excellent, and indeterminate or biochemical incomplete response).

Table 4 shows characteristics of patients with excellent response and adequate control compared to patients with inadequate control at 12 months. Patients with adequate control were more likely to be male (25.8 vs. 17.4%; P = 0.029), have incidental tumors (27.8 vs. 19.4%; P = 0.027), and have hypoparathyroidism (11.7 vs. 6.0%; P = 0.023). Conversely, they had lower rates of total thyroidectomy (88.3 vs. 93.8%; P = 0.026) and RAI treatment (55.2 vs. 75.1%; P<0.001). At the last visit, treatment adequacy was significantly associated with dose instability, which was higher in inadequately controlled patients (49.2 vs. 12.0%, P<0.001).

Table 4

Table 4. Comparison of patients with adequate and inadequate control at 12 months and at the last follow-up visit (patients with excellent response).

Patients with indeterminate and biochemical incomplete response were analyzed together (Table 5). At 12 months patients with adequate control had higher rates of follicular carcinoma (13.3 vs. 5.8%; P = 0.026), total thyroidectomy (99.0 vs. 88.4%; P = 0.001) and RAI treatment (72.4 vs. 53.1%; P = 0.001) compared with patients with inadequate control. They also had larger tumors (1.5 [0.8-2.0] vs. 1.0[0.6-1.8] cm; P = 0.021). At the end of follow-up, patients with adequate control had larger tumors than those with inadequate control (1.3 [0.8-2.2] vs. 0.9 [0.5-1.5] cm; P = 0.017), while no differences were observed in other variables.

Table 5

Table 5. Comparison of patients with adequate and inadequate control at 12 months and at the last follow-up visit (patients with indeterminate or biochemical incomplete response).

Multivariable logistic regression analysis

Results of several models of multivariable logistic regression analysis are shown in Supplementary Material (Supplementary Tables S4-S7). A summary of the most relevant findings is shown in Figure 2. At 12 months treatment adequacy was significantly associated with male sex and hypoparathyroidism in patients with excellent response and with total thyroidectomy in those with indeterminate or incomplete biochemical response. RAI treatment showed significant but inverse association with adequacy in the excellent response group. In the last visit adequacy was inversely correlated with dose instability in both excellent, indeterminate and biochemical incomplete response.

Figure 2

Figure 2. Summary of the results of the multivariate logistic regression analysis (model 2) to study the influence of several variables on the adequacy of levothyroxine treatment. Patients are classified according to treatment response (excellent response and indeterminate or biochemical incomplete response) both at 12 months and at the last follow-up visit. Data are the odds ratio with 95% confidence intervals. *P < 0.05, **P < 0.001.

Discussion

This study examines the adequacy of levothyroxine treatment in a large cohort of patients with low-risk DTC followed by expert endocrinologists. Three key findings emerge: first, the proportion of patients achieving adequate control is strikingly low; second, treatment adequacy improves at the last follow-up, but only in patients with excellent response; and third, levothyroxine dose instability is the main determinant of long-term inadequacy.

Low adequacy of levothyroxine treatment

Our results show a low level of levothyroxine therapy adequacy, with only 26.0% of patients within the target TSH range at 12 months of initial treatment and 39.5% at the end of the follow-up period. In an effort to decrease unnecessary adverse effects of overdose of levothyroxine, national (22) and international (14) clinical guidelines clearly propose a graded tailored approach to TSH suppression based on initial risk of recurrence, and subsequent response to therapy.

Accordingly, the results obtained in thyroid cancer patients in Spain seem discouraging. A previous study in 216 patients with DTC (69.2% of them low-risk) found that 30.7% of low-risk patients with an excellent response had unnecessarily suppressed TSH levels, though this percentage decreased to 16.3% after a mean follow-up of 6.9 years (23). Another study of 102 low-risk DTC patients reported that only 8.8% had appropriate TSH levels at 12 months, improving to 19.6% after a mean follow-up of 5.9 years (24). A multicenter study in Turkey (25), including 1125 patients with all-risk DTC, found that only 29.2% of patients achieved adequate target TSH levels with overtreatment observed in 50.4% of all analyzed patients and 80.2% of low-risk cases, whereas undertreatment was detected in 20.4%. Conversely, a Chinese study reported a 61.4% adequacy rate (26), though it included only intermediate- and high-risk DTC patients and had a follow-up of just one year.

In short, our findings reinforce the conclusion that levothyroxine overuse is prevalent particularly in patients with excellent response. However, overtreatment is not unique to thyroid cancer; it has also been reported in patients with subclinical hypothyroidism with the intention of alleviating symptoms or improving quality of life, despite a lack of supporting evidence (27).

Improvement in treatment adequacy over time

The proportion of well-controlled patients increased by the end of the follow-up compared to the 12-month visit; however, this improvement was observed only in patients with excellent response and not in other types of responses. In our study 62.3% of low-risk patients had an excellent response at 12-month increasing to 77.8% at the final visit. These results are comparable, though slightly lower, than those reported by other authors where excellent response rates range from 70 to 91% (14, 28, 29). The increase in the excellent response rate between the 12-month and the final assessments also suggests a corresponding decrease in the proportion of patients with less-than-excellent responses decreases over time, indicating that treatment intensity should be reduced in many of them. These results are consistent with those of other authors who have reported a favorable evolution of patients with an excellent response (29). In relation to these considerations, the improvement in the adequacy of levothyroxine treatment observed in this study could be related to the increase in the proportion of patients with an excellent response between the 12-month evaluation and the last visit, since the TSH target range for these patients is broader than that for patients with less than excellent responses. Other factors that could explain the observed improvement in TSH adequacy over time include better patient adherence to the prescribed treatment, greater diligence by physicians in adjusting levothyroxine doses, or increased frequency of laboratory monitoring.

The 2015 ATA guidelines recommend maintaining TSH levels between 0.5 to 2.0 mcU/ml for patients with an excellent response. However, only 25.8% of our patients achieved this target at 12 months, increasing to 44.3% at the final follow-up visit. Among patients with excellent response, inadequate control of TSH levels was primarily due to levothyroxine overdosing, whereas, in those with indeterminate response, it was more often due to insufficient dosing (Table 3). These data suggest a tendency among Spanish endocrinologists to favor excessive TSH suppression in patients with an excellent response, while being reluctant to lower TSH below 0.5 mcU/ml in patients with indeterminate or incomplete biochemical responses.

Therapeutic inertia in reducing levothyroxine dosage in patients with excellent response may stem from concerns about cancer recurrence if TSH suppression is relaxed (18, 30). Nonetheless, there is no evidence that aggressive TSH suppression reduces recurrence in low-risk patients (17, 31). Moreover, long-term TSH suppression is associated with serious health risks, including cardiac morbidity, bone loss, fractures, and impaired quality of life (13, 32). Furthermore, Qiang et al. (33) recently found that maintaining TSH in the range of 0.5–2 mIU/L showed no significant difference in DTC recurrence compared with TSH levels of 2–4 mIU/L, suggesting that guidelines may consider liberalizing TSH targets in low-risk cohorts.

Dose instability as the key determinant of inadequate treatment

Our multivariate analysis identified gender, RAI, and hypoparathyroidism as predictors of treatment adequacy at 12-months in patients with an excellent response, while total thyroidectomy was a determinant for patients with a less favorable response. These associations are challenging to interpret; however, they highlight the fact that classic histological variables (multifocality, vascular invasion, tumor size) were not significant in the multivariate analysis. These findings are consistent with previous reports by other authors (23). Nevertheless, caution should be exercised when interpreting these associations, as the design of our study does not allow us to establish causal relationships.

At the last visit, dose instability emerged as the most important and significant factor determining treatment adequacy. A strong inverse relationship was observed between instability and treatment adequacy, especially in patients with excellent response (HR 0.14), but also in those with suboptimal responses (HR 0.45). Dose instability was observed in 310 of 898 patients (34.5%) with over two years of follow-up. Identifiable causes included weight fluctuations, medication non-adherence, changes in risk classification, drug interaction, and malabsorption (34).

Poor adherence was detected in 13% (41 of 313) of our patients. This is a common cause of treatment inadequacy in various chronic conditions, including hypothyroidism (35, 36). Our results are similar to those reported by Yavuz et al. (25), who found that 16.4% of patients missed at least one dose in the past month. Other studies have reported even higher non-adherence rates, with 52% of thyroid cancer classified as non-adherent in one survey (37).

Additionally, 37.4% of our patients require dose adjustments for unidentified reasons, possibly due to spontaneous TSH variations. Previous studies indicate that up to 20% athyreotic patients exhibit significant spontaneous TSH variations despite stable levothyroxine dosing (28). Given the narrow therapeutic index of levothyroxine, small dose adjustments can result in significant TSH fluctuations, impacting serum Tg levels and DRS classification (38, 39), especially in low-risk DTC treated with thyroidectomy without RAI (40).

Clinical implications

Our study may have important clinical implications as we are currently experiencing an era of overdiagnosis of DTC due to the widespread availability and use of ultrasound and other imaging tests. This has led to an unprecedented rise in the incidence of these tumors (41). Overdiagnosis is often followed by overtreatment, which carries potential health risks and contributes to the excessive consumption of healthcare resources (42).

Our findings suggest that Spanish endocrinologists struggle to adhere to clinical guidelines. Various reasons have been put forward for clinicians’ failure to follow guidelines, including lack of familiarity, disagreement with recommendations, inertia of previous practice, or difficulty in reconciling patient preferences with guideline recommendations (43). Furthermore, some clinicians may fail to reassess their patients’ recurrence risk or may not fully recognize the appropriate TSH targets according to guideline-based risk stratification, further contributing to suboptimal management. In the case of low-risk DTC, clinicians should try to avoid levothyroxine overdosage in patients with excellent response. It has been well established that iatrogenic thyrotoxicosis is associated with the various above-mentioned health risks and also extra laboratory monitoring and physician visits (12, 13). Therefore, we believe that proper levothyroxine dose adjustment is essential at all visits in patients with thyroid cancer, and that the TSH targets established by guidelines should be pursued. In addition, patients with dose instability deserve special attention, and efforts should be made not only to determine the cause of the instability but also to take measures to prevent TSH fluctuations and continuous dose changes in these patients.

One final consideration should be added to our comments. It is true that while TSH suppression therapy has traditionally been regarded as an adjunctive treatment following thyroid cancer surgery, there remains an ongoing clinical question as to whether such therapy is genuinely necessary for patients with low-risk DTC. This suppression was based on the fact that DTC tumor cells express TSH receptors and respond to their stimulation with cell proliferation. Therefore, supraphysiological doses of levothyroxine have historically been used as adjuvant therapy after surgery, with the aim of reducing the risk of recurrence or tumor progression (12). However, current evidence has substantially modified this practice, especially in patients with low-risk DTC. The latest ATA guidelines (44), published after this study was conducted, do not recommend prolonged TSH suppression in patients with low- or intermediate-risk disease who do not have evidence of biochemical or structural recurrence. The rationale is that these patients have an excellent prognosis, and TSH suppression does not provide additional benefits in terms of recurrence or overall survival.

Strengths and limitations

The main strengths of our study include its large sample size, multicenter national setting, well-defined inclusion criteria, and rigorous data collection by specialists in thyroid disease. All data were obtained from standard practice at the participating centers, ensuring that the findings reflect real-life outcomes in thyroid cancer patients treated in Spain.

However, this study has limitations inherent to its retrospective nature. Follow-up protocols may have varied across centers and differences in laboratory measurements methods could affect comparability of serum Tg data. Therefore, we consider that future research would benefit from prospective cohort designs with pre-specified data collection protocols, ensuring standardized and complete documentation of clinical, biochemical, and treatment-related variables. Pragmatic randomized designs evaluating different TSH targets or levothyroxine management strategies could further reduce confounding. Furthermore, future multicenter studies should adopt harmonized follow-up protocols or, at minimum, collect detailed data on center-specific practices to adjust for these differences analytically. Whenever possible, future studies should standardize laboratory methods by using uniform assays or perform cross-calibration studies.

On the other hand, our study has the inherent limitation of excluding a group of patients with insufficient clinical information, which may have led to potential selection bias and a lack of longitudinal trend analysis of TSH. Prospective designs with standardized data collection and employing longitudinal TSH data will minimize missing information. Expanding the data sources (e.g., linking electronic health records with pharmacy and administrative databases) may also reduce the proportion of patients with incomplete information. Together, these limitations highlight the challenges of assessing adequacy of levothyroxine therapy in retrospective, multicenter settings. Prospective study designs, standardized protocols, and robust longitudinal analyses would substantially enhance the reliability and generalizability of future findings.

Conclusions

In conclusion, the adequacy of levothyroxine treatment in patients with low-risk DTC remains suboptimal in the studied cohort. Our findings indicate that, after a mean follow-up of 6.6 years, 30.5% of patients with excellent response are overtreated with supraphysiological doses of levothyroxine, while 62% of those with an indeterminate response and 50% of those with an incomplete biochemical response receive insufficient doses of thyroid hormone. Consequently, the former faces an increased risk of complications associated with subclinical thyrotoxicosis, whereas the latter may have a heightened risk of tumor recurrence. Preventing both overtreatment and undertreatment is mandatory, requiring greater adherence to clinical guidelines by the clinicians managing these patients.

The potential lessons for clinical practice derived from the findings of our study can be summarized in the following points: (a) clinicians should overcome barriers to adherence to clinical guidelines, (b) levothyroxine doses should be adjusted at all visits of patients with DTC, and (c) special attention should be paid to patients with dose instability. It is our opinion that these recommendations would serve to improve the adequacy of healthcare for patients with DTC. Achieving optimal therapeutic adequacy requires a personalized approach to treatment, considering each patient’s risk of recurrence and response to treatment, as assessed by the DRS at each follow-up visit.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

This study was conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because this is a retrospective analysis of data in clinical records. All patients’ data were obtained under the standard medical care conditions. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The patient’s confidential information was protected according to national law, and the study was approved by the local ethics committee of the Hospital Universitario Puerta de Hierro Majadahonda (Madrid, Spain) (PI 157/24).

Author contributions

JD: Data curation, Supervision, Methodology, Writing – review & editing, Conceptualization, Writing – original draft, Investigation, Visualization, Project administration, Validation, Formal Analysis, Resources. EA: Writing – review & editing, Writing – original draft, Formal Analysis, Methodology, Supervision, Validation, Data curation, Investigation. VA: Investigation, Validation, Writing – review & editing, Supervision, Writing – original draft, Formal Analysis, Methodology, Data curation. JG: Validation, Formal Analysis, Writing – review & editing, Methodology, Supervision, Data curation, Investigation, Writing – original draft. CF: Investigation, Validation, Supervision, Formal Analysis, Writing – review & editing, Data curation, Methodology, Writing – original draft. MP: Methodology, Data curation, Supervision, Writing – review & editing, Investigation, Validation, Writing – original draft, Formal Analysis. SG: Formal Analysis, Supervision, Data curation, Methodology, Validation, Writing – original draft, Writing – review & editing, Investigation. AH: Supervision, Writing – review & editing, Formal Analysis, Methodology, Writing – original draft, Investigation, Data curation, Validation. MA: Writing – review & editing, Investigation, Methodology, Validation, Formal Analysis, Writing – original draft, Supervision, Data curation. AP: Data curation, Investigation, Writing – original draft, Validation, Methodology, Writing – review & editing, Formal Analysis, Supervision. CS: Formal Analysis, Writing – original draft, Data curation, Methodology, Investigation, Validation, Supervision, Writing – review & editing. TM: Writing – review & editing, Supervision, Data curation, Investigation, Methodology, Writing – original draft, Validation, Formal Analysis. BR: Data curation, Writing – original draft, Formal Analysis, Methodology, Supervision, Investigation, Validation, Writing – review & editing. MM: Writing – review & editing, Investigation, Supervision, Writing – original draft, Validation, Data curation, Formal Analysis, Methodology. AO: Data curation, Investigation, Writing – original draft, Writing – review & editing, Validation, Formal Analysis, Supervision, Methodology. RS: Validation, Writing – review & editing, Supervision, Formal Analysis, Data curation, Investigation, Writing – original draft, Methodology. JS: Methodology, Writing – review & editing, Supervision, Investigation, Writing – original draft, Conceptualization, Visualization, Formal Analysis, Validation, Data curation.

Funding

The author(s) declared that no financial support was received for this work and/or its publication.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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