Dosage assessment for radioiodine therapy in benign thyroid disorders

Abstract

The general aim of this thesis was to investigate the value and the shortcomings of the becquerel-per-gram method for radioiodine therapy in various benign thyroid disorders. The history of this treatment form, which goes back to the late 1940s, is described in Chapter 1. Almost fifty years after the discovery of radioactivity, the first clinical experiences with 131 I-treatment were reported in the United States. A simple and effective treatment form had emerged as an alternative to surgery and antithyroid drug (ATD) therapy in Graves’ disease. The efficacy of radioiodine was initially tested – and demonstrated – in patients who could not be cured with ATD medication. With increasing experience in the management of Graves’ disease, it became apparent that the outcome of radio-iodine treatment was difficult to predict. No more than half of all patients treated became euthyroid with one 131 I administration. Higher or lower dosage protocols made the difference for the outcome in the other 50%. In other words, there was the choice between a greater risk of early hypothyroidism or persistent hyper-thyroidism. The development of different schools with regard to the desired therapy outcome (i.e., rapid cure of hyperthyroidism, or restoring euthyroidism) did not hamper the furthering of radioiodine therapy. By the late 1980s, radioiodine had replaced surgery as the first choice for the curation of Graves’ hyperthyroidism, toxic adenoma and toxic multinodular goiter. After this introduction, a number of items relevant to radioiodine treat-ment are reviewed: the physical and radiobiologic properties of iodine-131; pros and cons of different therapeutic aims; and factors influencing the outcome of radioiodine therapy. A statement of the aims of this thesis concludes Chapter 1. In Chapter 2, we present the clinical follow-up results of radioiodine treatment in patients with toxic adenoma and in patients with toxic multinodular goiter. The prevalence of both these disorders is relatively low in comparison with dif-fuse toxic goiter (Graves’ disease), and consequently the number of cases in-cluded in this investigation is limited. Because of their similar histopathologic and clinical profiles, they have been studied as one group. A standardized dos-age of 3.7 MBq per gram thyroid tissue was applied in patients with multinodu-lar goiter, and a dosage of 7.4 MBq per gram adenomatous tissue was used in patients with toxic adenoma. With a single radioiodine treatment good clinical results were obtained in patients with toxic adenoma (75% euthyroidism, 11% hypothyroidism, 14% relapse) over a follow-up period varying between one and eight years. In patients with toxic multinodular goiter, 70% became euthyroid, 22% suffered a relapse of thyrotoxicosis and 8% became hypothyroid. Repeat radioiodine therapy (3 for TA, 11 for TMNG) was successful in all patients with a relapse. Most other researchers have found somewhat fewer relapses and higher hypothyroidism rates for toxic multinodular goiter; the recurrence rate for TMNG varied between 2% and 52%. The lowest failure rate was obtained with a fixed dosage of 740 MBq (20 mCi). It seems contradictory that with that regimen also the hypothyroidism rate (6%) was slightly lower than what we found. At this stage, a fixed dosage regimen seems preferable over the more laborious indi-vidualized regimen. The underperformance of the individualized protocol could possibly be explained by inaccurate volume measurements, especially in toxic adenoma. Further optimization of the standardized regimen for these disorders may be expected from T3 suppression medication and from lithium co-medica-tion. Both may have the ability to increase the effect of a given amount of 131 I, although the mechanisms of action are entirely different. The aim of radioiodine therapy in patients with nontoxic goiter is the reduction of goiter size, while simultaneously preserving the normal thyroid function. This item is dealt with in Chapter 3. In 27 patients with sporadic nontoxic goiter, a therapeutic dose of 3.7 MBq per gram functioning thyroid tissue led to sub-stantial objective reduction of the goiter mass (by 34% on average). The subjec-tive results were more than adequate: 85% of all patients reported substantial improvement or complete relief of their complaints. Hypothyroidism resulted in 3/27 (11%) of the patients. Thyroid volume measurements with 99m Tc-pertech-netate scintigraphy were carried out for therapy dosage calculations as well as for follow-up measurements. For an objective assessment of the goiter reduc-tion, CT-scanning was used as the gold standard. It was concluded that the accu-racy of planar scintigraphic volume determinations in nontoxic goiter is suffi-cient for dosage calculation purposes if the thyroid volume does not exceed 200 ml. However, as the therapy results were no less in patients with thyroid vol-umes over 200 ml than in patients with smaller goiters, the accuracy of these measurements does not seem to carry much weight. Recently, other researchers have reported equally satisfying results in the reduction of goiter size. It seems that the indication for radioiodine therapy in patients with nontoxic goiter may be broader than has thus far been assumed. In Chapter 4, a summary is given of the radioiodine therapy results using a standardized megabecquerel-per-gram dosage protocol in patients with Graves’ disease. The overall results are in compliance with the results of other research groups. We found a cure rate of 70% (including 39% hypothyroidism), and re-current hyperthyroidism in 30%. The thyroid’s radioiodine uptake capacity and the thyroid’s mass appeared to be important factors with regard to the progno-sis of the therapy outcome. Patients with thyroid weights > 60 g more often suffered a recurrence of hyperthyroidism, whereas those with thyroid weights < 60 g appeared to be prone to a hypothyroid therapy outcome. Likewise, pa-tients with radioiodine uptake values < 60% had a higher risk of becoming hy-pothyroid than those with uptake values > 80%. From the preceding four chapters we may conclude that the standard therapy dosage formula D = W ´ (100%/U) ´ 3.7 MBq (where D is the therapy dosage in MBq, W is the thyroid weight in grams, and U is the 24-h radioiodine uptake percentage) is adequate for radioiodine therapy in all thyroid conditions under consideration, except in Graves’ disease. It remained unclear what particular dynamics of Graves’ disease make the prediction of the therapy outcome so much more difficult than in other thyroid disorders. We have looked into the technical, biologic and logistic aspects of the two cornerstones of the radioiodine dosage calculation, viz. the iodine uptake measurement and the scintigraphic thyroid volume measurement. Chapter 5 sets off with a survey of the clinical practice in The Netherlands, of radioiodine uptake measurements that are used for therapeutic 131 I dosage calculations in patients with Graves’ hyperthyroidism. From the response to a nation-wide questionnaire it was concluded that at most departments the radioiodine uptake was measured (and the therapy dosage was computed) several days or even weeks before the actual therapy date. Large dif-ferences prevailed between institutions. This survey is followed by an analysis of the clinical consequences of said practice. Variations in radioiodine uptake of over 10% occurred – within a short time – in more than half the patient popula-tion (62% of all patients with regard to the 5-hr 131 I uptake and 51% with regard to the 24-hr uptake). The radioiodine turnover rate, too, was recognized as a relevant parameter for the dosage calculation. The incidence of increased radio-iodine turnover as earlier reported in the literature (about 16%) was confirmed in our study, but in 14% of all patients the turnover rate had changed from normal to increased or vice versa during an interval of 6 weeks on average. The results of radioiodine treatment in patients with Graves’ hyperthyroidism were again reviewed; in comparison with the methods as used in Chapter 4 only one variable was altered, viz. the time-point of the 131 I uptake measurements. In the repeat study, described in Chapter 6, the uptake was measured on the day before therapy. The results differed significantly from those in the historic con-trols. A significant shift occurred from hypothyroidism to persisting hyper-thyroidism. The outstanding significance of the radioiodine turnover rate as a predictor of the clinical outcome was also recognized in this investigation. For patients who had become euthyroid after radioiodine therapy, the radioiodine turnover rates (i.e., 5/24-h 131 I uptake ratios) were 0.76-0.84 (95% confidence interval, C.I.), whereas in patients with persisting hyperthyroidism the turn-over rates were 0.84-0.92 (95% C.I.). There was some overlap between patients with euthyroid and hypothyroid outcomes (rates 0.69-0.79, 95% C.I.), but the differences were still highly significant. It seems that the radioiodine turnover rate has great predictive potential with regard to the therapy outcome. On the basis of the present data, proper quantitative dosage corrections can not yet be performed, but indicatively 131 I therapy dosage adaptations may be realized. The second cornerstone of ‘classic’ 131 I therapy dosage calculations, the thyroid volume, forms the center of interest in Chapters 7 and 8. Based on our earlier experience with CT-scanning in patients with nontoxic goiter, this modality was also chosen as the gold standard in a pilot study of 5 patients with Graves’ disease (Chapter 7). However, adequate manual segmentation was not feasible with native CT in 4 out of 5 patient studies. As CT with contrast enhancement is contra-indicated when radioiodine treatment is scheduled, it was concluded that CT is not suited for thyroid volume measurements under these conditions. It was argued that the discrepancies between the results in patients with non-toxic goiter and in patients with Graves’ disease may be caused by the relatively small thyroidal iodine pool in the latter. The lower iodine content would cause a lower signal intensity on CT, and less contrast between the thyroid gland and the surrounding tissues. In 25 patients with Graves’ disease, a direct comparison was made between pla-nar scintigraphy, ultrasound (US), and SPECT (with attenuation correction and scatter correction, using standard commercial hardware and software), while MRI was used as the gold standard. In this investigation (Chapter 8), it was con-cluded that MRI, SPECT, or US may be pursued for thyroid volume measurements. Planar scintigraphy is very inaccurate, and should be discarded as a means of pretherapeutic thyroid volume measurements. SPECT can be used as an alterna-tive to planar scintigraphy for the qualitative functional diagnosis; MRI or US should only be used as an ‘add-on’ to scintigraphy. A general discussion of radioiodine therapy for benign thyroid disorders is pre-sented in Chapter 9. In view of the good results in all nodular thyroid disorders under study, it was concluded that adjustments to the standard dosage formula are not indicated. In patients with Graves’ disease, it is much harder to make an accurate prognosis of the therapy outcome. It is argued that attempts to pre-serve normal endogenous thyroid function through a ‘patient-tailored’ model is to be preferred over the quick induction of hypothyroidism and subsequent levothyroxine substitution. Generalized proposals are made for adjustments to the standard radioiodine therapy dosage formula, making use of all optimiza-tion factors that were found in the investigations described in Chapters 2-7. This chapter is concluded by proposals for future research, primarily aimed at optimization of radioiodine dosage calculations in patients with Graves’ dis-ease. Dosimetric models and computer algorithms are needed to adjust for vari-ations in thyroid volume, 131 I uptake and radioiodine turnover rate. SPECT meas-urements of the 131 I concentration within the thyroid gland, instead of the thy-roid volume and the absolute amount of 131 I in the thyroid gland, deserve fur-ther investigation. Because of the clinical implications, we also propose a study of very-short-term variations in radioiodine uptake. The influence of antithy-roid drugs on the radioiodine turnover rate warrants further study, as well as a quantification of the dose-effect relationship of lithium co-medication in pro-longing the retention of radioiodine in the thyroid. Other proposed medication studies include the investigation of the clinical value of triiodothyronine (T 3 ) suppression therapy in autonomous thyroid disease, and of the clinical value of low-dose recombinant human thyrotropin (rhTSH) in patients with nontoxic goiter. Finally, it seems worthwhile from an endocrinologic viewpoint to do an open-label study of the merits of combined T 3 /T 4 medication versus T 4 alone in patients who have become hypothyroid after radioiodine therapy.