Radioactive iodine ablation (RAI), which entails the administration of radioactive iodine-131, is used for the treatment of hyperthyroidism and in the adjuvant setting for differentiated thyroid carcinoma (DTC).[1][2]

Ninety-five percent of thyroid carcinomas derive from the thyroid hormone-producing follicular cells of the thyroid gland; DTCs, the most common subtype, include both papillary and follicular histologies.[3] DTC is often treated with radioiodine-131 in the adjuvant setting due to the cell’s specificity to uptake iodine. Undifferentiated (or anaplastic) thyroid cancer, although still derived from the thyroid hormone-producing follicular cells, typically does not respond to RAI because of the complete loss of expression of the sodium-iodine symporter (NIS) in these cancer subtypes.[3][4][5] The goal of radioiodine therapy is to ablate any residual cancer cells and kill normal thyroid cells remaining post-thyroidectomy, resulting in undetectable serum thyroglobulin levels (a biomarker of viable thyroid tissue) and consequently improve disease-free and disease-specific survival.[1][6][7][8] The American Thyroid Association (ATA) has established indications for RAI in patients with thyroid cancer, based upon the risk of recurrence post-thyroidectomy. This three-tier risk classification system is based on various pathologic features, as indicated below:

Low risk

• Papillary carcinoma with all the following features:
  • No distant metastases
  • No lymph node involvement
  • Gross total tumor resection
  • No tumor invasion of local/locoregional structures
  • Non-aggressive histology
  • No radioiodine uptake outside the thyroid bed on post-thyroidectomy iodine whole-body scan
  • Clinical N0 or ≤ 5 pathologic N1 micrometastases (< 0.2 cm in largest dimension)
  • No vascular invasion
• Intrathyroidal encapsulated follicular variant of papillary thyroid carcinoma
• Intrathyroidal, well-differentiated follicular carcinoma with capsular invasion and no to minimal (< 4 foci) vascular invasion
• Intrathyroidal, papillary microcarcinoma

Intermediate risk

• Microscopic invasion into perithyroidal tissues
• Radioiodine uptake within the neck on a post-RAI whole body scan
• Aggressive histology (i.e., tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, follicular thyroid cancer, hobnail variant)
• Papillary carcinoma with vascular invasion
• Clinical suspicion of regional lymph node involvement (cN1), all involved lymph nodes < 3 cm in largest dimension; or > 5 regional lymph nodes containing cancer on pathologic analysis (pN1), all lymph nodes < 3 cm in the largest dimension
• Multifocal papillary microcarcinoma with extrathyroidal extension

High risk

• Gross extrathyroidal extension
• Incomplete tumor resection
• Distant Metastasis (either on imaging, pathology, or significantly elevated postoperative serum thyroglobulin level)
• Pathologic regional lymph node involvement (pN1) with at least one lymph node ≥3 cm in the largest dimension
• Follicular carcinoma with extensive (> 4 foci of) vascular invasion

In the case of patients with hyperthyroidism (which includes Grave’s disease, toxic multinodular goutier, and toxic adenoma) who are not candidates for, or who fail radical or partial thyroidectomy or antithyroid drug therapy, the ATA recommends radioiodine as a first-line or alternative treatment.[2] Specifically, RAI is preferable for the elderly, medically inoperable patients due to multiple significant comorbidities, and patients with a small-sized goiter.  

Radioactive iodine isotope administration also serves a role in the diagnosis and long-term follow-up of patients with DTC and the diagnosis of hyperthyroidism.[1][2] The ATA recommends whole-body SPECT-CT scans to measure the uptake of radioiodine-131 or radioiodine-123 (another radioactive iodine isotope) for the initial evaluation of thyroid nodules, as well as both immediately and 6 to 12 months following RAI therapy in intermediate and high-risk DTC patients. Whole-body radioiodine scans are also useful in patients with iodine uptake on initial post-RAI therapy scans and in the presence of serum thyroglobulin antibodies (which can interfere with the thyroglobulin laboratory assay, thereby producing a false-negative result).[1] Radioiodine uptake of thyroidal tissue is also used for the evaluation of thyrotoxicosis when etiology is unable to be determined with biochemical evaluation (TSH and thyroid hormone testing) and is an option for patients with clinical signs suspicious for toxic adenoma or toxic multinodular goiter.[2]

The efficacy of radioiodine therapy depends on the ability of thyroid cells to uptake iodine, primarily via the NIS.[5]  Radioiodine-131 beta particles react with intracellular water to produce free radicals, which are cytotoxic via damage to DNA and cellular organelles.[9]

Radioiodine is administered orally in pill form.[10]

In patients with low-risk or intermediate-risk DTC with low-risk features (i.e., low volume central neck metastases with no further extension or adverse features stated above), an ablative dose of 30 mCi is the recommendation from the ATA.  However, in patients with less than complete or near-complete thyroidectomy, or adverse pathologic features, the RAI administered dose should be increased accordingly, to a maximum of 150 mCi.[1]

To maximize RAI uptake into thyroid cells, thyroid-stimulating hormone (TSH) levels preferentially increase by either the injection of recombinant human TSH (rhTSH) or withdrawal of supplemental thyroid hormone (which the patient must take in the absence of a thyroid gland). rhTSH has the advantage of maintaining a euthyroid state, thereby minimizing the unwanted side-effects of hypothyroidism. Although both methods appear to have equivalent efficacy, the ATA does not recommend the use of rhTSH in high-risk DTC patients due to insufficient evidence. Patients typically consume a low iodine diet for approximately 1 to 2 weeks before RAI to facilitate radioiodine uptake further.[1]

The ATA recommends a single dose of 10 to 15 mCi for the treatment of Grave’s disease and a single dose of 10 to 20 mCi for toxic multinodular goiter or toxic adenoma.[2] Before the administration of radioiodine in patients with hyperthyroidism, the patient should take a β-adrenergic blocker or methimazole to prevent transient thyrotoxicosis resulting from the overwhelming release of thyroid hormone from cell death. This approach should especially merit consideration in at-risk populations such as the elderly and those with cardiovascular co-morbidities.[2]

Although iodine channels express predominantly in thyroid cells, additional cell types express this receptor, including the lactating breast, gastric mucosa, and salivary and lacrimal glands, leading to dose-dependent short- and long-term side effects.[11][12] Acute sialoadenitis, the most common short-term side effect from RAI (approximately 30% incidence), can occur as early as several hours after treatment and may persist for up to one year following therapy. Xerostomia (approximately 20 to 40% incidence), a complication associated with hyposalivation, manifests weeks to months following RAI and can persist for months to years.[13][14] Repercussions of chronic hyposalivation include increased incidence of dental caries, dysgeusia (altered taste), and difficulty with mastication and deglutition.[15] Other adverse effects of RAI therapy include nausea, alopecia, conjunctivitis, and xerophthalmia (dry eyes).[13][16]

Due to insufficient evidence, the ATA does not have specific guidelines for preventing or mediating these toxicities.  However, various interventions, albeit with limited efficacy, exist, including the use of sialagogues (i.e., lemon candies, chewing gum, lemon juice), sialoendoscopic surgery, and the co-administration of certain radioprotectors such as amifostine.[1][17][18][19][20][21]

Due to the presence of iodine channels in lactating breast tissue, RAI is contraindicated in pregnancy and women who are breastfeeding.[22][23][24]

Radioiodine has been found in breast milk for up to one month following the administration of therapeutic radioiodine-131.[25] The ATA, therefore, recommends the usage of diagnostic radioiodine-123 or low dose radioiodine-131 scanning to assess radioiodine uptake in breast tissue before RAI therapy in women who are breastfeeding and are unable to defer therapy due to the severity of their disease.[1] 

The ATA additionally recommends all women of childbearing age undergo a pregnancy test prior to RAI therapy and avoid pregnancy 6 to 12 months following treatment.[1]  Studies have demonstrated that up to one year following RAI therapy, there may be an increased risk of miscarriage.[25]