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Recombinant Human Thyrotropin Markedly Changes the ¹³¹I Kinetics during ¹³¹I Therapy of Patients with Nodular Goiter: An Evaluation by a Randomized Double-Blinded Trial

Departments of Endocrinology and Metabolism (V.E.N., S.J.B., L.H.) and Nuclear Medicine (H.B.-J., A.V.), Odense University Hospital, DK-5000 Odense, Denmark

Address all correspondence and requests for reprints to: Viveque Egsgaard Nielsen, M.D., Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: viveque.egsgaard{at}ouh.fyns-amt.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study compares, in a randomized double-blinded design, the expected and the actual absorbed thyroid radioactive dose in response to 0.3 mg recombinant human (rh)TSH (n = 35) or placebo (n = 28) given 24 h before ¹³¹I therapy in patients with nodular goiter (median volume, 69 ml; range, 20–440 ml). The ¹³¹I activity calculation was based on thyroid ¹³¹I uptake (RAIU) at 24 and 96 h after a tracer dose of 0.5 MBq ¹³¹I. After ¹³¹I therapy, 24- and 96-h RAIU were repeated allowing a more exact assessment of the actual absorbed thyroid dose. The median ¹³¹I activity was 617 and 632 MBq, respectively, in the rhTSH and the placebo group. At baseline, the 24- and 96-h RAIU and the expected thyroid dose were 32.8 ± 9.1%, 32.1 ± 8.2%, and 96.3 ± 16.3 Gy, respectively, in the rhTSH group and 35.7 ± 11.8%, 35.2 ± 11.3%, and 94.1 ± 18.5 Gy, respectively, in the placebo group (P value not significant between groups). After ¹³¹I therapy, the 24- and 96-h RAIU and the actual absorbed thyroid dose were 46.9 ± 11.7%, 45.0 ± 12.1%, and 136.7 ± 47.9 Gy, respectively, in the rhTSH group and 33.0 ± 11.4%, 31.0 ± 11.3%, and 76.9 ± 27.5 Gy, respectively, in the placebo group (P < 0.001 between groups). Comparing the expected with the actual absorbed thyroid dose, this corresponds to a mean increase of 36.4% (95% confidence interval, 21.3–53.4) in the rhTSH group and a decrease of 21.5% (95% confidence interval, –33.9 to –6.6) in the placebo group (P < 0.001), equivalent to an increase of 73.8% in the absorbed thyroid dose in the rhTSH-treated group. We have thus for the first time shown that stimulation with rhTSH before ¹³¹I therapy not only hinders the decrease in the thyroid RAIU observed with conventional ¹³¹I therapy but in fact also significantly enhances the absorbed thyroid dose. Whether this also leads to a significant increase in goiter size reduction needs additional study.

	Introduction

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DURING THE LAST two decades radioiodine (¹³¹I) therapy has, in some countries, become the cornerstone in the treatment of patients with benign nontoxic nodular goiter (1). In other countries, patients are primarily referred to surgery or offered L-thyroxine treatment (1, 2), although the effect of the latter is questionable (3). In patients with nodular goiter, ¹³¹I therapy results in a mean thyroid volume reduction ranging from 40–60% within 1–2 yr after treatment (4, 5, 6).

The observed reluctance for using ¹³¹I in most countries may rely on several factors. In areas with high dietary iodine intake, the thyroid radioiodine uptake (RAIU) is low, resulting in the need of a relatively high amount of thyroid radioactivity, which often hinders out-patient treatment. Individual susceptibility to ¹³¹I, an inaccurately estimated thyroid size and dose calculation because of the known irregular ¹³¹I uptake in nodular goiters, may also impede the treatment results. In Graves’ disease, the thyroid RAIU displays a considerable variation with time (7), and the iodine biokinetics are furthermore affected by the goiter reduction itself (8). Whether these factors also play a role in case of nodular goiter is unknown but may potentially lead to an imprecise applied thyroid dose and hinder assessment of a possible dose-response relationship.

With the recent advent of recombinant human (rh)TSH, which has been shown to approximately double the 24-h thyroid RAIU (9, 10, 11) and also seems to cause a more homogeneous distribution of ¹³¹I on thyroid scintigrams of nodular goiters (12), the possibility of increasing the absorbed radioactive dose in the thyroid gland appears promising in dealing with the limited effect of ¹³¹I therapy. In studies not using rhTSH, an association seems to exist between the calculated thyroid dose and the obtained goiter reduction (5, 13). Little is known regarding exact dosimetry after rhTSH-augmented ¹³¹I therapy (14).

The aim of the present study was to investigate, in a randomized double-blinded placebo-controlled trial, the possible changes in the expected and the actual absorbed thyroid dose during rhTSH-augmented ¹³¹I therapy.

	Subjects and Methods

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Subjects and study design

The patient cohort consisted of a total of 63 patients (10 men, 53 women) with nontoxic and toxic nodular goiter and a median age of 55 yr (range, 31–87 yr). They were treated with ¹³¹I during the period from January 2001 to December 2003. Of these, 27 (43%) were euthyroid, 31 (49%) were subclinically hyperthyroid (serum-TSH < 0.30 mU/liter and normal serum-free-T₄ index and serum-free-T₃ index), and five (8%) were overtly hyperthyroid.

Treatment indications were symptoms from a compressive nodular goiter and/or cosmetic discomfort or hyperthyroidism. One patient had previously undergone ¹³¹I therapy, and nine patients had had a hemithyroidectomy. None had received iodine-containing agents or medication known to affect thyroid function or thyroid RAIU 3 months before therapy. An exception was the patients with overt hyperthyroidism who were kept euthyroid with antithyroid drugs (methimazole or propylthiouracil), which were discontinued 5 d before ¹³¹I therapy, with no resumption after therapy. None had clinical suspicion of thyroid malignancy. Thyroid ^99mTc scintigraphy was performed before enrollment, and in case of dominant hypoactive nodules, fine-needle aspiration biopsy was performed to exclude malignancy.

Pregnancy was ruled out in all female patients of childbearing age by a urinary test immediately before therapy. Other exclusion criteria were breastfeeding, age less than 18 yr, and known ischemic heart disease (because of concern of transient thyrotoxicosis after rhTSH stimulation). Also patients with a 24-h thyroid RAIU less than 20% were excluded because we found it of concern to treat such patients in case they were randomized to the placebo group.

The study was performed in a randomized placebo-controlled double-blinded set-up in which each patient was randomized to receive either 0.3 mg rhTSH or isotonic saline injected im in the gluteal region 24 h before ¹³¹I therapy. Freeze-dried rhTSH (vials containing 0.9 mg rhTSH) (Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) was reconstituted with 3 ml isotonic saline. Of this dilution, 0.3 mg rhTSH corresponds to 1 ml. Randomization was performed by an independent pharmacist at the hospital. The study was approved by the local ethics committee of the county of Funen, Denmark (journal no. 20030128), and all patients provided signed informed consent before inclusion in the study.

Thyroid size

To reduce inaccuracy in thyroid size determination, patients were subdivided into group A with goiter size less than 100 ml (n = 42; median volume, 52 ml; range, 20–99 ml), and group B with goiter size more than or equal to 100 ml (n = 21; median volume, 183 ml; range, 100–440 ml). In the latter group, surgery would normally be the treatment of choice, but this was not feasible because of concomitant medical disorders, previous neck surgery, and/or patient preference.

Overall, the median goiter volume at baseline was 69 ml (range, 20–440 ml). Because of previous hemithyroidectomy, two patients had a goiter size of 20 ml and 24 ml, respectively. Thyroid size in group A was measured, as previously described (15), by a precise and accurate planimetric ultrasonic scanning procedure, using a 5.5-MHz compound scanner (type 1846; Brüel & Kjær, Copenhagen, Denmark). The average intraobserver variation of this method is approximately 5% (15). In case the initial ultrasound examination showed a thyroid volume above 100 ml, the patient was allocated to group B. In this group, magnetic resonance imaging (MRI) was performed on a superconducting system (Gyroscan T5^II, Phillips, Eindhoven, The Netherlands) operating at 0.5 Tesla. The procedure has previously been described in detail (16). The precision of thyroid volume estimates by MRI planimetry is high with an intraobserver coefficient of variation of 3.6% (16). Ultrasound and MRI measurements were performed by a single operator blinded toward the randomization.

Uptake measurements and ¹³¹I therapy

Calculation of the intended (i.e. expected) thyroid dose was based on the thyroid RAIU determined at 24 and 96 h after oral administration of a tracer activity of 0.5 MBq ¹³¹I (0.01 mCi). After ¹³¹I therapy, 24- and 96-h RAIU measurements were repeated, allowing an estimation of the actual absorbed thyroid dose.

Before administration, both tracer and therapy ¹³¹I dose was placed in a neck phantom, and count rate was measured at a fixed distance (30.0 cm from the detector) using a collimated 2-in NaI (TI)-scintillation probe (Atom-Lab 950, Biodex Medical Systems, New York, NY), with dead-time correction. When measuring uptake after therapy, the detector head was covered with an adjustable lead septum. The energy window was 364 KeV ± 15%, and the energy solution was controlled and corrected daily with a ¹³⁷Cs test source. All measurements were background corrected.

¹³¹I therapy was given as a single oral dose, 10–14 d after the last tracer thyroid RAIU measurement. Aiming at an intended thyroid dose of 100 Gy, the administered therapeutic ¹³¹I activity was calculated based on the following algorithm: activity (MBq) = thyroid volume (ml) x 22.4 (d·MBq/ml) x 100/[T1/2 (d) x 24 h ¹³¹I uptake (%)].

Thyroid volume (i.e. weight) was estimated by ultrasound (group A) and MRI (group B), respectively. The effective half-life (T1/2) was calculated from the 24- and 96-h thyroid RAIU measurements.

According to the official radiation regulations, group A patients were treated on an out-patient basis receiving a maximum of 600 MBq ¹³¹I, and group B patients were hospitalized in isolation, receiving a maximum activity of 3700 MBq ¹³¹I. In seven (15.6%) of the out-patients (group A), the calculated thyroid ¹³¹I-activity was greater than 600 MBq because of a low thyroid RAIU. Because in-house therapy was not planned for these patients, they were given only 600 MBq (four patients received placebo and three patients received rhTSH). Similarly, in two (9.5%) of the in-house patients (group B), the calculated thyroid ¹³¹I activity was greater than 3700 MBq (both received rhTSH), but the administered ¹³¹I activity was restricted at this limit for practical reasons.

Statistical analysis

The STATA 8 statistical software program was used for data analysis. Nonparametric (Mann-Whitney) or parametric (Student’s t test) statistical tests were used, depending on the normality of the data. Calculation of the percent mean difference was based on log-transformed data, thereby making a decline of a variable equivalent to an increase. A simple linear regression was used to test for correlation. Data are presented as medians (range) or means (± SD). The level of statistical significance was chosen as a P value < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Thirty-five patients were randomized to the rhTSH group and 28 patients to the placebo group. The slight skewness in the randomization was caused by exclusion of three patients initially randomized to the placebo group, in whom the dosimetric measurements had to be cancelled because of equipment failure.

Patient characteristics are shown in Table 1. No significant differences were found between the rhTSH group and the placebo group in any of the baseline variables.

At baseline, the tracer 24- and 96-h thyroid RAIU measurements were 32.8 ± 9.1 and 32.1 ± 8.2%, respectively, in the rhTSH group and 35.7 ±11.8 and 35.2 ± 11.3%, respectively, in the placebo group (P = 0.28 and P = 0.21, respectively, between groups), as shown in Fig. 1. In the rhTSH-treated group, the median ¹³¹I activity was 617 MBq (16.7 mCi; range, 241-3700 MBq) and in the placebo group it was 632 MBq (17.1 mCi; range, 180-3198 MBq), with no significant difference between the groups (P = 0.81) (Table 1). After ¹³¹I therapy, the 24- and 96-h thyroid RAIU increased in the rhTSH group to 46.9 ± 11.7 and 45.0 ± 12.1%, respectively, and decreased in the placebo group to 33.0 ± 11.4 and 31.0 ± 11.3%, respectively (P < 0.001 between groups at both times).

View larger version (15K): [in this window] [in a new window]   FIG. 1. The 24- and 96-h thyroid RAIU (%) after a tracer dose of 0.5 MBq 131I and 131I therapy aiming at a thyroid dose of 100 Gy.

In the rhTSH-treated group, the actual absorbed thyroid dose increased significantly compared with the baseline calculations (Table 1 and Fig. 2), whereas the kinetics changed oppositely in the placebo group. Thus, in the rhTSH group the expected thyroid dose was 96.3 ± 16.3 Gy and increased to an actual absorbed dose of 136.7 ± 47.9 Gy (P < 0.001). The corresponding figures in the placebo group were 94.1 ± 18.5 and 76.9 ± 27.5 Gy, respectively (P = 0.007). The individual mean reduction in the thyroid dose (expected vs. actual absorbed) was 21.5% (95% confidence interval, –33.9 to –6.6%) in the placebo group, contrasting with an increase of 36.4% (95% confidence interval, 21.3–53.4%) in the rhTSH group (Table 1 and Fig. 2). This corresponds to an overall increase of 73.8% in the rhTSH-treated group compared with conventional therapy.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Difference in expected thyroid dose (Gy) and actual absorbed thyroid dose (Gy) after prestimulation with 0.3 mg rhTSH or placebo. Left, Individual values; right, comparisons of the mean (SD) values for each group. The dotted lines denote the intended dose of 100 Gy.

Because it cannot be excluded that the withdrawal of the antithyroid drugs before ¹³¹I therapy in the five hyperthyroid patients may have affected the biokinetics, we reanalyzed our data omitting these individuals. However, this did not significantly affect the overall results (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this double-blinded placebo-controlled trial comprising 63 patients, we investigated the effect of rhTSH on thyroid ¹³¹I kinetics during ¹³¹I therapy. The thyroid dose calculation was based both on a precise thyroid size estimation and assessment of the effective ¹³¹I half-life. We found that the actual absorbed thyroid dose increased approximately 36% after stimulation with rhTSH, whereas it decreased 22% without rhTSH, corresponding to an overall increase in the absorbed thyroid dose of 74% in the rhTSH-treated group. Thus, we have shown, for the first time, that stimulation with rhTSH before ¹³¹I therapy not only hinders the observed decrease in the thyroid RAIU after conventional ¹³¹I therapy but in fact also significantly enhances the absorbed thyroid dose.

We found a change of the ¹³¹I kinetics during conventional ¹³¹I therapy (placebo group), resulting in a thyroid dose significantly less than 100 Gy. The factors responsible for this phenomenon are not yet identified but may be caused by ¹³¹I release from the thyroid gland during therapy. In nine of our patients, the ¹³¹I activity was restricted. Consequently, the thyroid irradiation probably is lowered, which may affect the ensuing goiter reduction. However, this is unlikely to have any significant impact on the biokinetics. A factor also of importance when considering the accumulated thyroid ¹³¹I absorption is the effective ¹³¹I half-life. With the reservation that the calculation of the ¹³¹I half-life might have been more accurate by including more than two time points, this variable was not altered to any greater extent by the ¹³¹I therapy in the rhTSH-prestimulated group.

Theoretically, the increase in the absorbed thyroid dose with rhTSH prestimulation may amplify the goiter reduction after ¹³¹I therapy, which might be useful when dealing with large nodular goiters or goiters with low RAIU. In studies not using rhTSH (5, 13), the thyroid volume reduction seems to correlate positively with the thyroid dose. However, these results were based on post hoc analyses, and so far no controlled study has investigated whether a dose-response relationship exists regarding goiter reduction.

It has been shown that the effect of rhTSH on the 24-h RAIU in patients with nodular goiter is inversely correlated to the initial RAIU (10), suggesting that patients with a low thyroid RAIU in particular might benefit from rhTSH stimulation before ¹³¹I therapy. We found only a trend in that direction, probably because patients with a 24-h thyroid RAIU less than 20% were a priori excluded. This fact may also explain why Silva et al. (17) found a much higher effect on the RAIU (an increase from 18 to 46% after stimulation with 0.45 mg rhTSH), because the baseline 24-h RAIU of 33% in our patients clearly was higher.

Previous noncontrolled trials with rhTSH stimulation in healthy subjects or in patients with benign goiter have primarily focused on the 24-h thyroid RAIU (10, 11). Huysmans et al. (10) evaluated the changes in thyroid RAIU after rhTSH in 15 patients with nontoxic nodular goiter and found that the administration of 0.03 mg rhTSH 24 h before ¹³¹I increased the mean 24-h thyroid RAIU from 33 to 63%, thus an approximate doubling of the thyroid RAIU. Torres et al. (11) reported similar findings after giving six healthy euthyroid subjects 0.9 mg rhTSH. Despite using a much higher rhTSH dose, the obtainable thyroid RAIU was lower than what was seen in nodular goiters (10). This discrepancy is probably because of differences in iodine intake, but an influence of the difference in thyroid morphology and a wide interindividual variation in the thyroid RAIU response cannot be excluded. In the case of multinodular goiter, the thyroid RAIU undoubtedly is dependent on the general iodine load, extent of nodular autonomy, and the serum TSH level, the latter being of importance for the paranodular tissue. These factors also contribute to the inhomogeneous scintigrams typical for multinodular goiter.

In the context of ¹³¹I therapy, an altered biokinetics during the irradiation, in addition to factors earlier mentioned (7, 8), probably influences the absorbed thyroid dose. When treating patients with Graves’ disease, the absorbed thyroid dose may deviate significantly from what has been calculated based on initial tracer measurements (18). In addition, the applied thyroid dose may be strongly overestimated in nodular goiters if dose calculation is based only on 24-h thyroid RAIU and not the half-life (19). Certainly, important issues related to the ¹³¹I kinetics after rhTSH and ¹³¹I therapy need to be clarified. Nieuwlaat et al. (14) recently demonstrated that prestimulation (24 h before ¹³¹I administration) with either 0.01 or 0.03 mg rhTSH followed by a proportional reduction of the thyroid ¹³¹I activity to patients with nodular goiter resulted in a significantly lower irradiation of the extrathyroidal organs, while attaining a similar absorbed thyroid dose as patients receiving conventional ¹³¹I therapy. However, that study (14) was not a randomized trial, and it comprised only 18 patients. One year after therapy, the reduced ¹³¹I activity resulted in a mean thyroid volume reduction of 35% in the 0.01-mg rhTSH group and 41% in the 0.03-mg rhTSH group (20), results that are comparable with those found in previous studies not using rhTSH (3).

At present, only one study (17) has investigated whether rhTSH prestimulation is able to amplify the goiter reduction after ¹³¹I therapy. Silva et al. (17) investigated 34 patients with a very large multinodular goiter, randomized to ¹³¹I therapy alone or to ¹³¹I therapy preceded by 0.45 mg rhTSH to increase the thyroid dose. The ¹³¹I activity was calculated without taking the thyroid RAIU into account, thereby hindering a precise thyroid dose calculation. In the group receiving rhTSH, a mean goiter volume reduction of 57.8% at 12 months was seen, significantly higher than the 39.7% obtained in the control group. Thus, based on the present investigation, the higher thyroid volume reduction in the rhTSH-pretreated group can be explained by a higher retention of ¹³¹I in the thyroid. Whether the goiter reduction can be even further amplified by a higher dose of rhTSH and/or by increasing the ¹³¹I activity remains to be clarified (21).

Additional questions such as the optimum rhTSH dose, the optimum time interval between rhTSH stimulation and ¹³¹I therapy, and a possible effect by fractioning the rhTSH dose need to be addressed in future randomized studies. Finally, it should be taken into account that subjects stimulated with rhTSH, probably in a dose-dependent manner, are at risk of developing an acute thyroid gland enlargement and transient thyrotoxicosis (11, 22). Also local cervical pain (17) and permanent hypothyroidism (9, 17) seem much more frequent when ¹³¹I therapy is augmented by rhTSH.

	Acknowledgments

 
We thank Peter B. Andersen, M.D. (Department of Radiology, Odense University Hospital), for performing the thyroid MRI and Lars Bastholt, M.D. (Department of Oncology, Odense University Hospital), for providing care for our in-patients.

	Footnotes

 
This study was supported by research grants from The Agnes and Knut Mørk Foundation, Hans Skouby’s and Wife Emma Skouby’s Foundation, Jacob Madsen and Wife Olga Madsens’s Foundation, Dagmar Marshall’s Foundation, King Christian the X’s Foundation, Oda Pedersens Research Foundation, Frode V. Nyegaard and Wife’s Foundation, The Research Foundation of the County of Funen, The Novo Nordic Foundation, and The A. P. Møller Relief Foundation.

First Published Online October 19, 2004

Abbreviations: MRI, Magnetic resonance imaging; RAIU, radioiodine uptake; rh, recombinant human.

Received August 4, 2004.

Accepted October 11, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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