Radioactive Iodine Therapy

Radioactive Iodine Treatment

Indications

For differentiated thyroid cancer patients, radioactive iodine (I-131 or radioiodine) is indicated for:

1) Ablation of residual healthy thyroid tissue following total or near total thyroidectomy

2) Adjuvant treatment of subclinical microscopic disease

3) Treatment of macroscopic residual/recurrent or metastatic disease.

What is Radioactive Iodine Treatment? How Does It Treat?

Theranostics is a recently developing field of the medicine. This approach takes body images using a tumor-specific agent to locate the tumor and its metastasis and their potential future locations and it also uses a specific agent with pre-determined therapeutic efficiency for the diseased tissue. This approach enables switching from traditional medicine to contemporary personalized medical procedures.

Administration of low-dose radioactive iodine (I-131 or I-123) to obtain images with high sensitivity and specificity of tumor tissues for diagnostic purposes combined with high-dose radioactive iodine (I-131) for specific and targeted treatment of these tumors is the oldest known example of theranostic practices in differentiated thyroid cancer.

Radioactive iodine treatment is a standard practice with proven effect on survival in patients with differentiated thyroid cancer, which has been frequently preferred for treatment of benign and malignant (cancer) diseases of thyroid since 1940s.

Thyroid tissue has a unique ability to collect all iodine from the bloodstream and store it in the gland. Similar to iodine, radioactive iodine is taken up to thyroid gland via sodium-iodine symporter (NIS) membrane proteins and stored in follicular cells of the thyroid gland. NIS membrane proteins are also found in papillary- and follicular-type differentiated thyroid cancers, although their levels are lower compared to healthy thyroid tissues. I-131 is a radionuclide with physical half-life of 8.1 days; it emits 364 KeV energy gamma radiation used in imaging studies and an average of 0.192 MeV energy beta particles used in treatment.

Anaplastic (undifferentiated) and medullary thyroid cancers as well as other rarer malignant diseases of thyroid gland show no iodine uptake; thus, radioactive iodine is not used for those patients.

Although majority of patients have a very high chance of prognosis in differentiated thyroid cancers, the risk of relapse or recurrence may be up to 20-30% and relapse may occur even decades after the baseline treatment. Therefore, regular follow-up is necessary for the patients to figure out a relapse and the follow-up should be maintained for the rest of the patient’s life.

Who is Eligible For Radioactive Iodine Therapy?

Radioactive iodine (I-131 or radioiodine) is indicated for ablation of normal residual thyroid tissue following total or near total thyroidectomy for patients with differentiated thyroid cancer and for adjuvant treatment of subclinical microscopic disease as well as treatment of macroscopic residual/recurrent or metastatic disease. 

Postoperative Radioactive Iodine Ablation

It implies radioactive iodine treatment that aims to ablate residual thyroid cancer cells or healthy thyroid tissue several weeks after the surgery. Moreover, ablation is also performed to eliminate thyroid cancer cells, which have already spread to other body parts. Destruction of healthy thyroid tissue residues will facilitate the ability to monitor potential relapse of the disease. In addition to this benefit, it has been demonstrated that radioactive iodine ablation improves survival rates in cases where the cancer has spread to neck or other parts of the body.

 

Up-to-date post operative radioactive iodine ablation therapy recommendations according to the American Thyroid Association (ATA) risk classification system and the AJCC/TNM staging system are as follows:

ATA risk staging	Definition	Indication of RAI ablation
ATA low risk T1a N0, Nx M0, Mx	Tumor size ≤1 cm (unifocal or multifocal)	None
ATA low risk T1b, T2 N0, Nx M0, Mx	Tumor size > 1-4 cm	The procedure might be considered. Not a routine treatment; it might be considered for patients with aggressive histology or vascular invasion
ATA low to moderate risk T3 N0, Nx M0, Mx	Tumor size > 4 cm	Usually preferred.
ATA low to moderate risk T3 N0, Nx M0, Mx	Microscopic extra-thyroidal metastasis, for all tumor sizes.	Usually preferred.
ATA low to moderate risk T1 -3 N1a M0, Mx	Metastasis of central cervical compartment lymph node	Usually preferred.
ATA low to moderate risk T1 -3 N1b M0, Mx	Metastasis of lateral cervical compartment or mediastinal cervical lymph node	Usually preferred.
ATA high risk T4 Any N Any M	Large extra-thyroidal metastasis, for all tumor sizes.	Yes
ATA high risk M1 Any T Any N	Distant metastasis	Yes

 

American Thyroid Association (ATA) risk classification system:

Low risk	No local or distant metastasis is present. Macroscopic tumor is totally removed. There is no tumor invasion in peripheral tissues and structures. There is no aggressive tumor histology (such as tall cell variant, hobnail variant, columnar cell carcinoma). No uptake excluding thyroid bed in screening after the treatment, if RAI is administered. There is no vascular invasion. Clinically N0 or ≤5, pathologically N1 micrometastases (maximum diameter <0.2 cm) Intra-thyroidal, encapsulated follicular variant papillary thyroid cancer Intra-thyroidal, well differentiated follicular thyroid cancer, with capsule invasion and without vascular invasion or minimum vascular invasion (<4 foci) Intra-thyroidal papillary microcarcinoma, uni- or multi-focal, V600E BRAF mutation (if known)
Moderate risk	Microscopic tumor invasion to perithyroidal soft tissues. Papillary thyroid cancer with vascular invasion. Uptake in neck excluding thyroid bed on the first total body scan following radioactive iodine therapy. Aggressive tumor histology (such as tall cell variant, hobnail variant, columnar cell carcinoma). Clinically N1 or >5 pathologic N1 with maximum diameter <3 cm Intra-thyroidal papillary thyroid cancer, primary tumor 1-4 cm, B600E BRAF mutation (if known) Multifocal papillary microcarcinoma, extra-thyroidal metastasis and V600E BRAF mutation (if known)
High risk	Macroscopic tumor invasion to perithyroidal soft tissues (Large extra-thyroidal metastasis) Incomplete tumor resection Distant metastasis Postoperative elevated serum Tg levels suggestive of distant metastasis Pathologically N1 metastatic lymph node which measures larger than 3 cm in any of them Follicular thyroid cancer with diffuse vascular invasion (>4 foci)

 

Treatment of Recurrent or Residual Differentiated Thyroid Cancer with Radioactive Iodine

Surgery is usually the first-line option if the cancer tissue is operable. Radioactive iodine treatment can be performed alone or in combination with surgery. Presence of differentiated thyroid cancer, which is refractory to radioactive iodine should be suspected if cancer foci that do not show significant uptake in radioactive iodine scan are identified in other imaging methods such as MRI or 18F-FDG-PET scan.

Treatment of Differentiated Thyroid Cancer Refractory to Radioactive Iodine

Definition:

• Malignant/metastatic tissue shows no radioactive iodine uptake (no uptake excluding thyroid bed in the first diagnostic total body scan)
• Tumor tissue with reducing radioactive iodine uptake, while there is past evidence of radioactive iodine-susceptible disease.
• Radioactive iodine uptake present in some of the lesions, while absent in others.
• Metastatic disease with progression despite significant radioactive iodine uptake.

Local treatments such as thermal ablation or stereotactic radiotherapy or systemic treatment with kinase inhibitors may be used in treatment of patients with radioactive iodine-refractory differentiated thyroid cancer. Cytotoxic chemotherapies may be considered for the patients who cannot be managed with methods listed .

Is Radioactive Iodine Treatment Safe?

Radioactive iodine treatment is contraindicated for pregnant women. Nursing mothers have to stop breastfeeding. 

Radioactive iodine treatment can be used in hemodialysis patients.

Patients with iodine allergy are eligible for radioactive iodine treatment.

The dose of rhTSH may be reduced by 50% or more for patients with renal failure.

It is necessary for both male and female patients to use effective contraception methods with their partners and avoid pregnancy for at least 6 months following the radioactive iodine treatment. 

 

Potential Side Effects of Radioactive Iodine Treatment

Early Side Effects	Recommendation/Explanation
Sensation of burn and tenderness in neck	In ablation; it is related to volume of postoperative residual thyroid tissue. Steroids or NSAIDs may be used.
Oral mucositis and associating small painful ulcers	This problem can be prevented in most cases by gently brushing the entire oral mucosa with a soft brush once every 3-4 hours at day time for 4-7 days. Repeating this once every 3 hours at night for the first 4 days following the surgery may be added to this procedure.
Nausea ( and vomiting in rare cases)	-5-HT3 antagonists (For example, ondansetron, granisetron, once every 8-12 hours) -Dexamethasone (once every 8-12 hours)
Swelling and tenderness in salivary glands	– Good hydration, 2.5-3 liters of liquid (except for milk) per day is consumed for approximately 1 week. -Increase flow rate of saliva associated with sialagougues (for example, sugar free chewing gum/candy, pylocarpin and ascorbic acid).  This should be started 2 hours after RAI and it should be repeated once every 3 hours throughout the day time (or while the patient is not sleeping) and during night for 4 days after the treatment. -Dexamethasone (once every 8-12 hours) -Amifostine
Partial loss or change in sense of taste	Usually transient
Decrease in tear production
Temporary decrease in white blood cell and platelet counts	This may occur following high-dose radioactive iodine treatment (150-200 mCi).  However, it is not an expected condition in case of normal blood count and normal renal function prior to the treatment.
Bone ache or edema in brain or spinal cord (neurologic symptoms) or pulmonary (dyspnea) metastases secondary to rhTSH.	It is rare.
Late side effects	Recommendation/Explanation
Male fertility	Temporary infertility secondary to increased FSH level or decreased spermatogenesis may occur secondary to high doses of RAI. Irreversible fertility is likely if the cumulative dose exceeds 200-300 mCi in repeated treatments. Sperm cryopreservation might be considered before high dose RAI. Dose exposure of testicles can be decreased through frequent urination.
Female fertility	Impairment of female fertility or increase in miscarriage risk is not expected in female patients who receive RAI therapy.
Dry mouth (xerosis)
Change in sense of taste (dysgeusia)
Salivary gland stone (sialolithiasis)
Dental caries
Dry eye (xerophthalmia) or epiphora
Development of secondary malignancy	This condition occurs very rarely (<1%) following high-dose radioactive iodine treatment. Reported cases generally consist of patients who received multiple RAI therapies. One should always remember that this risk is negligible in comparison to the risks caused by thyroid cancer.

 

Preparation before Radioactive Iodine Treatment

Prior to radioactive iodine total body scan, a physician performs an examination , reviews medical history regarding the thyroid gland, surgery/pathology reports and past imaging studies as well as doses of past radioactive iodine therapy and below listed blood tests are analyzed, when necessary:

• Thyroid function tests (e.g. TSH, fT3, fT4)
• Tg, antiTg
• Serum calcium, calcitonin
• Complete blood count
• Renal profile (for example, BUN, Creatinine)
• Beta-hCG, which should performed to rule out pregnancy for all female patients of child-bearing age.

Patient preparation is crucial as thyroid hormone supplements (LT4, LT3) and iodine-containing drugs and food block radioactive iodine uptake in residual thyroid tissue and extra-thyroidal metastatic lesions.

High TSH level is also very important for achieving maximum effect in radioactive iodine therapy. TSH increases radioactive iodine uptake both in healthy thyroid tissues and thyroid cancer cells. There are several ways to increase the level of this hormone prior to Radioiodine therapy.

Cessation of Thyroid Hormone Replacement

If it is planned to stop thyroid hormone replacement before radioactive iodine ablation/treatment, LT4 hormone preparations (Levotiron, Tefor, Euthyrox, and Bitiron) should be stopped for minimum 4 weeks and LT3 hormone supplements (Tiromel) should be stopped for at least 2 weeks. Patients who take LT4 can use LT3 for the first two weeks. Targeted TSH is > 30 mIU/L and TSH should be analyzed before administration of radioactive iodine.

Use of Recombinant TSH (rhTSH)

rhTSH (Thyrogen) is administered to hip muscle in 2 doses at 24-hour interval as an alternative to cessation of thyroid hormone replacement. Radioactive iodine is administered by mouth 24 hours after the last dose of rhTSH. Diagnostic serum thyroglobulin (Tg) analysis should be done 72 hours after the final rhTSH injection when recombinant TSH is used. 

The rhTSH dose may be reduced by 50% or more for patients with renal failure.

Low-Iodine Diet

Low iodine diet is an important component of preparation for treatment and it is started 2 weeks before the radioactive iodine treatment and maintained for 1 to 2 days after the treatment. This diet increases the efficiency of radioactive iodine treatment.

Medicines Which Prevent Administration of Radioactive Iodine

Medications	Recommended Duration of Cessation
Thionamide medications (i.e. Propylthiouracil, methimazole, carbimazole)	3 days
Multivitamins that contain iodine	7-10 days
For natural/synthetic thyroid hormones, triiodothyronine (LT3 ,Tiromel)	10-14 days
For natural / synthetic thyroid hormones, thyroxin (LT4, Levotiron, Tefor, Euthrox, Bitiron)	3-4 weeks
Kelp, agar, carrageenan, Lugol solution	2-3 weeks, depending on the iodine content
Saturated solution of Potassium iodure	2-3 weeks
Topical iodine (i.e. surgical skin preparation)	2-3 weeks
Intravenous radiographic contrast agent, water-soluble	6-8 weeks
Intravenous radiographic contrast agent, fat-soluble	1-6 months
Amiodarone	3-6 months or longer
Hair dye (containing iodine)	8 weeks

 

Food That Are Not Allowed Due to High Iodine Concentration

Source	Example/explanation
Iodized salt
Dairy products	Milk, yoghurt, cheese, ice cream
Egg yolk	Egg whites could be consumed.
Seafood	Shellfish and fish
Turkey and liver
Algae and algae products	Carrageenan and alginate
Milk chocolate
Multivitamins that contain iodine
Products which contain red food dye (E127, erythrocyte ) (etc. hair dye, fizzy drink)
Cereals	It could be consumed in small servings (1/4 of a plate) per meal.

 

Allowed Food

Fresh fruit and vegetables Salt-free peanuts/hazelnuts and hazelnut/peanut butter Egg (white) Fresh meat Cereals/cereal products which do not contain iodine at high concentration (limited to 4 servings per day) Pasta, which do not contain iodine at high concentrations Sugar Jelly Jam Honey Black pepper Fresh or dried weeds and spices All vegetable oils [including soy oil] Soda (which do not contain Red dye (E127)) Coke, Diet coke Coffee (Not instant) Tea (Not instant) Lemonade Fruit juices

 

How is Radioactive Iodine Therapy Performed?

Oral food and water intake should be stopped for 4-6 hours before radioactive iodine is administered and this restriction should be maintained for approximately 2 hours after the treatment.

Prophylactic oral anti-emetic agent, if considered, can be given before the treatment.

Dose of radioactive iodine, which is planned for the treatment, is in liquid or capsule form and is administered by mouth in a special treatment room.

Hospital stay varies from 3 days to 1 week, although it depends on the dose and patient measurements.

Total body radioactive iodine scan/SPECT/CT is performed 3-7 days after the treatment for staging the disease.

Dose selection is based on the evaluation of recurrence or mortality risk.

Radioactive Iodine (RAI) Doses Which Are Recommended For Different Clinical Conditions

Indication	Recommended RAI dose
Ablation of postoperative remnant tissue in thyroid bed	1.11 – 3.7 MBq	30 -100 mCi
Treatment of cervical/mediastinal lymph nodes.	5.55-7.4 MBq	150 -200 mCi
Patients with severe local/regional disease may be treated with surgery followed by RAI or external radiation, if it is indicated clinically.
Treatment of distant metastasis	≥ 7.4 MBq	≥ 200 mCi

 

Patients with normal renal functions are recommended to drink 2.5-3 liters of liquid (except for milk) per day and void frequently for 1 week following the radioactive iodine treatment. Thus, radiation exposure of the urinary bladder and salivary glands can be minimized.

Defecation at least once a day is important for minimizing the radiation exposure of bowels. Mild laxatives can be used in case of constipation.

Indication of inpatient treatment depends on the dose administered to the patient and is determined by relevant regulations.  Here, the aim is to protect family members of patients and the community from radiation.

Patients who receive radioactive iodine treatment at outpatient or inpatient settings require certain precautions in order to be discharged. Patients who receive this treatment can only be discharged after the residual activity level in their body declines under the discharge limit which is determined in the regulation of the Turkish Atomic Energy Authority (TAEK).

It is necessary for both male and female patients to use effective contraception methods with their partners and avoid pregnancy for at least 6 months following the radioactive iodine treatment.

Restrictions Recommended by the TAEK for Patients Who Received Radioactive Iodine

ACTIVITY ADMINISTERED TO PATIENT (MBq)
TYPE OF RESTRICTION	30-200	200-400	400-600	600-800
DURATION OF RESTRICTION (DAY)
1) Stay at a distance of at least 1-meter from family members, except for very short periods of time.	5	9	12	14
II) Avoid close physical contacts (hugging etc.) with family members for longer than 15 minutes; lie in a separate bed.	15	21	25	27
III) Do not stay closer than 1-meter to adults other than family members for 3 (three) days.				1
NOTE: Excluding necessities, close contacts with children for short periods of time in the first 5 days and maximum 15 minutes in the next 10 days, if the activity is 30-200 MBq.
III applies only to people who will probably face the patient for once only.

 

Activity (MBq)	Travel in public transport (day/time)		Duration of a Sick Leave	Lying Separate From the Spouse		Close contacts with children
	Week 1/time (hour)	Week 2/time (hour)	day	Pregnancy If yes, day	Pregnancy, if not, day	<2 days	2-5 days	5-11 days
200	3.5	24	0	15	1	15	11	5
400	1.5	14	3	20	8	21	16	11
600	1	9	6	24	11	25	20	14
800	0.5	7	8	26	13	27	22	16