Broadening the TSH Target to 0.5 to 4 mU/L Appears Safe for Low-Risk Differentiated Thyroid Cancers

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Qiang JK, Sutradhar R, Everett K, et al. Association between serum thyrotropin and cancer recurrence in differentiated thyroid cancer: a population-based retrospective cohort study. Thyroid. Epub 2024 Dec 26; doi: 10.1089/thy.2024.0330. PMID: 39723994.
  • Background:
    • In addition to surgery (thyroidectomy with or without lymphadenectomy) and radioactive iodine treatment (RAIT), patients with differentiated thyroid cancer (DTC) may benefit from thyroid hormone therapy that suppresses TSH to reduce the risk of recurrence
    • The 2015 American Thyroid Association (ATA) guidelines recommend:
      • Maintaining TSH levels below 0.1 mU/L in patients with high-risk DTC:
        • As this has been shown to improve survival in these patients
    • The level of TSH suppression should be adjusted based on:
      • Comorbidities and response to treatment
    • However, TSH suppression is not without risks, and has been associated with an increased risk of:
      • Osteoporosis
      • Atrial fibrillation
      • A reduced quality of life
  • In patients with low-risk DTC:
    • The ATA guidelines recommend maintaining TSH levels between 0.5 and 2.0 mU/L:
      • As further TSH suppression in these cases increases the risks associated with subclinical hyperthyroidism without affecting cancer recurrence rates
    • The present study aimed to evaluate whether a broadened TSH range up to 4.0 mU/L is equally safe in terms of DTC recurrence as compared with the recommended low-normal TSH goal range (0.5–2.0 mU/L)
  • Methods:
    • A retrospective, population-based cohort study was conducted using data from the Ontario Cancer Registry, covering the period from 2007 to 2018
    • Serum TSH values and their measurement dates were obtained from the Ontario Laboratories Information System, which captures nearly all outpatient laboratory tests in Ontario
    • The study included patients ≥ 18 years of age, diagnosed with DTC, and with available follow-up information, including at least one TSH value recorded during follow-up
    • Patients were followed for TSH measurements and DTC recurrence starting from the index date, defined as 12 months after thyroidectomy
    • The primary outcome was the time from the index date to DTC recurrence
    • Recurrence was defined as death due to DTC or the need for additional treatment, including new surgery (thyroidectomy or neck dissection) or RAIT, after the index date
    • TSH was treated as a time-dependent covariate, updated every 90 days if a new TSH measurement was available
    • TSH levels were classified into mutually exclusive categories, with TSH >2 to ≤4 mU/L as the primary exposure and TSH 0.5–2 mU/L as the reference category
    • Secondary exposures included TSH <0.5 mU/L and TSH >4 mU/L
  • Results:
    • A total of 26,336 patients were included; 21% underwent hemi-thyroidectomy, 41% total thyroidectomy, and 38% total thyroidectomy combined with RAIT
    • The median follow-up was 5.9 years (interquartile range [IQR], 3.6–8.6) from the index date and the median TSH was 0.6 mU/L (IQR, 0.1–1.8)
    • During the follow-up period, there were 2,817 cases of DTC recurrence (10% of the cohort), including 103 DTC-specific deaths (0.3%)
    • No significant increase in recurrence risk was observed with each additional 3 months of cumulative exposure to TSH levels between 2 and 4 mU/L as compared with 0.5–2 mU/L (hazard ratio [HR] 0.99, confidence interval [CI], 0.97–1.02; P = 0.55):
      • However, a significantly higher risk of DTC recurrence was associated with each additional 3 months of cumulative exposure to TSH levels > 4 mU/L as compared with 0.5–2 mU/L (HR, 1.07; CI, 1.04–1.09; P<0.01)
    • The risk of composite recurrence increased in a dose-dependent manner with longer exposure to TSH >4 mU/L:
      • For instance, after 4 years of cumulative exposure to TSH > 4 mU/L:
        • The adjusted HR was 2.86 (CI, 1.88–4.08)
    • These findings were consistent when analyses were stratified by baseline treatment and when the index date was adjusted from 12 to 18 months
  • Conclusions:
    • Patients with low-risk DTC may safely maintain TSH levels within the higher normal range without increasing the risk of thyroid tumor recurrence:
      • Accordingly, serum TSH targets could be broadened to 0.5 to 4 mU/L in patients with low-risk DTC
  • Summary:
    • This large, population-based cohort study provides evidence that maintaining TSH levels between 2 and 4 mU/L in low-risk DTC patients results in recurrence rates similar to those of the 0.5–2 mU/L range recommended by the 2015 ATA guidelines
    • Although earlier observational studies proposed a threshold of 2 mU/L as optimal for differentiating recurrence-free survival from thyroid carcinoma–related deaths and recurrences, confirmatory large-scale studies have been lacking
    • As such, guidelines were based largely on low-quality evidence
    • The potential for broadening TSH target ranges also carries significant health care implications:
      • Managing thyroid cancer in the United States is projected to cost over $3.5 billion by 2030
    • Relaxing TSH targets could reduce health care costs by decreasing the frequency of blood tests and lessening the need for intensive monitoring
    • From a clinical standpoint, a less stringent TSH range could improve patient compliance
    • Fewer blood tests would not only reduce stress but could also enhance quality of life
    • A more uniform dosing regimen, without the need for frequent adjustments to maintain a strict TSH target, could simplify treatment and make it more manageable for patients
    • A broader TSH range is particularly beneficial for frailer patients, particularly those with comorbidities like atrial fibrillation or osteoporosis, since it may reduce the risk of inadvertently causing subclinical hyperthyroidism
    • On the other hand, TSH should not exceed 4 mU/L
    • In this study, a TSH > 4 mU/L was associated with a higher risk of DTC recurrence, and previous studies also linked TSH > 4 mU/L to increased risks of cardiovascular disease, dysrhythmias, and fractures as compared with patients whose TSH levels are within the reference range
    • Despite its findings, this study has some limitations
    • It does not provide detailed pathological data, which hampers our ability to precisely assess the ATA risk classification of these tumors
    • Additionally, recurrences were recorded only if they required treatment, meaning that some recurrences may not have been captured
    • This highlights the need for further comprehensive studies, especially with longer follow-up periods, to confirm these results
    • This is particularly important in patients who undergo lobectomy, where the optimal TSH target and the decision to start levothyroxine remain areas of ongoing debate
    • In conclusion, this study provides valuable reassurance regarding a broader TSH range of 0.5 to 4 mU/L; however, further research is needed to refine treatment protocols and guide clinical decision-making.
  • Key points:
    • In patients with low-risk differentiated thyroid cancer (DTC), TSH levels from 0.5 to 4 mU/L were not associated with an increase in cancer recurrence in a retrospective population-based analysis
    • There was an increased risk of recurrence in patients with low-risk DTC when TSH was > 4 mU/L, whereas maintaining TSH levels within the higher normal range may be safe and does not increase the risk of thyroid tumor recurrence
    • Broadening the serum TSH target to 0.5 to 4 mU/L in patients with low-risk DTC could be considered
  • References:
    • McGriff NJ, Csako G, Gourgiotis L, et al. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med. 2002; 34(7-8):554-564.
    • Diessl S, Holzberger B, Mäder U, et al. Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 2012;76(4):586-592.
    • Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.
      4. Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid2006;16(12):1229-1242.
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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