INTRODUCTION  Radioiodine (131-I) has been an important treatment for patients with well-differentiated (papillary or follicular) thyroid carcinoma for fifty years. Thyroid tissue has a unique ability to take up iodine from blood. Like iodine, radioiodine is taken up and concentrated in thyroid follicular cells because they have a membrane sodium-iodide transporter. Compared with normal thyroid follicular cells, thyroid cancer cells have reduced expression of the transporter, which may account for the low 131-I uptake in thyroid cancer tissue. 131-I causes acute thyroid-cell death by emission of short path-length (1 to 2 mm) beta rays. The uptake of 131-I by thyroid tissue can be visualized by scanning to detect the gamma radiation that is also emitted by the isotope.

131-I must be taken up by thyroid tissue to be effective. As a result, it is of no value in patients whose thyroid cancers do not concentrate iodide, for example patients with medullary carcinoma, lymphoma, or anaplastic carcinoma.

INDICATIONS FOR RADIOIODINE THERAPY  Surgery is the primary therapy for patients with differentiated thyroid cancer. There are two indications for 131-I administration in these patients: to ablate presumably normal thyroid tissue that remains after thyroidectomy; and to treat known residual or metastatic disease.

Ablation of residual thyroid tissue  There are three rationales for ablation of residual thyroid tissue with 131-I:

• To destroy any microscopic foci of disease remaining after surgery.
• To increase the specificity of 131-I scanning for detection of recurrent or metastatic disease by eliminating uptake by residual normal tissue.
• To improve the value of measurements of serum thyroglobulin as a tumor marker.

Combining data from multiple retrospective studies, the relapse rate after 131-I ablation may be reduced by as much as 50 percent. Decreased mortality has been demonstrated in several large retrospective studies among patients whose primary tumors were at least 1 to 1.5 cm in diameter or were multicentric, or who had soft tissue invasion at diagnosis. A meta-analysis found that remnant ablation reduced the 10 year risk of locoregional recurrence (RR 0.31) and reduced the risk of distant metastases by 3 percent. However, given the lack of randomized, prospective trial data, there remains considerable disagreement about the role of 131-I ablation in these patients, especially those with low-risk disease (ie, no soft tissue invasion and no distant metastases). At the Mayo Clinic, there were no differences in mortality or recurrence rates in the decades when 131-I was rarely given (1940 to 1969) and the decades (1980 to 1999) when half of the patients received 131-I.

Treatment of residual and metastatic disease  Treatment of residual and metastatic disease with 131-I reduces the frequency of recurrence and mortality. In patients with local or regional residual disease after thyroidectomy, for example, 131-I treatment decreased the 30-year recurrence and disease-specific mortality rates by about 50 percent. 131-I treatment of regional nodal metastases yields a complete response in 75 to 80 percent of patients when at least 8000 to 10,000 cGy is delivered; this may be difficult to achieve in patients with bulky disease.

Patients treated for 131-I-concentrating pulmonary metastases, which occur in about 5 percent of cases of differentiated thyroid cancer, have a five-year survival rate of 60 percent, compared with 30 percent in those whose tumors do not concentrate 131-I. Long-term survival is highest in those patients with pulmonary metastases seen on 131-I scans but not seen on chest x-ray or computed tomography. Patients with micronodular disease respond better than those with macronodular disease. Nevertheless, in one study, only 2 of 12 patients with micronodular disease had a complete remission, perhaps because metastases smaller than 1 mm in size are not destroyed by 131-I.

Rare patients have metastatic pulmonary nodules seen on chest x-ray but not detected by 131-I scanning. Some of these patients may respond to large doses of 131-I, using withdrawal or human recombinant TSH (rhTSH, thyrotropin-alfa, Thyrogen®).

Skeletal metastases often do not concentrate 131-I; complete resolution of disease occurs in fewer than 10 percent of treated patients, and partial remission in only 35 percent.

131-I TREATMENT  The efficacy of 131-I for both scanning and treatment depends upon patient preparation, tumor-specific characteristics, sites of disease, and dose of 131-I.

Patient preparation Iodide uptake by thyroid tissue is stimulated by TSH and is suppressed by increased endogenous iodide stores. Thus, after thyroidectomy or cessation of thyroxine (T4) therapy, the patient's serum T4 concentration must decline sufficiently to allow the serum TSH concentration to rise to above 25 to 30 mU/L. After thyroxine withdrawal, this took 11 to 28 days in one study and 9 to 29 days in another study (mean 17 to 18 days).

To minimize the symptoms of hypothyroidism resulting from the withdrawal of T4, the shorter-acting hormone triiodothyronine (T3, liothyronine) can be given in doses of 25 mcg two to three times per day. Lower doses (eg, 10 to 12.5 mcg two or three times per day) should be given to elderly patients and those with ischemic heart disease. After cessation of T3, the serum TSH concentration should rise to 25 to 30 mU/L within one to two weeks. Thus, the interval during which the patient receives no thyroid hormone is shortened. Whatever preparative regimen is used, serum TSH should be measured before any 131-I is given to confirm that the concentration is high.

Another way to minimize hypothyroid symptoms in patients already taking T4 is to reduce the dose of oral T4 by 50 percent for approximately one month rather than stopping it entirely. This will usually result in a rise in serum TSH concentration to 25 to 30 mU/L.

Hypothyroidism can be avoided altogether by administering recombinant human TSH (rhTSH, thyrotropin alfa) before administration of 131-I for thyroid remnant ablation; however, the FDA has approved the use of thyrotropin alfa only to prepare patients for diagnostic radioiodine scans and thyroglobulin testing (see below). Using detailed dosimetric analysis, administration of a tracer amount of radioiodine to a euthyroid patient who receives two injections of thyrotropin alfa was shown to yield at least as high a radiation dose to a thyroid bed remnant as when the patient was hypothyroid following hormone withdrawal, anticipating that therapeutic administration would produce equivalent outcomes.

Two uncontrolled studies have reported differing assessments of the efficacy of this approach. Successful ablation of radioiodine uptake visualized on subsequent follow-up scans was seen in 84 percent of patients prepared with thyroid hormone withdrawal, compared with only 54 percent of patients prepared with thyrotropin alfa, using 131-I activities of 30 mCi for adjuvant treatment in all patients. In contrast, using higher administered activities for treatment, similar ablation efficacies of 81 and 84 percent were noted following thyroid hormone withdrawal or thyrotropin alfa, respectively. The explanation of this discrepancy is not immediately obvious, and may await the results of a randomized clinical trial now underway. Also, neither study analyzed ablation efficacy based upon the combined endpoint of radioiodine uptake and serum thyroglobulin levels, an important consideration given the twin goals of adjuvant therapy in the post-thyroidectomy patient.

In a third study of 16 patients prepared with rhTSH compared to 24 patients prepared by thyroid hormone withdrawal, the percentage of complete ablation (undetectable thyroglobulin and negative scan) was similar in both groups after a 30 mCi dose (81 versus 75 percent, respectively) [18]. Thyroxine was stopped the day prior to rhTSH injection to avoid interference from the iodine content of the hormone. Note, however, that the FDA has approved the use of rhTSH only to prepare patients for diagnostic radioiodine scans (see below).

Patients are also advised to avoid foods with high iodine content for at least two weeks before 131-I is given for scanning. In a retrospective study, patients prescribed a low-iodine diet (24-h urine iodine excretion 27 ± 12 mcg) compared with controls (24-h urine excretion 159 ± 9 mcg), were more likely to have negative radioiodine uptake and thyroglobulin values <2 mcg/L when assessed six months after radioiodine treatment. The benefit of a low-iodine diet before radioiodine treatment of metastatic nodal uptake is less well documented.

Other strategies can increase the efficiency of 131-I uptake by tumor, but at some risk. We do not use these strategies in the typical patient.

• Regimens to deplete body stores of iodine, such as the use of loop diuretics, mannitol, or strict low iodine diets may increase uptake by tumor; however there may also be a concomitant increase in total body irradiation.

• Lithium can prolong 131-I retention by thyroid tissue. In a small study of patients who had diagnostic 131-I scans before and then again after receiving lithium for one to two days, 131-I retention was higher and more prolonged during lithium administration in metastatic lesions and the thyroid remnants in most patients, so that the estimated 131-I dose to the metastases was higher. Whether these findings will result in improved eradication of metastases remains to be determined.

Laxatives that do not contain iodine are recommended to prevent hypothyroidism-induced constipation and prolonged retention of 131-I in the gut.

131-I scanning  131-I scans for localization of uptake before ablation or therapy are usually performed using orally administered activities of 2 to 5 mCi (74 to 185 MBq) 131-I. Greater sensitivity for the detection of residual or metastatic tumor can be attained with the use of higher activities, but higher amounts can lead to "stunning," in which there is reduced uptake of the subsequent therapeutic radioiodine due to sublethal radiation delivered by the diagnostic dose. The importance of this phenomenon may be overstated; one study found no difference in the success of subsequent treatment in patients who received 3 to 5 mCi (111 to 185 MBq) 131-I for scanning as compared with those not scanned before treatment. Stunning can also be minimized by using 123-I for scanning. We routinely give 5 mCi (185 MBq), but lower activities are also commonly used.

Between 24 and 96 hours after administration of the diagnostic dose, whole body scans are performed with a large field-of-view gamma-scintillation camera fitted with a high energy parallel hole collimator. Spot images of the neck and other areas of uptake can be obtained using either the same equipment or a rectilinear scanner. In some institutions, quantitative dosimetry is performed to determine lesion uptake and to predict effective tumor radiation dose; however, this requires specialized equipment and software.

Between 75 and 100 percent of patients with thyroid carcinoma have 131-I uptake in the thyroid bed after thyroidectomy. Most often, this likely represents remnants of normal thyroid tissue rather than residual thyroid cancer. In contrast, only about 50 percent of metastatic lesions in the lungs or bones concentrate 131-I. Combining results from multiple studies, there is probably no significant difference between papillary and follicular carcinomas in frequency of detectable uptake by recurrent or metastatic disease. However, certain histologic subtypes, such as oxyphilic follicular carcinoma (commonly called Hürthle-cell carcinoma), the tall cell variant of papillary carcinoma, and poorly differentiated carcinomas, concentrate 131-I less often. Older patients and women may also be less likely to have adequate uptake in metastases.

Scans performed during follow-up that show apparent distant metastases must be interpreted with care. A few are false-positive scans due to physiological uptake of the 131-I in the breast, salivary glands, or thymus; false-positive scans can also occur with pathologic exudates, dilated hepatic ducts, or nonthyroid benign tumors.

Because most patients have thyroid remnants or metastases, one approach is to omit the pretreatment diagnostic scan and obtain only a post-treatment scan. The disadvantage to this approach is that patients with metastases may be under-treated by a strategy that gives all patients the same initial dose of radioiodine. Such a strategy may be reasonable for patients with a very low risk of metastases in whom the goal is to ablate remnants.

123-I scanning  123-I may be superior to 131-I for diagnostic scans. In one study of 14 patients following thyroidectomy, images obtained 5 hours after administration of 1.3 to 1.5 mCi (48 to 56 MBq) of 123-I detected more thyroid remnants than images obtained 48 hours after 3 mCi (111 MBq) of 131-I. Another study evaluated 12 patients, previously treated with radioiodine, who had high thyroglobulin concentrations and negative 131-I diagnostic scans. Eleven of the 12 patients had positive images 2 and 24 hours after administration of 5 mCi (185 MBq) 123-I; 10 of these 11 patients had concordant post-therapy (150 to 216 mCi [5.6 to 8.1 GBq] 131-I scans [40]. Since 123-I is primarily a gamma emitter, it does not impair cellular function, and should not cause stunning, but it is considerably more expensive than 131-I.

131-I ACTIVITY SELECTION FOR ADJUVANT TREATMENT  Ablation of thyroid gland remnants can be performed by several methods. With fixed-activity regimens, patients are typically given between 29 and 150 mCi (1073 and 5550 MBq) of 131-I. In the past, patients given 30 mCi (1110 MBq) or more had to be hospitalized, but that is no longer the case except in the few states that have not changed their rules. The impetus to give the lowest radioiodine activity necessary has also been spurred by concern for complications after radioiodine therapy, such as sialoadenitis and secondary malignancy.

The results of studies of the relative efficacy of low-activity versus high-activity ablation are conflicting:

• In the initial report of low-activity ablation, about 60 percent of patients had complete ablation with an activity of 30 mCi (1110 MBq), which did not differ from the outcome in patients given 100 mCi (3700 MBq) or more.

• A second study found only 25 percent efficacy after a single low administered activity, but one-half of the patients had thyroid bed uptake above five percent, indicating the presence of a substantial remnant.

• Other reports of efficacy of low activities include 60 percent complete ablation (including 25 of 26 patients who had total thyroidectomy), and 83 percent in patients with thyroid bed uptakes less than six percent.

In all of the above studies, similar response rates were reported for high-activity ablation. In addition, in a study of doses ranging from 15 to 30 mCi, all doses between 25 and 50 mCi resulted in similar rates of complete ablation (78 to 84 percent).

There are, however, other reports suggesting that lower administered activities are less effective. In one study, activities of less than 30 mCi (1110 MBq) did not result in successful ablation in any patient, while another study found 10 percent complete ablation after 30 mCi (1110 MBq) versus 53 percent after 100 mCi (3700 MBq).

Finally, a meta-analysis of ten cohort studies and three randomized trials suggested that a single high administered activity of 131-I is more effective than the standard treatment with 30 mCi (1110 MBq).

To some degree, the differences in results may be due to different definitions of "complete ablation," along with variable amounts of remnant tissue and variable 131-I uptake. In general, however, ablation is more difficult and probably requires high activities in patients who have large remnants and whose remnant takes up more than five percent of the dose given for the diagnostic study.

An attempt at retrospective evaluation of the dose of radiation necessary to ablate normal thyroid remnants suggested that complete ablation requires an effective radiation dose delivered to the tissue of at least 30,000 cGy. In a subsequent study in which 131-I was administered in amounts calculated to deliver at least 30,000 cGy to normal remnants based upon dosimetric measurements, 81 percent of patients had complete ablation after a single treatment with 131-I; one-third were outpatients who received less than 30 mCi (1110 MBq). By multivariate analysis, smaller mass of remnant tissue and longer effective half-life of 131-I predicted of complete ablation. There are no long term data regarding the efficacy of dosimetrically-determined 131-I treatment on cancer recurrence or mortality.

With respect to long-term efficacy, there was no difference in the 30-year recurrence rate among patients given activities of less than 50 mCi (1850 MBq) and those given 50 mCi (1850 MBq) or more; however, only a small number of patients were treated with the higher activities. Another reason to use lower doses for ablation is the potential increased risk of secondary malignancies.

Residual or metastatic disease  Patients with residual postoperative disease in the thyroid bed or in local regional lymph nodes are usually treated with higher administered activities of 131-I. Efficacy has been reported with 150 mCi (5550 MBq) as an average activity, either as a result of empiric therapy or as determined by dosimetry. Similarly, 150 to 175 mCi (5550 to 6575 MBq) is advocated for treatment of pulmonary metastases and 150 to 200 mCi (5550 to 7500 MBq) for skeletal disease. Advocates of dosimetry suggest treatment of distant metastases with the maximum tolerable dose, ie, that administered activity that delivers no more than 200 cGy to the red marrow and 80 to 120 (2960 to 4440 MBq) mCi whole body retention. Such activities may exceed 300 to 400 mCi (11,100 to 14,800 MBq).

Posttreatment scanning Tumor uptake of the treatment dose of 131-I should be confirmed by performing a whole body scan two to seven days after treatment. In about 20 percent of these posttreatment scans, foci of uptake that were not seen on the corresponding low-dose diagnostic scan are seen. However, in only 10 percent of cases does the posttreatment scan reveal new sites of uptake that significantly alter the patient's prognosis and were not known to exist by other means, such as radiography or surgery. Similarly, in a comparison of diagnostic 123-I scans with post-treatment scans, additional areas of uptake were found in 6 percent of patients scanned for the first time, 18 percent of patients scanned for the second time, and 44 percent of patients with high serum thyroglobulin concentrations and negative scans; however, treatment was altered in few patients. The clinical utility of these scans is lowest in older patients receiving their first 131-I treatment; the scan is probably not necessary in these patients.

Follow-up scanning and treatment  We usually repeat the 131-I scan 6 to 12 months after treatment with 131-I. If uptake is seen within the thyroid bed, 150 mCi (5550 MBq) of 131-I are given to complete the ablation. If there is uptake outside of the thyroid bed, we give doses of 131-I appropriate to the site of uptake. This process of rescanning and retreatment is repeated until the patient has one (and preferably two) negative scans, at which time scanning is discontinued. Two successive annual negative scans predict a 97 percent 10-year relapse-free survival, as compared with 91 percent after only one negative scan (P<0.02).

With the advent of thyrotropin alfa stimulated thyroglobulin testing, a single negative scan may be sufficient in many patients, and some may not require follow-up scanning at all.

In traditional practice, for each scan the patient must discontinue T4 therapy (and therefore become overtly hypothyroid) so that the serum TSH concentration will be high enough to maximize the uptake of 131-I by any residual thyroid tissue. However, patients do not like becoming hypothyroid; this problem can be minimized by switching to oral T3, by decreasing but not eliminating oral T4 (see patient preparation section above), or by administering recombinant human TSH (rhTSH, thyrotropin alfa).

In two phase III studies, thyrotropin alfa stimulation of 131-I uptake for scanning was nearly as sensitive as endogenous TSH stimulation for detecting thyroid carcinoma. Combined with thyrotropin alfa stimulation of serum thyroglobulin, the sensitivity of thyrotropin alfa for diagnosis of residual or recurrent thyroid cancer was very similar to that of standard thyroid hormone withdrawal. However, maximum diagnostic sensitivity using thyrotropin alfa requires careful attention to the 131-I scanning technique, because 131-I is cleared more rapidly (by 50 percent) when the patients are euthyroid.

We now routinely perform thyrotropin alfa stimulated scans in all patients who require radioiodine scanning, unless they are thought to be likely in need of subsequent radioiodine therapy that would otherwise require thyroid hormone withdrawal. For greater patient convenience, we generally do whole body imaging 24 hours after administration of the radioiodine activity, although formal comparative studies to demonstrate similar diagnostic efficacy have not been performed.

Complications  Acute and chronic complications of 131-I can limit the usefulness of this treatment. In the short term, radiation thyroiditis, painless neck edema, sialoadenitis, and tumor hemorrhage or edema occur in 10 to 20 percent of patients, particularly when higher doses are given . Nausea after 131-I administration can be treated with oral prochlorperazine, 10 mg.

  Sialoadenitis  To minimize the risk of sialoadenitis by promoting salivary flow, patients should be encouraged to drink large volumes; in patients with a history of sialoadenitis, concurrent treatment with reserpine can reduce the risk of recurrence. We also commonly recommend that patients suck on tart candies during the first 24 hours after treatment. Nonsteroidal antiinflammatory drugs are usually adequate for relieving symptoms of acute sialoadenitis; glucocorticoids are rarely required but are effective in more severe cases.

Amifostine, which functions as a radioprotectant by scavenging radiation-induced free radicals in non-malignant tissue, has been advocated to reduce the frequency and severity of sialoadenitis after radioiodine therapy. But, it is possible that amifostine would protect normal thyroid tissue from radiation-induced damage, and therefore its use should probably be limited to the occasional patient who requires multiple radioiodine administrations for metastatic disease rather than for adjuvant remnant ablation. Fewer side effects have been reported with subcutaneous administration, 500 mg, before radioiodine ingestion.

  Secondary malignancy  A excess risk of secondary malignancies has been reported after radioiodine therapy for thyroid cancer. Given the presence of sodium iodide symporters in salivary and estrogenized breast tissue, and the gastrointestinal and urinary routes of excretion of radioiodine, salivary gland, breast, bladder, and gastrointestinal cancers can be plausibly hypothesized to occur more frequently in thyroid cancer patients treated with radioiodine.

• An increased prevalence of bladder cancer has been reported in a study of thyroid cancer patients whose cumulative 131-I doses exceeded 1000 mCi (37,000 MBq).

• In an analysis of a U.S. national cancer database, women diagnosed with thyroid cancer in the two decades after puberty had an increased risk of subsequent development of breast cancer of approximately 58 excess cases per 100,000 person-years (RR 1.4). Other studies have reported an excess risk of breast cancer in women with a history of thyroid cancer, but the increase in risk has thus far not been definitively shown to be related to either I-131 therapy or external beam radiation.

• Salivary and gastrointestinal tract cancer risk also appears to be increased after I-131 treatment.

The risk of acute myelogenous leukemia is also increased. The reported prevalence is approximately 0.5 percent, usually occurring between two and 10 years after I-131 therapy. The risk is considerably lower when the total blood dose per treatment is less than 2 to 3 Gy and multiple treatments are given.

In a report of 6,840 patients treated for thyroid carcinoma in Sweden, Italy, and France, 62 percent received radioiodine therapy (mean cumulative activity 162 mCi [6.0 GBq]). Secondary malignancies that occurred with significantly increased risk included bone and soft tissue (relative risk [RR] 4.0), female genital organs (RR 2.2), central nervous system (RR 2.2), and leukemia (RR 2.5). A dose-response relationship was seen between the administered activity and the risk for solid malignancies as well as leukemia. Although breast carcinoma was more commonly diagnosed in women treated for thyroid carcinoma, no relationship was identified between radioiodine and breast disease.

  Infertility  Oligospermia and transient ovarian failure also occur, but subsequent infertility is rare except after high doses. In a study of women who had received 131-I therapy for thyroid cancer before age 45 years, menopause occurred on average 1.5 years earlier than in women with nodular goiter treated with equivalent doses of T4.

Genetic and chromosomal abnormalities in children due to parental exposure to 131-I probably occurs in only one percent of live births after cumulative administered doses of 500 mCi (18500 MBq), and even less frequently after lower doses. The outcome of pregnancy in women treated with 131-I before becoming pregnant is usually normal.

  Nasolacrimal duct obstruction  Nasolacrimal duct obstruction, presenting as epiphora (excessive tearing), has been reported to occur after as low an administered activity as 100 mCi  and can be a cause of a false-positive radioiodine scan in the orbit. (See "Anomalies and infection of the lacrimal system").

  Safety for household members The 131-I doses given to patients with thyroid cancer are much higher than those given to patients with hyperthyroidism, and the patients may be hospitalized for treatment. However, in a study of 30 patients with thyroid cancer who received 75 to 150 mCi (2775 to 5550 MBq) of 131-I as outpatients, exposure of family members was minimal when certain precautions were followed. Patients were instructed to sleep alone, drink fluids liberally, and avoid prolonged close personal contact with family members for two days after treatment. Surveillance of family members and pets demonstrated that doses to household members were well below the limit (5.0 mSv) mandated by NRC regulations.

RECOMMENDATIONS  As noted above, there are insufficient data to make definitive recommendations for the use of adjuvant 131-I ablation in all patients with differentiated thyroid cancer. We recommend 131-I ablation in all such patients who have one or more of the following:

• Age 45 years or older at diagnosis
• Primary tumor at least 1 to 1.5 cm in diameter
• Evidence of extrathyroidal disease, either by direct invasion outside of the gland or local or regional metastases

We recommend the following dosing regimen:

• We administer 30 mCi (1110 MBq) for ablation to those patients with papillary thyroid carcinoma whose tumor is less than 3 cm in diameter, who have no extrathyroidal invasion, who have no involved nodes, and their 24-hour 131-I uptake is less than 5 percent.

• For all other patients receiving 131-I ablation, we administer 100 mCi (3700 MBq) as an empiric activity.

• When therapy is needed for uptake in the regions of cervical or mediastinal nodes, we administer 150 mCi (5550 MBq). The same activity is given to patients with pulmonary uptake, and 200 mCi (7400 MBq) is given to those with skeletal or other distant sites of uptake.

• Higher activities may be given to patients who have residual or recurrent uptake after previous attempts at ablation or therapy.