Most thyroid cancers can be cured with surgery, sometimes with radioactive iodine therapy. However, some patients have cancer that has spread, and some have cancer that comes back after treatment. For those with remaining cancer, lowering TSH levels is recommended. This is because thyroid cancer growth can depend on TSH, so reducing TSH can lower the risk of cancer returning and slow its growth in patients with cancer that can't be surgically removed.

International guidelines recommend keeping TSH levels as low as <0.1 mU/L for patients with advanced thyroid cancer. This advice is based on past studies, but it hasn't been tested in a controlled way. One old study suggested that not lowering TSH enough could lead to more cancer relapses. Another study suggested that lowering TSH more could help prevent cancer from getting worse in high-risk patients. However, a recent study found no link between TSH levels and better outcomes, and the researchers suggested doing a new study to confirm if this practice is truly beneficial.

Lowering TSH levels to <0.1 mU/L using levothyroxine has been the standard of care for treating advanced thyroid cancer for a long time. The researchers would like to investigate whether using levothyroxine to keep TSH levels between 0.1 and 0.5 mU/L is just as safe and effective for cancer treatment as the current recommendation of keeping it below 0.1 mU/L. The researchers also believe this study can help set TSH suppression targets based on cancer type, reducing unnecessary side effects from too much TSH suppression while still achieving the same cancer treatment results.

If the researchers can prove that keeping TSH levels between 0.1 and 0.5 mU/L is just as safe and effective as the standard of care practice, we can change our standard treatment approach. This would help reduce symptoms for our patients.

Inclusion Criteria:

1. Minimum age of 18 years, with no upper limit of age.

2. ECOG 0-2

3. Patients must be capable of providing consent to enrollment and willing to comply with study treatment and follow-up.

4. Diagnosis of differentiated thyroid cancer (including papillary, follicular, oncocytic, and poorly differentiated subtypes) with advanced structural disease (defined as unresectable persistent/ recurrent locoregional disease and/or distant metastases).

5. Residence within Alberta and referral to the Cross Cancer Institute in Edmonton, for consideration of anticancer therapy and/or follow-up.

6. Absence of any condition hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the study.

7. Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 30 days after the last dose of study drug. A highly effective method of birth control is defined as those resulting in low failure rate (i.e., less than 1% per year) when used consistently and correctly.

   Note: abstinence is acceptable if this is established and preferred contraception for the patient.

8. Women of childbearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause.

9. Females must not be breastfeeding (timeframe: during study treatment period and for a period of 30 days after the last dose of the study drug).

10. Ability to obtain sufficient thyroid cancer tissue to conduct baseline NGS testing (could be fresh or archived tissue).

Exclusion Criteria:

1. Recent acute coronary event (within 6 months of randomization).

2. History of atrial fibrillation.

3. Known hypersensitivity to levothyroxine.

   - Treatment with other investigational drugs within 30 days prior to randomization.

4. History of fragility fractures or established diagnosis of osteoporosis.

   • Prior treatment with levothyroxine before study entry at any dose and with any TSH target is not an exclusion criterion.