How Should the Dose of Iodine-131 Be Determined in the Treatment of Graves’ Hyperthyroidism?

Judith E. Kalinyak and I. Ross McDougall

Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: I. Ross McDougall, M.D., Division of Nuclear Medicine, Stanford University School of Medicine, 300 Pasteur Route 8, Stanford, California 94305-5281.

Radioactive iodine-131 (131I) has been used to treat hyperthyroidism for more than 6 decades (1, 2, 3, 4) because it is clinically effective, safe (5), and cost-effective in comparison with the therapeutic alternatives. Despite its wide use, there remain many controversies surrounding 131I use, including how clinicians should determine the optimal dose. There are three general approaches: 1) to prescribe a fixed dose for all patients; 2) to prescribe a dose corrected for the size of the thyroid and its ability to accumulate iodine; and 3) to prescribe a quantity of 131I calculated to deliver a specific radiation dose to the thyroid. In this issue of JCEM, Leslie et al. (6) compare the outcome in four randomly selected groups of patients: two groups treated with either low or high fixed 131I doses, and two groups with low or high calculated dose regimes based on gland size and 24-hour uptake. Here, we review the complexities of 131I dose selection and comment on how Leslie et al. (6) and other investigators have contributed to our understanding and decision-making regarding in radioiodine treatment of hyperthyroid Graves’ disease.

The optimal outcome after 131I therapy for hyperthyroidism is obviously euthyroidism without postablative hypothyroidism and the need for lifelong thyroid hormone replacement. It is now well accepted, however, that there is no single radioiodine dose or treatment method that can reliably accomplish that goal. This is not surprising considering the number of variables affecting the outcome, including characteristics of the patient (i.e. age, gender, and gland size); severity and duration of the underlying autoimmune thyroid stimulus; radiation delivered to the gland (i.e. 131I fractional uptake, homogeneity of distribution, and effective half-life); and preceding antithyroid drug therapy (i.e. whether thionamides were used, which one, and the time that the drug was stopped before radioiodine treatment) (7, 8, 9). Nonetheless, two facts are apparent. First, the higher the prescribed dose, the higher the fractions of patients who are cured and who develop postablative hypothyroidism (10, 11, 12). Second, some patients become hypothyroid after treatment with even small doses of 131I.

Clinicians prefer to apply quantitative principles to ensure reproducible and consistent responses to therapy. It would appear that optimal doses of 131I could be determined with sophisticated dosimetry based on four facts: 1) the absorbed thyroid radiation dose required; 2) mass of the thyroid gland; 3) effective 131I half-life within the; and 4) distribution of radioiodine within the gland, as shown by scintigraphy. These data should permit calculation of the precise quantity of 131I required to deliver a specific absorbed radiation dose to the thyroid. Although several authors claim to have defined the required absorbed dose, their reports recommend a wide range of absorbed doses from 60 Gy to 300 Gy (see Table 1Go for units and definitions). Moser et al. (13) found that absorbed doses of 60 Gy and 150 Gy cured 54% and 86% of patients, respectively. More recently, however, Howarth et al. (14) reported that absorbed doses of 60 Gy and 90 Gy cured only 41% and 59% of patients after 6 months. Guhlmann et al. (15) cured hyperthyroidism in 83% of patients at 1 year with a 150 Gy absorbed dose. Willemsen et al. (16) eliminated hyperthyroidism in all patients at 1 year with an absorbed dose of 300 Gy; but as expected, these authors reported that 93% of their patients became hypothyroid. Similarly, Reinhardt et al. (17) recently concluded that 250 Gy or more must be delivered to cause hypothyroidism in all patients at 1 year. This relatively broad range of recommended absorbed doses makes it apparent that authorities agree on neither the absorbed dose that successfully treats hyperthyroidism, nor on the acceptable incidences of treatment failures and subsequent hypothyroidism.


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Table 1. Units and definitions

 
Measurement of the gland mass (or volume) is an important source of inaccuracy that is inherent in both simple and sophisticated dose calculations. Techniques include an estimate based on physical examination, technetium-99m O4 scintigraphy, iodine-123 single photon emission computed tomography (18), 124I positron emission tomography, and three-dimensional ultrasound (19). The study by Leslie et al. (6) confirms that trained clinicians can usually estimate a thyroid gland size that approximates that determined by ultrasound. However, there is always some imprecision when gland size is estimated only by palpation, and the error is greater as the gland size increases. In fact, the rising incidence of postablative hypothyroidism has been linked to a conscious or unconscious decision to inflate gland size and, therefore, the quantity of 131I prescribed (20).

Although the fractional thyroid uptake of radioiodine is a precise measurement, determinations at one or two time points provide limited information about isotope residence in the gland over time (i.e. area under the curve). The effective half-life (Teff) cannot be determined from a single 24-hour uptake measurement, which can be greater or less than uptake at earlier times (e.g. 4 or 6 hours). Teff is related to the physical half-life (i.e. determined by the 131I decay rate) and the biological half-life (determined by clearance of iodine from the gland) based the following formula:

Consequently, Teff cannot be greater than the 8-day physical half-life of 131I; but hypothetical biological half-lives of 5 and 50 days, respectively, would result in very different effective half-lives of 3 and 7 days, respectively. This difference would result in a more than 2-fold difference in the absorbed thyroid radiation if an administered dose is fixed or based on a formula using a single uptake measurement. This would seem to argue for dosimetry based on more complex and prolonged protocols, as have been advocated for radioiodine treatment in thyroid cancer. However, there are both empiric and practical problems with implementing such approaches. Van Isselt et al. (21) found variability of more than 10% in more than one half of duplicate measurements made an average of 40 days apart in patients with Graves’ disease. These variations have been attributed to fluctuations in the underlying autoimmune process. There are also practical limitations in patient cooperation, facility utilization, and payer reimbursement for more demanding dosimetry regimes.

In the current study, two patient groups were randomized to treatment with 2.96 MBq/g or 4.44 MBq/g doses; correction for thyroidal radioiodine uptake resulted in mean prescribed doses of 315 Mbq and 455 MBq, respectively. The third and fourth patient groups received fixed doses of 235 MBq and 350 MBq 131I. Despite this considerable range of administered doses, the outcome was almost identical in the four treatment arms. Hyperthyroidism was cured in 73–82%, with the lowest failure rate (18%) occurring, somewhat surprisingly, in the low-dose corrected-uptake group. Among those in whom hyperthyroidism was cured, the majorities in all groups were hypothyroid. Again, the best outcome (i.e. the lowest incidence of hypothyroidism) was in the low adjusted group. How are these results possible? Randomization was performed in blocks of four patients, but it is unlikely that unblinding treatment in every fourth patient biased the results. The same clinician estimated thyroid gland size, which correlated relatively well with ultrasound measurements. The authors do note that most study patients had been previously treated with antithyroid medications; whether their distribution was even among the four arms is not specified. Although the impact of preceding antithyroid medications on the outcome of 131I treatment is debated (8), the preponderance of data suggest that propylthiouracil, but not methimazole, reduces the therapeutic efficacy of subsequent 131I therapy (9).

Leslie et al. (6) conclude that fixed 131I doses, which are simpler and more economical to implement, are as effective as calculated ones for treatment of hyperthyroid Graves’ disease. However, they still do not define the ideal fixed dose to prescribe. Some would argue that the percentage of patients remaining hyperthyroid after 80 months in their series is unacceptably high, and the administered doses they selected should have been larger. In a recent trial, Al-Kaabi et al. (22) treated six groups of patients with fixed doses from 350–399 MBq to greater than 600 MBq and concluded that optimal results (93% cure) were obtained with a 550–599 MBq dose. Scott et al. (23) reported the uniformly successful treatment of 75 patients with a single 600 MBq dose; no patient had hyperthyroidism after 3 months.

Conversely, it could also be argued from the data of Leslie et al. (6) that calculated doses are just as effective as fixed ones. In some patients, calculated doses will result in individual patients receiving lower 131I doses than fixed dose regimes. We agree with the authors that an uptake measurement is necessary, in any case, to ensure that the gland is capable of trapping iodine (24). Because that determination would be obtained anyway and a physician examining the patient could estimate gland size, there would be little additional commitment of time and no incremental cost. What is the down side of administering more 131I for larger glands and giving less to those with high fractional radioiodine uptakes if it ensures the minimum radiation exposure to each patient for the same benefit?

Based on previous work and the current study by Leslie et al. (6), three things remain clear. First, 131I is an effective treatment for hyperthyroid Graves’ disease when an adequate dose is given, whether fixed or adjusted gland size and fractional radioiodine uptake. Second, cure of hyperthyroidism in a reasonable time causes hypothyroidism in most patients. And third, there are still opportunities for research to refine this already remarkably effective and safe option for patients with hyperthyroidism.

Footnotes

Abbreviation: 131I, Iodine-131.

Received November 15, 2002.

Accepted January 17, 2003.

References

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