Clinical Context
Radioactive iodine (RAI) ablation is a cornerstone of differentiated thyroid cancer (DTC) management following total thyroidectomy. Effective RAI uptake by thyroid tissue (remnant or metastatic) requires elevated TSH levels to stimulate iodine transporters. Traditionally, this was achieved through thyroid hormone withdrawal (THW)—stopping levothyroxine for 3-4 weeks to induce hypothyroidism and raise endogenous TSH. While effective, THW causes significant morbidity: fatigue, cognitive impairment, depression, cold intolerance, weight gain, and reduced quality of life.
Recombinant human TSH (rhTSH, Thyrogen) offers an alternative: exogenous TSH stimulation while maintaining euthyroidism on levothyroxine. Patients avoid hypothyroid symptoms entirely. However, questions remained about whether rhTSH stimulation achieves equivalent ablation rates to THW-induced endogenous TSH elevation, particularly in higher-risk patients where treatment adequacy is critical.
Previous studies established rhTSH equivalence primarily in low-risk DTC. This trial specifically enrolled intermediate-risk patients—those with larger tumors, microscopic extrathyroidal extension, or aggressive histologic variants—to determine whether rhTSH remains non-inferior in patients where RAI efficacy matters most.
Study Summary (PICO Framework)
Summary:
In intermediate-risk differentiated thyroid cancer patients, rhTSH + 3.7 GBq RAI was non-inferior in ablation effectiveness to thyroid hormone withdrawal + 3.7 GBq RAI, with fewer adverse events and better tolerability.
| PICO | Description |
|---|---|
| Population | Intermediate-risk differentiated thyroid cancer (DTC) patients. |
| Intervention | rhTSH (Thyrogen) + 3.7 GBq RAI. |
| Comparison | Thyroid hormone withdrawal (THW) + 3.7 GBq RAI. |
| Outcome | Non-inferior ablation effectiveness. Fewer adverse events with rhTSH. Better tolerability and quality of life. |
Clinical Pearls
1. rhTSH can now be confidently used in intermediate-risk DTC, not just low-risk. Previous hesitancy about using rhTSH in higher-risk patients was based on limited data in these populations. This non-inferiority trial provides evidence that rhTSH achieves equivalent ablation in intermediate-risk disease, expanding its appropriate use.
2. The adverse event reduction is clinically meaningful. Thyroid hormone withdrawal is profoundly miserable for patients. Beyond subjective symptoms, hypothyroidism impairs work capacity, driving, and cognitive function for weeks. Avoiding these effects while maintaining treatment efficacy represents a genuine quality-of-life improvement.
3. rhTSH also has potential radiation safety advantages. With THW, elevated endogenous TSH causes whole-body iodine avidity, potentially increasing radiation exposure to non-target tissues. rhTSH’s shorter TSH elevation window may reduce whole-body exposure while maintaining thyroid bed targeting.
4. Cost considerations remain relevant but shouldn’t override patient welfare. rhTSH is expensive compared to simply withdrawing levothyroxine. However, when considering lost workdays, reduced function during hypothyroidism, and patient suffering, the cost-benefit analysis often favors rhTSH. Many insurance plans now cover rhTSH for RAI preparation.
Practical Application
Prefer rhTSH over THW for most patients undergoing RAI ablation: Given non-inferior efficacy and superior tolerability, rhTSH should be the default preparation method for RAI in low and intermediate-risk DTC. Reserve THW for situations where rhTSH isn’t available, isn’t covered by insurance, or where concern about adequate TSH stimulation exists (rare).
Discuss preparation options with patients: Some patients may not know alternatives to THW exist. Explaining that they can receive RAI without becoming hypothyroid improves shared decision-making. Most patients strongly prefer rhTSH when given the choice.
Standard rhTSH protocol: Administer rhTSH 0.9 mg IM on two consecutive days, followed by RAI on day 3 (or day after second injection). Measure stimulated thyroglobulin 72 hours after RAI administration. Maintain levothyroxine throughout—no withdrawal needed.
Consider patient-specific factors for method selection: For patients with cardiac disease, significant depression, or jobs requiring cognitive function (pilots, surgeons), rhTSH is particularly valuable. For very high-risk patients where maximizing TSH stimulation is desired, some experts still prefer THW, though evidence for superior efficacy is limited.
How This Study Fits Into the Broader Evidence
The HiLo trial and earlier studies established rhTSH equivalence for remnant ablation in low-risk DTC. American Thyroid Association guidelines endorsed rhTSH as equivalent to THW for ablation preparation. However, intermediate and high-risk populations had less direct evidence, leading to variability in practice.
This trial specifically addresses the intermediate-risk gap, providing randomized evidence that rhTSH maintains efficacy in patients with more concerning disease features. Combined with the better safety profile, this shifts the balance further toward rhTSH as the preferred preparation method across risk categories.
The broader trend in thyroid cancer care is toward less aggressive treatment for low-risk disease (smaller RAI doses or no RAI) while maintaining appropriate treatment intensity for higher-risk disease. This trial supports rhTSH use across the spectrum of patients who do receive RAI.
Limitations to Consider
Non-inferiority design establishes “not worse” but doesn’t prove equivalent or superior. The definition of intermediate-risk and ablation success criteria affect interpretation. Long-term recurrence outcomes (beyond ablation success) would strengthen conclusions. Very high-risk patients (gross extrathyroidal extension, distant metastases) may have been underrepresented. Cost-effectiveness analysis would help with resource allocation decisions.
Bottom Line
Recombinant human TSH (rhTSH/Thyrogen) preparation for radioactive iodine ablation is non-inferior to thyroid hormone withdrawal in intermediate-risk differentiated thyroid cancer, with fewer adverse events and better tolerability. This extends the evidence supporting rhTSH use beyond low-risk disease, supporting its use as the preferred preparation method across most patients receiving RAI. For patients and clinicians, this means effective RAI treatment without the weeks of debilitating hypothyroidism that thyroid hormone withdrawal causes. rhTSH should be offered to intermediate-risk (and low-risk) DTC patients undergoing RAI ablation.
Source: Hui Tan, et al. “Recombinant Human Thyrotropin Plus Radioactive Iodine Among Patients With Thyroid Cancer: A Noninferiority Randomized Clinical Trial.” Read article here.
