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REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1109-1113

Radioiodine as an adjuvant therapy and its role in follow-up of differentiated thyroid cancer


Department of Nuclear Medicine and PET CT, Amrita Institute of Medical Sciences, Cochin, Kerala, India

Date of Web Publication4-Jan-2017

Correspondence Address:
S Padma
Department of Nuclear Medicine and PET CT, Amrita Institute of Medical Sciences, Cochin - 680 2041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.163677

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 > Abstract 

Papillary and follicular cancers of thyroid are the most common varieties of differentiated thyroid cancers exhibiting excellent long-term prognosis when carefully managed. Being a slow-growing malignancy, guidelines exist on the staging, preoperative risk stratification, and management of these cancers to increase the overall survival of these patients. Radioactive iodine has a central role in differentiated thyroid malignancies. It has the same physical properties as stable iodine, thus both normal and malignant thyrocytes cannot differentiate radioactive from stable iodine. Differentiated thyroid carcinoma (DTC) cells concentrate cytocidal amounts of Iodine -131 (131 I) by trapping (the function of the sodium iodine symporter, or NIS) and organifying the iodide ion to produce levothyroxine and triiodothyronine. We shall discuss the role of radioiodine in the management and followup of DTC patients.

Keywords: Follicular thyroid cancer, papillary thyroid cancer, radioiodine, whole body Iodine scan


How to cite this article:
Padma S, Sundaram P S. Radioiodine as an adjuvant therapy and its role in follow-up of differentiated thyroid cancer. J Can Res Ther 2016;12:1109-13

How to cite this URL:
Padma S, Sundaram P S. Radioiodine as an adjuvant therapy and its role in follow-up of differentiated thyroid cancer. J Can Res Ther [serial online] 2016 [cited 2017 Jun 26];12:1109-13. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1109/163677


 > Introduction Top


Differentiated thyroid carcinoma (DTC), arising from thyroid follicular epithelial cells, accounts for the vast majority of thyroid cancers. Of the differentiated thyroid cancers, papillary thyroid cancer (PTC) comprises about 85% of cases compared to about 10% of follicular histology, and 3% of hurthle cell or oxyphil cell types.[1],[2] The prognosis of PTC and follicular thyroid cancer are almost similar while certain histologic subtypes of PTC (such as tall cell, columnar cell, and diffuse sclerosing variants) have a worse prognosis.

Total thyroidectomy is the mainstay of management in thyroid malignancies. It is followed by radioiodine uptake scan and therapy in those patients with DTC. Postoperative Iodine-131 (131I) ablation of functioning thyroid tissue has become established in the management of differentiated thyroid cancer as the long-term risk of recurrence and death is reduced. This beneficial effect results from the destruction of potentially malignant cells or occult multifocal disease that may occur in up to 30% of patients with papillary tumors. Furthermore, the specificity of thyroglobulin as a tumor marker is increased post ablation. This also increases the sensitivity of subsequent whole body 131I scans as normal residual thyroid tissue may compete with recurrent or metastatic thyroid cancer cells for radioiodine (131I) uptake. Indeed, it has been demonstrated by Verburg et al. that patients with successful ablation of remnant thyroid tissue have a better prognosis than those with unsuccessful ablation (disease-free survival of 87% vs. 49% after 10 years, while thyroid cancer-related survival was 93% vs. 78%).[3] This suggests that it is important to achieve complete ablation as soon as possible after diagnosis in order to ensure the best possible prognosis for a DTC patient.


 > High Dose Iodine-131 Ablation Top


Why we need to ablate?

Radioiodine ablation refers to the total destruction of residual macroscopically normal thyroid tissue after complete gross surgical resection of cancer. To explain the ablative effect, DTC cells concentrate cytocidal amounts of 131I by trapping (the function of the sodium iodine symporter, or NIS) and organifying the iodide ion to produce levothyroxine and triiodothyronine. Intracellular radioiodine exerts a crossfire or bystander effect and thus destroys the adjoining cells also. Although ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy, the American Thyroid Association (ATA) does not recommend routine radioactive 131I ablation in lieu of completion thyroidectomy. Radioiodine 131I ablation is a simple and easy therapeutic procedure. It is administered orally in the form of 131I sodium iodide solution or capsule. This treatment is given 3–4 weeks postoperatively and is beneficial for three reasons. First, it destroys any remaining normal thyroid tissue, thereby increasing the sensitivity of subsequent 131I whole body scanning and the specificity of serum thyroglobulin (S. Tg) measurements for the detection of persistent or recurrent disease during followup. Second,131I therapy can destroy occult microscopic carcinoma foci subsequently decreasing the long-term risk of recurrent disease. Third, the use of a large amount of 131I for therapy permits postablative 131I whole body scanning, a sensitive test for detecting persistent carcinoma and unsuspected distant metastases.

Goals of postoperative staging of thyroid cancer as proposed in ATA guidelines 2009[4] are: To permit prognostication of DTC patients; to tailor decisions regarding postoperative adjunctive therapy, including 131I therapy and thyroid-stimulating hormone (TSH) suppression, to assess the patient's risk for disease recurrence and mortality; to take decisions regarding the frequency and time interval of follow-up, follow-up of poorly DTC and hurthle cell cancers; prognostication and follow-up after external beam radiation, surgical resection, embolization, or systemic therapy.


 > Selection of Patients for 131I Ablation/therapy Top


  1. Patients with multifocal, multicentric, and microscopic differentiated thyroid malignancy
  2. Gross extrathyroidal extension or incomplete tumour resection of the tumor regardless of tumor size or,
  3. Primary tumor size less than 4 cm regardless of age or,
  4. Nonpapillary histologies (such as Follicular thyroid cancer and Hurthle cell cancer) because they are generally regarded as higher risk tumors
  5. Selectively used in patients with 1–4 cm thyroid cancers confined to the thyroid who have documented lymph node metastases or other features that predict an intermediate to high risk of recurrence or death from thyroid cancer
  6. DTC patients of age more than 45 years, microscopic invasion of tumour into the perithyroidal soft tissues, tumor with aggressive histology (such as tall cell, columnar, insular and solid variants as well as poorly DTC)
  7. Patients with 131I concentrating distant metastases (lymph node, pulmonary, and skeletal)
  8. Patients with residual thyroid tissue for whom revision surgery is not possible or patient is not willing.


There is new evidence to support that patients with a lobectomy or lumpectomy can also successfully undergo 131I lobar ablation.[5] The success of ablation however depends on factors such as histology of the tumor, age of the patient, size of lesion, presence or absence of lymph nodal, distant metastases, and lastly the patient preparation prior to therapy. As aggressive and undifferentiated tumors show poor radioiodine uptake, they need not undergo 131I scan or therapy as undifferentiated tumours remain unresponsive.

Based on guidelines put forward by the ATA, evidence for radioiodine effectiveness is only available for high-risk patients, On the other hand, current evidence indicates that 131I ablation is not effective in T1a tumors (microcarcinomas, <1 cm). For all patients in between these extremes, evidence for 131I high dose therapy effectiveness is largely inconclusive, conflicting, or lacking.[6]

Who should not be ablated?

Patients with low-risk factors need not be ablated with radioiodine. They include patients with Papillary carcinoma of thyroid of tumor size <1–1.5 cm with no capsular invasion or distant metastasis. Minimally invasive follicular cancer of tumour size more 4cm. Patients with neither papillary nor follicular histology subtypes need no high dose 131I therapy. Postoperative metastatic or recurrent medullary thyroid carcinomas also need not be treated with radioiodine based on the fact that these cancers arise from parafollicular C-cells which cannot concentrate radioiodine. Hence, they need to be treated with 131I labeled Meta Iodo Benzyl Guanidine (MIBG), an analogue of a biogenic amine precursor, norepinephrine.


 > Controversies in Iodine-131 Ablation of Thyroid Gland Top


The recommendation to withhold 131I ablation in adults with micropapillary cancer and low-risk DTC, however, has been challenged on the following grounds:[7] (1) Small amounts of 131I (30 millicuries [mCi] or 1.11 Gigabecqueral [GBq]) can be administered to ablate remnant tissue in 90% of the patients after thyroidectomy; (2) it is possible to use recombinant human TSH (rhTSH) in preparation for therapy to reduce total-body irradiation; (3) patients can be more reliably assured to be disease free when there is no clinical or ultrasound evidence of tumor and S. Tg is undetectable during both TSH suppression and stimulation when thyroglobulin antibody are not present; and (4) TSH can be maintained in the nonsuppressed ranges when the patient is disease free.


 > Properties of Radioiodine Top


Both 131I and 123I are radioisotopes of iodine which are routinely used in thyroid imaging. Radioiodine (131I/123I) is the radioactive form of naturally occurring stable 127I.

123I is preferred for imaging because of its better image quality, and less radiation burden to the patient. As it is produced in a cyclotron and has a short half-life, its availability is limited in India.

On the other hand 131I is widely available and popularly termed as “magic bullet.” It gets organified in thyroid cells similar to stable iodine, thereby exerting its cytotoxic effect on thyroid cells. Owing to its relatively long half life of 8 days, it is easily transportable even to remote centres. It emits therapeutically useful beta particle (with a higher energy and a gamma ray of 364 keV (kiloelectron volt) which is used for imaging.


 > Patient Preparation Top


It is important that patients undergoing an 131I diagnostic scan or 131I ablation/metastatic therapy is weaned off from stable iodine-containing foods such as seafoods, iodised salt, drugs (cough expectorants, povidone iodine, amiodaraone) and iodinated contrast agents for 3-4 weeks prior to the procedure. It is mandatory to stop Thyroxine prior to 131I imaging or therapy so as to increase the TSH, thyroid stimulating hormone levels above 30 µIU/ml. By following these salient instructions, the uptake of 131I by thyrocytes gets accentuated thereby provides a higher therapeutic benefit to the patient.


 > Pretherapy Dosimetry Top


The concept of pretherapy imaging is based on the dosimetric potential of 131I to estimate the dose required to completely ablate the residual thyroid tissue. This calculation is ideally performed using a thyroid uptake probe. Thyroid probe is a collimated Nal scintilation detector that is placed at a reproducible distance from the neck. 25 to 50 microcurie of 131I is orally administered to the patient. Radioactivity emitted from the thyroid gland are counted at 4,6 and 24 hours. The cumulative lesion activity is thus obtained. In the event of nonavailability of a thyroid uptake probe,131I low dose imaging is performed (prior to therapy) using a conventional gamma camera 24–48 h after the oral administration tracer dose of 131I [Figure 1]. Anterior and posterior whole body images along with images of anterior neck are obtained. The region of interest is drawn over the residual thyroid tissue and percentage of 131I uptake by remnant thyroid tissue is calculated.
Figure 1: Diagnostic 131I thyroid images of two patients. (a) Significant residual thyroid tissue in both lobes. (b) Negligible residual thyroid tissue postthyroidectomy status (if stimulated thyroglobulin is <2 ng/ml, then radioiodine therapy is not necessary)

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 > Algorithm for the Management of Differentiated Thyroid Carcinoma Patients Top


Conventionally, 3–4 weeks after total thyroidectomy, a low dose (diagnostic)131I scintigraphy is performed to assess the presence of residual thyroid tissue and also to quantify the amount of remnant tissue either by thyroid uptake method or by planar imaging. In the presence of residual thyroid tissue, patients undergo 131I ablation 131I therapy is the term used when higher doses are used to treat metastatic foci. Two important determinants of the success of thyroid ablation are the mass of remaining thyroid tissue in the neck, and the dose delivered to residual thyroid tissue. Generally the dosage of 131I that is used to ablate residual thyroid tissue is in the range of 30 to 70 mCi. Doses less than 35 gray (Gy) to tumor are likely not to respond to I-131 therapy. 300 Gy is needed by thyroid remnant, and 120 Gy by metastatic foci to achieve a good therapeutic response.

Following 131I ablation/therapy [Figure 2], posttherapy 131I whole body scintigraphy is performed 5–7 days later to ascertain whether there is optimal concentration of 131I in the residual thyroid tissue/known metastatic foci and also to screen the patient for any unsuspected regional/distant metastases. The patient is advised suppressive doses of thyroxin thereafter. At 6 months,131I whole body and neck scintigraphy is usually performed to assess the success of 131I ablation. Yearly follow-up of DTC patients is done especially in high risk cases with 131I whole body scintigraphy, S. Tg and thyroglobulin antibody estimation. It is mandatory that all these investigations be performed when the patient is off thyroxin at least for 3–4 weeks (S. TSH should be above 30 µIU/ml) [Table 1]. Nowadays with the availability of rhTSH assistance injection (rhTSH marketed as thyrogen), patients with extensive functioning metastases, those with poor compliance, psychiatric disorders can be treated without thyroxine withdrawal. Patients treated with rhTSH assistance typically receive 0.9 mg rhTSH intramuscular injections on 2 consecutive days, and after monitoring the rise of TSH above 30 µIU/ml, therapeutic dose of 131I is given orally on the 3rd consecutive day in fasting status.
Figure 2: Iodine-131 whole body scintigraphy (in dual intensity) performed 5–7 days posttherapy – 56 year old patient with Follicular thyroid carcinoma post thyroidectomy - whole body 131I images show significant 131I uptake in residual thyroid tissue and in extensive skeletal and pulmonary metastases

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Table 1: Algorithm of management of differentiated thyroid carcinoma postthyroidectomy

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Patients presenting with distant metastases [Figure 3] need a higher therapeutic dose of radioiodine that is repeated over multiple sittings depending on the clinical response. High dose I 131 therapy is performed either by fixed dose or dosimetry method. Conventionally, fixed dose is favoured; 100–120 mCi of 131I is administered orally in patients with lymph node metastases. Patients with pulmonary metastases are treated with 150 mCi and those with skeletal metastases are administered 200 mCi as a one time dose. The limiting factor of 131I dosage is the radiation dose delivered to bone marrow and blood; should not be more than 2 rads. Also, the retained whole body activity of 131I should be no more than 120 mCi at 48 h (or 80 mCi in patients with lung metastases to avoid potential complication of pulmonary fibrosis).
Figure 3: Anterior and posterior whole body iodine-131 scan images of a recently operated follicular thyroid carcinoma showing iodine-131 concentrating residual thyroid tissue, functioning lymph nodal, and extensive skeletal metastases

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Patients undergoing an ablative therapeutic dose of more than 30 mCi need isolation from general public to minimize the radiation exposure as per Atomic Energy Regulatory Board (AERB) guidelines (AERB, India). Hence,131I therapy isolation wards with specialized sewage facility are mandatory. Once the patients' radiation exposure rate reduces to permissible levels, which is usually achieved within 2–3 days depending on the dose administered, they are discharged from isolation ward with special instructions to restrict their movements with young children <13 years and pregnant ladies for next 1-week.


 > Side Effects of Iodine-131 High Dose Therapy Top


Transient effects

131I residual thyroid ablation or therapy can produce transient side effects that include gastritis (nausea and/or vomiting), neck pain and sialadenitis which can be easily treated. Sialadenitis can occur in the first few days after therapy, with pain and enlargement of salivary glands but rarely progressing to chronic xerostomia. Prophylaxis usually takes the form of ingestion of large quantities of fluids and sialogogues such as lemon juice or chewing gum. Some patients also complain of altered taste, discoloration of the tongue due to the destruction of tongue papillae which is reversible. Temporary sterility in both sexes is also documented.

Long-term effects

Infertility, gonadal failure, and genetic effects

Administration of 131I is strictly contraindicated in pregnant and lactating women. In males, repeated radioiodine administration is associated with an impairment of spermatogenesis, increased levels of follicular-stimulating hormone, and decreased levels of inhibin B. In females a transient ovarian failure, mainly in older premenopausal women has been reported. Ladies in reproductive age are advised not to plan pregnancy for 6 months following high dose I 131 ablation or therapy. The notion that radiation is mutagenic and may affect germ cells (thereby resulting in genetic damage to offspring) has raised concern regarding the use of 131I in the management of thyroid disorders in patients of childbearing ages.[8] Exposure to 131I did not alter the likelihood of preterm birth, low birth weight, stillbirth, congenital malformations, death during the 1st year of life, thyroid disease, or nonthyroidal malignancies in offspring. On the basis of these data, there is no reason for patients exposed to radioiodine to avoid pregnancy.[8]

Carcinogenic effects

The incidence of leukemia and solid malignancies in post 131I treated cases versus general public has been long debated. Follow-up studies of patients exposed to 131I did not demonstrate any tumorigenic effect of 131I on the thyroid gland in adults, but do exclude such an effect in children. The dose delivered to other tissues is relatively low, and significant risk of cancer and leukemia has been found only in patients exposed to high cumulative activities of 131I (>500–600 mCi). No genetic effect has been found in studies on the outcome of subsequent pregnancies in women treated with 131I for thyroid carcinomas. When treated with 131I, simple measures such as overall good hydration and use of laxatives help in reducing overall tissue radiation doses.


 > Absolute Contraindications to Iodine-131 Therapy Top


  1. Pregnancy
  2. Patients with elevated urine iodine levels (over 200 µg/L) either from intravenous contrast or from dietary intake. Therapy should be postponed until levels return to normal.



 > Conclusion Top


Postoperative DTC is followed up mainly with whole body 131I scans and S. Tg. The use of radioactive 131I ablation after thyroidectomy reduce the recurrence rates and prolong survival in all patients with differentiated thyroid cancer who are high risk for recurrent disease and has been accepted as part of the standard of care for these patients. Higher doses of 131I are used to treat functioning thyroid metastases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Koh KB, Chang KW. Carcinoma in multinodular goitre. Br J Surg 1992;79:266-7.  Back to cited text no. 1
    
2.
Lam KY, Lo CY. Metastatic tumors of the thyroid gland: A study of 79 cases in Chinese patients. Arch Pathol Lab Med 1998;122:37-41.  Back to cited text no. 2
    
3.
Verburg FA, de Keizer B, Lips CJ, Zelissen PM, de Klerk JM. Prognostic significance of successful ablation with radioiodine of differentiated thyroid cancer patients. Eur J Endocrinol 2005;152:33-7.  Back to cited text no. 3
    
4.
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214.  Back to cited text no. 4
    
5.
Bal CS, Kumar A, Pant GS. Radioiodine lobar ablation as an alternative to completion thyroidectomy in patients with differentiated thyroid cancer. Nucl Med Commun 2003;24:203-8.  Back to cited text no. 5
    
6.
Mäenpää HO, Heikkonen J, Vaalavirta L, Tenhunen M, Joensuu H. Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: A randomized study. PLoS One 2008;3:e1885.  Back to cited text no. 6
    
7.
Mazzaferri EL. What is the optimal initial treatment of low-risk papillary thyroid cancer (and why is it controversial)? Oncology (Williston Park) 2009;23:579-88.  Back to cited text no. 7
    
8.
Robbins RJ, Schlumberger MJ. The evolving role of (131) I for the treatment of differentiated thyroid carcinoma. J Nucl Med 2005;46:28S-37.  Back to cited text no. 8
    


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