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Departments of Endocrinology and Metabolism (S.J.B., V.E.N., L.H.), Radiology (P.B.A.), Oncology (L.B.), and Nuclear Medicine (H.B.-J., P.G.), Odense University Hospital, DK-5000 Odense, Denmark
Address all correspondence and requests for reprints to: Steen J. Bonnema, M.D., Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: steen.bonnema{at}dadlnet.dk.
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Abstract |
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Methods: Twenty-nine patients (22 females; age range 37–87 yr) with a large multinodular goiter (median 160 ml, range 99–440 ml) were randomized to receive placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before 131I administration. Goiter volume was monitored by magnetic resonance imaging.
Results: On average, the goiter volume was unchanged 1 wk after therapy in both groups, but the largest deviations from baseline were observed in the rhTSH group. After 12 months the median goiter volume was reduced from 170 to 121 ml in the placebo group and from 151 to 72 ml in the rhTSH group, respectively (within group: P = 0.001; between group: P = 0.019). This corresponds to reductions of 34.1 ± 3.2 and 53.3 ± 3.3%, respectively (between group: P < 0.001). In the placebo group, the goiter reduction correlated positively with the retained thyroid 131I dose, whereas such a relationship was absent in the rhTSH group. Adverse effects, mainly related to thyroid pain and cervical compression, were more frequent in the rhTSH group. At 12 months, goiter-related complaints were significantly reduced in both groups without any between-group difference. One and three patients in the placebo and the rhTSH group, respectively, developed hypothyroidism.
Conclusion: rhTSH-stimulated 131I therapy improves the reduction of very large goiters by more than 50%, compared with 131I therapy alone, but at the expense of more adverse effects after therapy. Our data suggest that rhTSH stimulation may work through mechanisms that go beyond the increase in thyroid 131I uptake.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Recombinant human (rh) TSH approximately doubles the thyroid 131I uptake in patients with nodular goiter (14). This effect seems inversely correlated with the thyroid 131I uptake (15, 16). We have previously shown that 0.3 mg rhTSH increases the retained thyroid dose by 75%, compared with placebo (15). Studies have evaluated the efficacy of rhTSH stimulated 131I therapy on goiter reduction (13, 16, 17, 18, 19, 20). However, most of these studies either did not include a control group or had other shortcomings. We recently published the first randomized, double-blinded, placebo-controlled trial in this field (13). A thyroid volume reduction of 62% when 0.3 mg rhTSH was given before 131I therapy, compared with 46% using placebo prestimulation, was demonstrated (13). That study enrolled patients with a nontoxic nodular goiter less than 100 ml. We have now refined the design, applied the concept to a group of patients with very large goiters, and can report of an even better effect.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients eligible for the study were those admitted to our endocrine outpatient clinic with a very large nodular goiter resulting in cervical compression and/or cosmetic discomfort. Surgery would normally be the treatment of choice for such patients. However, if surgery was not feasible because of concomitant medical disorders, previous neck surgery, and/or personal aversions, study enrollment was offered. Exclusion criteria included a history of cardiac failure or ventricular arrhythmias, previous malignant disease, or physical or psychiatric disabilities suggestive of difficulties in adherence to the protocol. Thus, the study population comprised a selected group of patients. Before inclusion the diagnosis was based on clinical examination, ultrasonography, and 99mTc-pertechnetate thyroid scintigraphy. Fine-needle aspiration biopsy of any scintigraphically dominant hypoactive nodule was performed to exclude malignancy.
The study was performed in a randomized, placebo-controlled, double-blinded set-up, in which each patient received either 0.3 mg rhTSH or isotonic saline injected im in the gluteal region 24 h before 131I-therapy. Randomization was performed by an independent pharmacist at the hospital using a random number generator. 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. The follow-up period was 12 months. The study was approved by the local ethics committee, and all patients provided signed informed consent.
Uptake measurements and 131I therapy
A baseline thyroid 131I uptake was determined at 24 and 96 h after oral administration of a tracer activity of 0.5 MBq 131I. Aiming at a thyroid dose of 100 Gy (by conventional 131I therapy without rhTSH prestimulation), the therapeutic 131I activity was calculated based on the following algorithm:
Activity (megabequerels) = thyroid volume (milliliters) x 22.4 (days x megabequerels per milliliter) x 100/[T1/2 (days) x 24 h 131I uptake (percent)]. The effective half-life was calculated from the 24- and 96-h thyroid 131I uptake measurements. Approximately 14 d after the last tracer 131I uptake measurement, the calculated therapeutic 131I activity was administered orally in a capsule. For further details please see our previous publications (13, 15). All patients were treated in-hospital in isolation for a variable period of time. However, the administered 131I activity was restricted at 3700 MBq for practical reasons.
Thyroid size estimation
Goiter size was estimated by magnetic resonance imaging (MRI) using a superconducting system (Gyroscan Intera; Philips, Eindhoven, The Netherlands) operating at 1.5 Tesla. T1-weighted images [repetition time = 680 msec; echo time = 12 msec] were obtained in the axial and coronal planes using a standard neck coil. The slice thickness was 8 mm, with an interslice gap of 0.8 mm covering the entire thyroid gland. On each axial slice, the cross-sectional area of the thyroid was measured manually by drawing a line along the outer contours of the thyroid. To achieve planimetric calculation of the thyroid volume, the measured areas were multiplied by the slice thickness and interslice gap. The precision of thyroid volume estimates by this method is high with an intraobserver coefficient of variation of 3.6% (21). MRI was performed before as well as 1 wk and 1 yr after therapy by a single operator blinded toward the randomization.
Thyroid function
Thyroid function testing was performed before and at 1, 3, 9, and 12 wk and thereafter every 3 months after 131I therapy. This included serum TSH, serum total T4 and serum total T3 and were measured at our Department of Clinical Chemistry, Odense University Hospital, Denmark. Reference ranges are as follows: TSH, 0.30–4.00 mU/liter; total T4, 70–140 nmol/liter; and total T3, 1.45–2.50 nmol/liter. Serum free T4 index (FT4I) and free T3 index were calculated by multiplying the total values by the percentage of T3 resin uptake (reference interval 0.77–1.33 arbitrary units). In addition, thyroid peroxidase antibodies (values > 60 IU/ml are regarded as positive) and TSH receptor antibodies (values < 1 IU/liter are regarded as negative and values > 2 IU/liter as positive) were measured before and at the end of follow-up. Characteristics of these routine assays have been reported previously (22).
Patient satisfaction
The subjective benefit of the 131I therapy on goiter-related symptoms (i.e. cervical obstructive symptoms and cosmetic discomfort) was registered by a visual analog scale (VAS). Before treatment and at the end of follow-up, each individual was asked to indicate on the VAS, ranging from 0 to 10, the degree of cervical compression and cosmetic discomfort; 0 represented no complaints and 10 the worst possible degree of compression/discomfort.
Statistical analysis
Accepting a type I error of 5%, a type II error of 10%, and assuming a SD of 20% on the percent goiter volume reduction, at least 13 patients in each randomization group were required to detect a difference of 25%. The SPSS statistical software program (version 14; SPSS Inc., Chicago, IL) was used, and data are presented as medians (range) or means (± SD/SE). Nonparametric (Wilcoxon’s and Mann-Whitney’s tests) or parametric (Student’s t test) statistical tests, depending on the normality of the data, were used to detect within-group and between-group differences. The calculation of the mean percentage difference was based on log-transformed data, thereby making a decline of a variable equivalent to an increase. To compare frequencies, the 
2 test was used. Linear regression analysis was used to test for a relationship between variables. The level of statistical significance was chosen as P < 0.05.
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Results |
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Between September 2002 and May 2005, 29 patients (22 women, seven men; median age 60 yr; range 37–87 yr.) with a large multinodular goiter (median 160 ml; range 99–440 ml) were enrolled in the study and randomized to receive placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before 131I therapy. No patient dropped out during the study period. Baseline clinical and laboratory data are given in Table 1
. No significant differences between the randomization arms were found in any of the key variables. Due to coexisting hyperthyroidism, five patients were treated with methimazole. This medication was adjusted to ensure euthyroidism before therapy (median dose of methimazole 10 mg). It was discontinued 8 d before the 131I therapy and not resumed afterward.
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Goiter volume reduction
At baseline the median thyroid volume was 170 ml (range 99–440) in the placebo group and 151 ml (range 112–395) in the rhTSH group (P = 0.31 between groups, Table 1
). On average, the thyroid volume was unchanged 1 wk after therapy [median 170 ml (range: 98–418) in the placebo group; P = 0.20; 153 ml (range: 104–442) in the rhTSH group; P = 0.81]. However, the deviation from the baseline volume was most pronounced in the rhTSH group (Fig. 1). After 12 months the median thyroid volume was reduced to 121 ml (range 61–269) and 72 ml (range 32–207) in the placebo group and the rhTSH group, respectively (within groups: P = 0.001; between groups: P = 0.019). The relative reduction was 34.1 ± 3.2% (SE) in the placebo group and 53.3 ± 3.3% in the rhTSH group, respectively (P < 0.001 between groups). Thus, compared with conventional 131I therapy, the goiter reduction was increased by 56.3% at 12 months when stimulating with 0.3 mg rhTSH.
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) between the degree of goiter reduction and the retained thyroid dose. Such a correlation did not exist in the rhTSH group (r = 0.26, P = 0.38, Fig. 2), implying that the goiter reduction was dependent on not only the thyroid dose but also other factors induced by rhTSH prestimulation. A regression analysis including rhTSH prestimulation, age, male gender, use of antithyroid drug pretreatment, thyroid 24 h 131I uptake at baseline, initial goiter volume, and serum TSH before therapy revealed that only rhTSH stimulation had an impact on the goiter reduction.
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Compared with the baseline level (Table 1), the serum FT4I, 1 wk after131I therapy, had increased significantly in both the placebo group (192 ± 61 nmol/liter, P < 0.001) and the rhTSH group (246 ± 74 nmol/liter, P < 0.001), the between-group difference being borderline significant (P = 0.07). At 3 wk, the serum FT4I had dropped and although still higher than at baseline large individual variations were found (placebo group: 157 ± 57 nmol/liter, P = 0.003; rhTSH group: 165 ± 119, P = 0.16). At this time one patient in each group was receiving methimazole for a short period of time due to hyperthyroid symptoms. At 3 months, the median serum FT4I had normalized in both groups (data not shown). The fluctuations in serum free T3 index showed a similar pattern (data not shown). Permanent hypothyroidism developed in one patient (positive for thyroperoxidase antibody pretreatment) in the placebo group, compared with three patients (all negative for thyroperoxidase antibody pretreatment) in the rhTSH group (P = 0.54 between groups).
None had TSH receptor antibodies before treatment, nor did any develop these or a Graves’-like disease during the follow-up period.
Adverse effects
Adverse effects were significantly more frequent in the rhTSH group (26 and eight events in the rhTSH group and the placebo group, respectively; P < 0.02). Only two patients in the rhTSH group vs. seven patients in the placebo group were free of any adverse events during the 131I therapy. The symptoms appeared for the most part between d 2 and 7 after therapy and faded within 3 wk. They were especially related to cervical pain or a sensation of thyroid growth. In two patients, both randomized to the rhTSH group, prednisolone (25 mg daily) was given for a short period of time. One of these patients was readmitted to the hospital, 1 wk after discharge after the 131I therapy (and 11 d after131I administration), due to a stridorous respiration and a pronounced tender thyroid. A paralysis of the recurrent nerve could not be detected. Her goiter volume 1 wk after the 131I therapy had decreased by 9%. After prednisolone she recovered quickly and ended up with a goiter reduction of 65%.
Patient satisfaction
At inclusion no significant correlation was found between the individual VAS scores and the goiter size (r = –0.09, P = 0.64). In both groups, the goiter-related symptoms were markedly improved after 1 yr. In the placebo group, the VAS score reflecting cervical compression improved from a baseline of 4.2 ± 0.5 (SE) to 1.7 ± 0.5 (P < 0.001), whereas the corresponding figures in the rhTSH group were 4.1 ± 0.8 and 1.3 ± 0.6, respectively (P < 0.001). The between-group difference at 12 months was insignificant (P = 0.46). As regards the cosmetic complaints, the VAS score in the placebo group improved from a baseline of 3.2 ± 0.7 (SE) to 0.8 ± 0.4 (P < 0.006) and from 2.8 ± 0.9 to 0.8 ± 0.4 in the rhTSH group (P < 0.007). However, the response varied considerably between individuals. Three patients in the placebo group were offered a thyroidectomy at 12 months because of persistent symptoms; two of them declined due to a strong aversion against surgery.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We found that the relative goiter reduction at 12 months was significantly augmented from 34% in patients receiving conventional 131I therapy to 53% in those who received rhTSH stimulated 131I therapy. Because the 131I dose was restricted in two patients in the latter group the effect of rhTSH stimulation may have been underestimated. Because the gain in goiter reduction in our study of smaller goiters was 35% (13), as opposed to 56% in the present study, the most obvious candidates for rhTSH-stimulated 131I therapy are patients with a very large goiter and/or a low baseline thyroid 131I uptake.
The majority of patients were very satisfied, independent of whether rhTSH was given. There may be several reasons for this. First, there is a poor or no correlation between goiter size and the degree of discomfort among patients with goiter (23). Second, the VAS is most likely too insensitive a tool to detect any difference. Finally, many of the patients had declined surgery suggesting an a priori positive attitude toward any nonsurgical treatment offered. Nevertheless, until long-term studies have evaluated the risk of goiter regrowth, development of hypothyroidism, and quality of life issues (24, 25, 26), it remains unclarified whether the improved goiter reduction resulting from rhTSH stimulated 131I therapy is unequivocally beneficial to the patient.
In the placebo group, we found a positive correlation between the thyroid dose and the goiter reduction, in accordance with previous reports (9, 13). In the rhTSH group, however, we found that the goiter reduction was unrelated to the retained thyroid dose, an observation in line with our study in patients with smaller goiters (13). This raises the intriguing question of whether the effect of rhTSH relies on factors independent of the thyroid irradiation. For example, rhTSH might induce reactivation of dormant thyroid tissue or in general render the thyrocytes more vulnerable to ionizing radiation. Indeed, the existence of such preconditioning by TSH has been suggested in studies of hyperthyroid patients treated with 131I (27).
Caution is recommended when applying rhTSH-stimulated 131I therapy in large goiters because rhTSH may result in a clinically significant swelling of thyroid tissue (24, 25). Therefore, we measured the goiter volume 1 wk after the 131I therapy, which has not been done in previous studies. On average, goiter volume was unchanged in both groups. In the rhTSH group, however, goiter swelling by more than 10% occurred in a few patients and in one case by more than 30%. Worth noting, the patient with the most severe early adverse event had achieved a goiter reduction of 9% at 1 wk, although it cannot be excluded that a thyroid swelling in fact was present when the symptoms peaked. This suggests that the severe acute problems that may follow rhTSH-stimulated 131I therapy are not restricted to thyroid growth.
The serum levels of the thyroid hormones at 1 wk were significantly above the baseline levels with a subsequent decline in the following weeks. This temporary hyperthyroidism was most pronounced in the rhTSH group, but the nine patients who suffered from hyperthyroid symptoms during the therapy were equally divided between the two groups. Using a lower dose of rhTSH, in a context with a lower applied thyroid irradiation, seems to have less impact on the thyroid function (17, 19). Overall and in line with the findings of others (16, 17, 20), we demonstrated that early adverse effects were significantly more frequent in the rhTSH group, especially those related to thyroid pain and cervical compression. Unfortunately, it is impossible, with the present technology, to predict which individuals are at risk of developing these complications.
Based on the present and previous studies, rhTSH prestimulation can beyond doubt improve the goiter reduction resulting from 131I therapy. Although our trial demonstrates a particularly beneficial effect in patients with a very large goiter, we believe that surgery remains first choice in such cases. The risk of adverse effects should not be ignored when combining 131I therapy with rhTSH, and vigilance in the early period after therapy is recommended. Most likely, although yet to be proved, a smaller dose of rhTSH will limit side effects without compromising the goiter reducing effect. Finally, our data imply that rhTSH in relation to 131I therapy works through mechanisms beyond the increase in thyroid 131I uptake.
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Footnotes |
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Disclosure Statement: S.J.B., V.E.N., H.B.-J., P.G., P.B.A., and L.B. have nothing to declare. L.H. has received consultancy fees from Genzyme Corp. (Cambridge, MA).
First Published Online June 12, 2007
Abbreviations: FT4I, Free T4 index; MRI, magnetic resonance imaging; rh, recombinant human; VAS, visual analog scale.
Received March 5, 2007.
Accepted June 1, 2007.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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