[P] If radioactive iodine is chosen as treatment for GD in children, how should it be accomplished?

[P] If radioactive iodine is chosen as treatment for GD in children, how should it be accomplished?

[P1] Preparation of pediatric patients with GD for 131I therapy

  • RECOMMENDATION 60
    We suggest that children with GD having total T4 levels of >20 ug/dL (260 nmol/L) or free T4 estimates >5 ng/dL (60 pmol/L) who are to receive radioactive iodine therapy be pretreated with methimazole and beta-adrenergic blockade until total T4 and/or free T4 estimates normalize before proceeding with radioactive iodine. 2/+00

Although the frequency of short-term worsening of hyperthyroidism following pretreatment with ATD therapy is not known, there are rare reports of pediatric patients with severe hyperthyroidism who have developed thyroid storm after receiving 131I (223).

Technical remarks: When children receiving MMI are to be treated with 131I, the medication is stopped 3–5 days before treatment (224). At that time, patients are placed on beta-blockers, which they continue to take until total T4 and/or free T4 estimate levels normalize following radioactive iodine therapy. Although some physicians restart ATDs after treatment with 131I (225), this practice is seldom required in children (188,189,224,226). Thyroid hormone levels in children begin to fall within the first week following radioactive iodine therapy. ATDs can complicate assessment of post-treatment hypothyroidism, since it could be the result of the MMI rather than the 131I therapy.

[P2] Administration of 131I in the treatment of GD in children

  • RECOMMENDATION 61
    If 131I therapy is chosen as treatment for GD in children, sufficient 131I should be administered in a single dose to render the patient hypothyroid. 1/++0

The goal of 131I therapy for GD is to induce hypothyroidism, rather than euthyroidism, as lower administered activities of 131I result in residual, partially irradiated thyroid tissue that is at increased risk for thyroid neoplasm development (69,227). Because of an increased risk of thyroid nodules and cancer associated with low-level thyroid irradiation in children (192–194,228,229), and poor remission rates with low-administered activities of 131I (61,64,65,188), it is important that larger (>150 µCi of 131I per gram of thyroid tissue) rather than smaller activities of 131I be administered to achieve hypothyroidism (230). With large glands (50–80 g), higher administered activities of 131I (200–300 µCi of 131I per gram) may be needed (224). The administered activity of 131I to patients with very large goiters is high, and there is a tendency to underestimate the size of the gland (and thereby administer insufficient radiation to these patients) (64). Therefore, surgery in patients with goiters larger than 80 g may be preferable to radioactive iodine therapy.

 Physicians at some centers administer a fixed dose of about 15 mCi 131I to all children (226), whereas others calculate the activity from estimation or direct measurement of gland size and 123I uptake (224). To assess thyroid size, particularly in the setting of a large gland, ultrasonograhy is recommended (231). There are no data comparing outcomes of fixed versus calculated activities in children; in adults, similar outcomes have been reported with the two approaches (232). One potential advantage of calculated versus fixed dosing is that it may be possible to use lower administered activities of 131I, especially when uptake is high and the thyroid is small. Calculated dosing also will help assure that an adequate administered activity is given.

When activities >150 µCi of 131I per gram of thyroid tissue are administered, hypothyroidism rates are about 95% (188,233,234). While there are reports that hyperthyroidism can relapse in pediatric patients rendered hypothyroid with 131I, this is very infrequent.

Technical remarks: Radioactive iodine is excreted by saliva, urine, and stool. Significant radioactivity is retained within the thyroid for several days. It is therefore important that patients and families be informed of and adhere to local radiation safety recommendations following 131I therapy. After 131I therapy, T3, T4, and/or estimated free T4 levels should be obtained every month. Because TSH levels may remain suppressed for several months after correction of the hyperthyroid state, TSH determinations may not be useful in this setting for assessing hypothyroidism. Hypothyroidism typically develops by 2–3 months posttreatment (224,226), at which time levothyroxine should be prescribed.

[P3] Side-effects of 131I therapy in children

Side effects of 131I therapy in children are uncommon apart from the lifelong hypothyroidism that is the goal of therapy. Less than 10% of children complain of mild tenderness over the thyroid in the first week after therapy; it can be treated effectively with acetaminophen or nonsteroidal antiinflammatory agents for 24–48 hours (189,224).

If there is residual thyroid tissue in young children after radioactive iodine treatment, there is a theoretical risk of development of thyroid cancer. Detractors of the use of 131I therapy in children point to the increased rates of thyroid cancer and thyroid nodules observed in young children exposed to radiation from nuclear fallout at Hiroshima or after the Chernobyl nuclear reactor explosion. However, these data do not apply directly when assessing risks of 131I therapy. The risk of thyroid neoplasia is greatest with exposure to low level external radiation (0.1–25 Gy; ~ 0.09–30 µCi/g) (192,193,228,235,236), not with the higher administered activities used to treat GD. It is also important to note that iodine deficiency and exposure to radionuclides other than 131I may have contributed to the increased risk of thyroid cancer in young children after the Chernobyl reactor explosion (192). Notably, thyroid cancer rates were not increased among 3000 children exposed to 131I from the Hanford nuclear reactor site in an iodine-replete region (237). Increased thyroid cancer rates also were not seen in 6000 children who received 131I for the purpose of diagnostic scanning (238).

TABLE 7. THEORETICAL PROJECTIONS OF CANCER INCIDENCE OR CANCER MORTALITY RELATED TO 131I THERAPY FOR HYPERTHYROIDISM AS RELATED TO AGE

 

Lifetime attributable risk of cancer mortality

 

Age at exposure (year)

Total-body 131I dose (rem or rad)

Per 100,000 per
0.1 Gy or SV

Per 100,000 per
rad or rem

Lifetime cancer risk for 15 mCi 131I

Relative lifetime cancer risk for 15 mCi 131Ia

Per mCi

Per 15 mCi

Males

Female

Average

Males

Female

Average

Cases per 100,000

%

0

11.1

167

1099

1770

1435

110

177

143

23,884

23.9

1.96

1

4.6

69.0

1099

1770

1435

110

177

143

9898

9.9

1.40

5

2.4

36.0

852

1347

1100

85

135

110

3958

3.96

1.16

10

1.45

21.8

712

1104

908

71

110

91

1975

1.97

1.08

15

0.9

13.5

603

914

759

60

91

76

1024

1.02

1.04

20

0.85

12.8

511

762

637

51

76

64

812

0.81

1.03

40

0.85

12.8

377

507

442

38

51

44

564

0.56

1.02

60

0.85

12.8

319

409

364

32

41

36

464

0.46

1.02

aUsing a gross average of dying from a spontaneous cancer of 25% data analysis by Dr. Patrick Zanzonico, Memorial Sloan Kettering Cancer Center (New York, NY).

There is no evidence to suggest that children or adults treated for GD with more than 150 µCi of 131I per gram of thyroid tissue have an increased risk of thyroid cancer directly attributable to the radioactive iodine. While there are several studies of this issue in adults treated with radioactive iodine for GD (see section D2), few studies have focused on populations exposed to 131I for the treatment of GD in childhood or adolescence.

In one study, an analysis was carried out of 602 individuals exposed to 131I below 20 years of age in Swedish and U.S. populations (239). The average follow-up period was 10 years, and the mean administered activity of radioactive iodine to the thyroid was 88Gy (approximately 80µCi/g equivalent), an activity known to be associated with thyroid neoplasia and below that recommended for treatment of GD. Two cases of thyroid cancer were reported compared to 0.1 cases expected over that period of time. Effects on the development of nonthyroid cancers were not examined.

The pediatric study with the longest follow-up reported 36- year outcomes of 116 patients, treated with 131I between 1953 and 1973 (240). The patients ranged in age at treatment from 3 to 19 years. No patient developed thyroid cancer or leukemia. There was no increase in the rate of spontaneous abortion or in the number of congenital anomalies in offspring. It is important to note that sample size was small; thus, the statistical power was inadequate to address this issue fully.

Total body radiation dose after 131I varies with age, and the same absolute activities of 131I will result in more radiation exposure to a young child than to an adolescent or adult (241). At present, we do not have dosimetry information regarding 131I use in children with GD to assess total body exposure in children. Using phantom modeling, it has been estimated that at 0, 1, 5, 10, and 15 years of age, and adulthood, respective total body radiation activities are 11.1, 4.6, 2.4, 1.45, 0.90, and 0.85 rem (1 rem = 0.1 Sv) per mCi of 131I administered (241). Based on the Biological Effects of Ionizing Radiation Committee VII analysis of acute, low-level radiation exposure (242), the theoretical lifetime attributable risk of all-cancer incidence and all-cancer mortality for a large population of treated children can be estimated (Table 7).

To date, long-term studies of children treated with 131I for GD have not revealed an increased risk of nonthyroid malignancies (239). If a small risk exists, a sample size of more than 10,000 children who were treated at <10 years of age would be needed to identify the risk, likely exceeding the number of such treated children. Based on cancer risk projections from estimated whole-body, low-level radiation exposure as related to age, it is theoretically possible that there may be a low risk of malignancies in very young children treated with 131I. Thus, we recommended above that radioactive iodine therapy be avoided in very young children (<5 years) and that radioactive iodine be considered in those children between 5 and 10 years of age when the required activity for treatment is <10 smCi. It is important to emphasize that these recommendations are based on theoretical concerns and further direct study of this issue is needed. The theoretical risks of 131I use must therefore be weighed against the known risks inherent in thyroidectomy or prolonged ATD use when choosing among the three different treatment options for GD in the pediatric age group.

The activity of radioactive iodine administered should be based on thyroid size and uptake, and not arbitrarily reduced because of age in young individuals. Attempts to minimize the radioactive iodine activity will result in undertreatment and the possible need for additional radioactive iodine therapy and radiation exposure.