Continuing Education Activity

Iodine-131 (I-131) is a radiopharmaceutical that can be used for diagnostic and therapeutic purposes. Therapeutic purpose includes treatment of thyroid malignancy in a postoperative patient and hyperthyroidism. This article summarizes thyroid malignancies, anatomy and physiology of the thyroid gland, indications and contraindications of radioactive iodine treatment for thyroid malignancy, patient preparation for treatment, and possible treatment complications. Well-differentiated thyroid carcinomas respond well to I-131 therapy. The activity highlights the role of the interprofessional healthcare team in patient evaluation and treatment for better clinical outcomes.

Objectives:

• Describe the mechanism of action of RAI in the treatment of thyroid malignancies.

• Outline RAI treatment indications and contraindications in thyroid cancers.

• Explain the patient's preparation for RAI treatment in thyroid cancer.

• Identify the significance of efficient coordination and shared decision-making between interprofessional healthcare team members for a better outcome.

Introduction

Thyroid cancer is the most common endocrine cancer. They are histologically classified as papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), Hurthle cell carcinoma (HTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC).[1] PTC, FTC, and HTC are classified as differentiated thyroid cancers (DTC). DTC is the most common type, out of which 80 to 90% are PTC which has a better prognosis. The typical standard of care for DTC is surgery followed with or without radioactive iodine (RAI) treatment.[2] 

Sodium-iodide symporter (NIS) on the differentiated thyroid cancer cell absorbs radioactive iodine that destroys the cancer cells. The need and dose of RAI vary on an individual basis depending on the risk factors.

Anatomy and Physiology

The embryonic thyroid gland descends from the foramen cecum at the posterior tongue to below the thyroid cartilage at the C5-T1 vertebral levels in the midline anterior neck by the 7th week of gestation.[3] The thyroid gland has two lobes connected by an isthmus at the level of the second and third tracheal rings; approximately 10% to 30% of people have a normal anatomical variant extending from the isthmus called the pyramidal lobe.[4] The thyroid gland is attached to the trachea by the lateral suspensory ligament; the parathyroid glands and recurrent laryngeal nerves are closely approximated to the posterior surface of the thyroid.

Thyroid function depends on the availability of dietary iodine. Iodine is absorbed from the gastrointestinal tract and dispersed in the extracellular fluid. Most absorbed iodine is concentrated in thyroid follicular cells via a sodium-iodide symporter (NIS); the fetal thyroid begins to concentrate iodine at 12 weeks gestational age.[5][6][5] Under the influence of thyroid-stimulating hormone (TSH), iodine is conjugated with tyrosine to form triiodothyronine (T₃) and thyroxine (T₄). Thyroid hormones are released from the thyroid, again under the influence of TSH, and travel to body tissues to exert their effects on cellular metabolism. Iodine is excreted predominately in the urine, although small amounts are excreted in feces, sweat, and saliva.

Each major type of thyroid carcinoma has a distinct pathogenesis. All malignancies derived from thyroid follicular epithelium have driver mutations that constitutively activate protein kinase pathways and promote carcinogenesis. A feature of most papillary thyroid carcinomas is the activation of a mitogen-activated protein (MAP)-kinase signaling pathway. Follicular thyroid carcinomas frequently exhibit mutations in RAS or components of the phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathways.[7] Progression from well-differentiated to poorly differentiated thyroid cancer requires additional mutations that further alter the function of cells.

Well-differentiated thyroid malignancies retain the ability to absorb iodine via NIS, making RAI an effective therapeutic intervention.[8] Anaplastic and poorly differentiated malignancies have decreased NIS expression and do not respond well to RAI therapy. Sodium iodide I 131 (¹³¹I) induces cellular necroptosis through beta emission. Public radiation concerns are due to the gamma emission of 364 KeV high-energy photons.

Indications

Radioactive iodine treatment is indicated in patients with DTC after thyroidectomy. Postoperative disease status must be assessed to optimize proper patient selection and determine therapeutic dosing of ¹³¹I.[9] Postoperative assessment of disease status includes serum thyroglobulin (Tg) measurement, neck ultrasound, and diagnostic whole-body radioactive iodine imaging.[10]

The three primary goals of RAI therapy in well-differentiated thyroid cancers are remnant ablation, adjuvant therapy, or treatment of known disease. While listed as separate therapeutic goals, it is recognized that ¹³¹I used for remnant ablation may have a tumoricidal effect and that ¹³¹I used for adjuvant treatment may also destroy normal remnant thyroid.[10]

Remnant ablation refers to the destruction of presumably benign thyroid tissue remaining after total or subtotal thyroidectomy. Remanat ablation promotes the accurate interpretation of postoperative ¹³¹I whole-body imaging and serum thyroglobulin levels, mitigating confusion between what may be residual remnant thyroid tissue, local disease recurrence, or metastatic disease. 

Adjuvant treatment refers to additional therapy after surgery to lower the risk of cancer recurrence in patients with an intermediate or high risk of recurrence. Adjuvant therapy improves the progression-free survival in patients with no obvious evidence of disease but the possible presence of subclinical micrometastases.

Treatment of known disease refers to destroying known residual cancer or recurrent structural or biochemical disease. This shall be done with curative or palliative intent. The therapy improves progression-free and overall survival.

RAI therapy is appropriate in patients with tumor size more than 2 cm and has one or more risk factors, including obvious extrathyroidal extension, patients more than 45 years of age, lymph node metastases, and distant metastases. RAI therapy is recommended if the tumor is less than 2 cm and there are distant metastases.[11]

Based on the available data, choosing low or intermediate-risk patients for remnant ablation or adjuvant treatment is challenging. Patients are grossly classified into low risk, intermediate-risk, and high-risk categories, as indicated below.[12]

Low Risk

• Papillary carcinoma with gross total thyroidectomy and no distant metastases, no lymph node involvement, no invasion of adjacent structures, no vascular invasion, no aggressive histology, no RAI uptake outside the thyroid bed, no palpable lymph nodes, and five or fewer pathologic nodal micrometastases
• Encapsulated intrathyroidal follicular variant of PTC
• Well-differentiated intrathyroidal follicular carcinoma with capsular invasion with or without less than four foci of vascular invasion

Intermediate Risk

• Aggressive histology (Hurthle cell cancer, FTC, columnar cell or tall cell variants, insular carcinoma)
• Multifocal papillary microcarcinoma with extrathyroidal extension
• Clinically positive lymph node/nodes less than 3 cm in the largest dimension or more than five pathologically positive lymph nodes less than 3 cm in the largest dimension

High Risk

• Incomplete resection
• Gross extrathyroidal extension
• Pathologically positive lymph nodes with at least one node equal to more than 3 cm in the largest dimension
• Distant metastasis
• Follicular carcinoma with more than four foci of vascular invasion

The RAI dose should be determined based on a multidisciplinary approach. Patients with no imaging, biochemical, pathological, or clinical evidence of disease after initial definitive curative surgery shall be observed or could undergo RAI treatment for remnant ablation or adjuvant treatment, depending on the institutional protocol.

Contraindications

Pregnancy and breastfeeding are absolute contraindications for RAI therapy.[13] RAI can cross the placenta and cause fetal thyroid damage. A pregnancy test must be done before treatment in females of the childbearing age group. Nursing mothers should stop breastfeeding as RAI is secreted through breast milk.[14] 

Vomiting and diarrhea are contraindications as radioiodine absorption could be hampered and possess the risk of radiation exposure to others. Inefficiency and noncompliance with following the radiation protection and safety instructions and recommendations are contraindications for therapy. History of intake of interfering medications, the recent history of imaging using iodinated contrast, and incontinence issues should be properly addressed.

Preparation

Being on a low iodine diet for 1to 2 weeks will be beneficial to maximize the absorption of RAI as high blood pool iodide can compete with RAI.[15] Adequate TSH stimulation is necessary to obtain a better therapeutic benefit. Endogenous TSH could become elevated by thyroid hormone withdrawal. The optimal TSH level is ≥ 30 mIU/ml.

Desirable TSH levels could be obtained by exogenous administration of recombinant human TSH (rhTSH) in patients for whom thyroid hormone cannot be withdrawn due to undesirable effects.[16] 

Renal function tests and complete blood count should be checked before therapy. As RAI is mainly excreted through the urinary system, significant renal dysfunction can cause a delay in clearance of radioactivity and exacerbate the possibility of probable bone marrow suppression.

The patient should be fasting at least 2 to 4 hours before and 1 hour after RAI administration. Informed consent should be obtained after explaining the purpose of treatment, possible side effects, the need for additional RAI treatment if required, and the need for hormone replacement therapy.

Radiation safety precautions to reduce exposure to others shall be explained, and a written directive should be signed. There should be a negative serum pregnancy test for females of the reproductive age group. Nursing mothers should completely stop breastfeeding the current infant starting six weeks before treatment. To reduce the absorbed dose to the urinary bladder, patients should be encouraged to drink plenty of water and frequently void it.

Technique or Treatment

Wait for at least three weeks post-surgery or around 4-6 weeks after stopping levothyroxine from attaining an adequate TSH level before therapy. When exogenous TSH administration is necessary, 0.9 mg of rhTSH is injected intramuscularly on two consecutive days, followed by RAI after 24 hours.

Radioiodine is commonly administered orally in pill form. The patient’s identity should be verified before therapy. In patients with a low risk for recurrence, a dose of around 30 mCi can attain adequate ablation. In moderate and high-risk patients, the administered dose has to be escalated accordingly to a maximum of around 250 mCi. Written informed consent should be obtained from the patient. Before administration, the dose should be verified by an authorized user. After therapy, the administration area should be surveyed to detect any contamination. Radioactivity released from the patient should be checked with a survey instrument before the patient’s discharge from the hospital. The calculation should stipulate an effective dose of ≤5 millisieverts to caregivers and family members for patient discharge.[17]

The patient should drive straight home after therapy. If possible, drive home alone. If it is not possible to drive alone, choose a seat that keeps maximum distance from others in the vehicle. For 3-4 days following treatment, patients should be advised to restrict contact with others, sleep in a separate room, avoid kissing, use a separate bathroom, avoid sweat and urine cross-contamination, flush the toilet twice after use, wash their clothes and utensils separately and not to come in contact with children and pets. Check for the potential for extended leave from work if the patient works for food service or childcare.[17]

The long half-life of 8.04 days of RAI helps in acquiring images after several days of therapy, permitting the tracer to adequately concentrate in the metastatic lesions and thus improving the sensitivity of the whole body therapeutic scan. After RAI therapy, the patient can return to the Nuclear Medicine department in 3 to 10 days to obtain a whole-body image. The patient is advised to follow up with an endocrinologist for long-term hormone replacement therapy and other related issues.

Radiation detection devices could be triggered for several weeks after treatment. Hence, patients having plans to travel should be given adequate written records of treatment and contact information of the treatment facility.[17]

Typically ablation is completed in 4 to 6 months when a follow-up I-131 whole-body diagnostic scan could be obtained to determine whether the patient had a successful ablation. Retreatment is recommended if there is a persistent disease.

Complications

I-131 treatment related toxicity can be classified as acute and chronic. Side effects of I-131 therapy are rarely lethal at typical therapeutic doses for thyroid cancer treatment and in the setting of Grave's disease. The physiologic concentration of I-131 in the thyroid and salivary glands, as well as other organs to include the stomach can lead to toxicity related to emitted beta particle-related locoregional tissue injury. Acute sialadenitis, or salivary gland inflammation, secondary to I-131 therapy is a frequent complication in the acute setting, seen in up to 20% of patients. [18] The risk of sialadenitis and xerostomia is dose dependent. [19] Salivary gland stimulation and other measures such as hydration and the use of sialagogues, while not standardized, can be utilized to minimize the risk of sialadenitis. 

Other acute side effects include dysgeusia, or dysfunction of taste, secondary to taste bud injury and can last up to several days to weeks after treatment. [20] Oral I-131 as it transits through the stomach and small bowel can also result in acute radiation gastritis/radiation enteritis, with symptoms most frequently manifesting as nausea. Finally, in the setting of significant residual thyroid tissue in the neck(whether native tissue post-thyroidectomy or papillary/follicular cancer metastasis), painful radiation thyroiditis can also occur in patients, and often manifests as neck pain or fever. [21]

Chronic toxicity resulting from I-131 treatment include the reduction of male fertility owing to the radiosensitive nature of live sperm, a feature not shared by female oocytes. Other chronic I-131 treatment related toxicity includes lung fibrosis, chronic xerostomia/sialadenitis, and epiphora secondary to chronic lacrimal gland damage and fibrosis. The risk of leukemia and salivary gland malignancy associated with I-131 treatment is controversial and beyond the scope of this article.

Clinical Significance

Radioactive iodine plays a significant diagnostic and therapeutic role in managing patients with thyroid cancer depending on histopathology. Ninety percent of thyroid cancers are well-differentiated and can take up radioactive iodine. Papillary thyroid carcinoma, the most common type, is twice common in females than in males.

Papillary carcinoma commonly shows lymphomatous spread to the cervical lymph nodes. The common route of spread of follicular carcinoma is hematogenous and can metastasize to lungs and bones and less frequently to the liver and brain. Patients with differentiated thyroid cancer usually have a good prognosis if appropriately treated. Among the differentiated thyroid cancers, the occurrence of metastases is more in Hurthle cell cancer and may not take up radioactive iodine.

After 6 to 8 weeks of total thyroidectomy, which is the definitive treatment for thyroid cancer, the patient may or may not be treated with radioactive iodine depending on the histopathology report for risk of recurrence. Patients may undergo a low dose whole body radioactive iodine scan approximately two months after thyroidectomy to see for any residual thyroid tissue, lymph node metastases, or distal metastases. The physician can determine the dose for the treatment depending on the distribution of radioactive iodine on the scan.

Depending on individual cases, follow-up radioactive iodine scans and repeated I-131 treatments could be performed. Three to ten days following radioactive iodine treatment, a whole-body scan is performed, which is more sensitive for disease detection than a low-dose whole-body scan due to the high dose the patient received.

Follow-up of thyroid cancer patients is usually done with serum thyroglobulin levels testing. Multiple repeat treatments at six months to 1-year intervals can be done to achieve complete response keeping in mind the probable side effects and adjusting the dose. Since I-131 emits high-energy gamma radiation and has a long physical half-life, it imparts the risk of radiation exposure to the treating staff and household members. Hence, radiation protection regulations should be strictly followed.[22]

Enhancing Healthcare Team Outcomes

The appropriate treatment for DTC is surgery followed with or without radioactive iodine. The necessity and the amount of radioactive iodine to be administered are determined on an individual basis as per the risk category of the patient and institutional protocol. Assessing the patient risk, the need for radioiodine therapy, determining the dose, administering the dose, maintaining radiation safety protocol, and making sure the patient is compliant with the protocol requires an interprofessional team approach including primary care clinician, endocrinologist, pathologist, Nuclear Medicine physician, radiopharmacy staff, nurses, technologists, and radiation safety officer.

An evidence-based integrated management approach brings superior results. The interprofessional team should educate the patient about the risks and benefits of RAI treatment. The patient should be informed of the importance of following a low iodine diet before therapy.

There should be efficient provider-patient communication, and giving proper radiation safety instructions to the patient is essential. Small children or pregnant partners should not accompany the patient while arriving for treatment. Female patients of reproductive age should have a negative serum pregnancy test to proceed with RAI treatment. The patient should be made aware of the possible short and long-term side effects of RAI treatment.

Having checklists can help explain to the patient all aspects of therapy, thus attaining better clinical outcomes and reducing radiation exposure to the public. For the first few days after RAI therapy, the patient should keep at least 3 feet from others, especially pregnant females and children. Patients should be advised of the need for effective contraception for 6 to 12 months following RAI therapy.

Routine follow-up thyroglobulin and TSH levels and, if required, radioactive iodine diagnostic whole-body scans are to be done in post-treatment thyroid cancer patients. Efficient communication and collaboration between the different interprofessional team members are necessary for a better outcome. [Level 5]