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.
- 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.
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). 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.
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
During the gestational period, the thyroid gland descends from the foramen cecum at the posterior tongue and completes the descent to the expected location by the seventh week of gestation. The normal location of the thyroid gland is below thyroid cartilage at the C5-T1 vertebral levels in the midline anterior neck. The gland has two lobes that are connected by the isthmus at the level of the second and third tracheal rings.
The gland is attached to the trachea by Berry’s ligament or the lateral suspensory ligament. Many important structures like parathyroid glands and recurrent laryngeal nerve lie near the thyroid gland.
The function of the thyroid gland depends on the availability of dietary iodine. Iodine is absorbed from the gastrointestinal tract and dispersed in the extracellular fluid. Most of the absorbed iodine gets concentrated in the thyroid cells with functioning sodium-iodide symporter (NIS). The thyroid follicular cells absorb iodine through the NIS. Then, the iodine combines with tyrosine to form the thyroid hormones triiodothyronine (T3) and thyroxine (T4). T3 and T4 are then released into the bloodstream and play a significant role in controlling body metabolism, growth, and other body systems function.
The predominant excretion of iodine is through the urinary route, although a fraction is excreted through feces and other body fluids like sweat and saliva. The fetal thyroid starts concentrating iodine at 12 weeks of gestation, which causes RAI treatment to be a contraindication in pregnancy.
A multistep transformation of thyroid follicular cells results in thyroid follicle carcinogenesis. In most thyroid cancers, mutations occur that cause selective growth advantage called driver mutations. There also occurs dysregulation of many protein kinase pathways. Mitogen-activated protein kinase (MAPK) activation is pivotal for the initiation of PTC, and phosphatidylinositol-3 kinase (PI3K)/AKT activation is crucial for FTC initiation. Progression from well-differentiated to poorly differentiated thyroid cancer requires additional mutations that further alter the function of cells.
The ability of the well-differentiated thyroid cancer cells to absorb iodine through the sodium-iodide symporter makes RAI an effective treatment for them. As the cancer cells become undifferentiated, they lose the NIS expression, hence cannot take up RAI and do not respond to RAI treatment. The glucose metabolism of poorly differentiated (PD) cancers is high, so fluorine-18 fluorodeoxyglucose (F-18 FDG) PET might detect the PD cancer lesions.
Iodine-131 (I-131) destroys the cancer cells due to the beta emission. The predominant gamma emission of I-131 is the 364 KeV high-energy photons, which causes radiation exposure concerns to the public. Gamma radiation is also used in imaging biodistribution.
Radioactive iodine treatment is indicated in patients with DTC who had a total thyroidectomy. Post-operative disease status needs to be assessed to optimize proper patient selection and determine the dose for therapy. Postsurgical assessment of disease status includes serum thyroglobulin measurement, neck ultrasound, and diagnostic whole-body radioactive iodine imaging.
The three primary goals of RAI therapy in well-differentiated thyroid cancers are remnant ablation, adjuvant therapy, or treatment of known disease.
Remnant ablation refers to the destruction of the functioning remnants of presumably benign thyroid tissue remaining after total or subtotal thyroidectomy in patients at low risk of recurrence. Ablation of the residual tissue allows better interpretation of the follow-up I-131 whole-body imaging, avoiding confusion between residual remnant versus local recurrence or lymph node metastases. Remnant ablation also helps keep the thyroglobulin level low and aids in follow-up for recurrence. 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.
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.
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.
- 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
- 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
- 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.
Pregnancy and breastfeeding are absolute contraindications for RAI therapy. 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.
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.
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. 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.
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.
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.
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.
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.
Nausea and vomiting can occur due to gastric irritation. Patients can experience metallic taste and complications of sialadenitis that may rarely progress to xerostomia. A high RAI dose can cause transient bone marrow suppression, particularly with widespread bone metastases or altered renal function, or low baseline blood counts.
Transient infertility and dry eye are yet other complications. Although rare, long-term side effects can occur, especially with a very high therapeutic dose. Pulmonary fibrosis may occur in patients with lung metastases treated with multiple high doses (cumulative dose of 600 mCi). A small risk of leukemia, other secondary cancers, and permanent marrow suppression is reported in patients receiving a very high cumulative dose of RAI. A cumulative dose of 800 mCi may result in substantial bone marrow toxicity.
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.
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]