ALARA in rhTSH-stimulated post-surgical thyroid remnant ablation: what is the lowest reasonably achievable activity?

For several years now recombinant human TSH (rhTSH) has been approved by the European Medicines Agency (EMEA) for the preparation of differentiated thyroid carcinoma (DTC) patients for radioiodine (¹³¹I) ablation of thyroid remnants after surgery. Its effectiveness in patient preparation before ¹³¹I ablation has been shown in multiple prospective studies [1–7].

In this editorial we will review the existing literature on the topic of rhTSH-stimulated ¹³¹I ablation with emphasis on factors that may influence the success rate of ablation, such as the administered activity, the size of the post-surgical thyroid remnant and the amount of stable iodine present in patients at the time of ablation.

The available studies in the literature differ greatly in the activities of ¹³¹I used for ablation as well as the stages of patients eligible for inclusion, although most studies have used fairly uniform criteria for successful ablation. The available studies with their key criteria and results are summarized in Table 1. In this table, it can be seen that in those studies using 1.85 GBq (50 mCi) ¹³¹I or more, there is little or no reason to doubt the equivalence of rhTSH to levothyroxine (LT₄) withdrawal for the preparation of ablation, while rhTSH stimulation significantly decreases the whole-body radiation exposure [8]. The effectiveness of ¹³¹I ablation using rhTSH, which led to its approval by European and US authorities for this indication, is corroborated by a recent retrospective study of 394 patients in which the short-term clinical recurrence did not differ between subjects prepared by rhTSH or LT₄ withdrawal [9].

Table 1 An overview of prospective studies on rhTSH ablation, ordered by activity used for ablation. All studies were rhTSH vs withdrawal unless otherwise noted

For the studies using 1.11 GBq (30 mCi) ¹³¹I, the results are more differentiated: whereas the studies by Barbaro et al. [6, 7] did not show a significant difference in the rates of successful ablation between patients prepared with rhTSH and LT₄ withdrawal, Pacini et al. [5] did find a considerable difference. Some speculation is possible about the reason for the difference found by Pacini et al.; the most likely explanation is that the administration of the ablative ¹³¹I activity on the second day after the last administration of rhTSH is too late. Based on a large international trial [10] it was recommended in the registration that ¹³¹I should be administered on the first day after the last rhTSH injection.

The exact activity that needs to be administered in order to achieve successful ablation is still a subject of debate [11]. There are only a few studies comparing the success rate of ablation during classic LT₄ withdrawal and none that compare different activities under rhTSH stimulation. Those studies which are available, such as the one by Bal et al. [12], seem to indicate that there is no real increase in ablation success rates for activities exceeding 1.85 GBq (50 mCi), albeit under classic withdrawal conditions. However, in the UK and in France two major trials are currently ongoing, both of which contain an rhTSH arm, which aim to determine what activity is required for a successful ¹³¹I ablation; the first results of these trials are expected to emerge later in the year 2010. Even if these trials may not be able to provide the definitive and nuanced answer to the question on how high the ablative ¹³¹I activity should be precisely, they will certainly be able to give a good sense of the range for further detailed research.

The second major consideration in ¹³¹I ablation is the size of the thyroid remnants. This parameter strictly depends on the true extent of the total thyroidectomy, which in turn largely depends on the skill and experience of the surgeon performing the procedure, as well as the concomitant thyroid pathology such as goitre.

Measuring the size of the thyroid remnant remains a difficult matter, certainly in the immediate post-operative period where tissue oedema prevents the acquisition of a clear image and accurate measurements. A post-surgery ultrasound probably represents the easier diagnostic tool to evaluate the size of the post-operative thyroid remnants and should be part of any post-surgical evaluation. Ideally (though in clinical practice this is often difficult as ablation is often scheduled ca. 4 weeks after surgery) it should not be performed before 40–60 days after surgery to allow the post-surgical oedema to recede. Nonetheless volume estimation of small thyroid remnants remains difficult and imprecise, which in turn makes an meaningful thyroid remnant dosimetry all but impossible.

A final important point that deserves attention when trying to use lower activities of ¹³¹I is the potential role of the iodine metabolism. Some important differences exist in this regard between LT₄ withdrawal and rhTSH stimulation. The iodine clearance in euthyroid state is considerably higher than in hypothyroidism [8, 13–16] for example. Therefore the biological whole-body half-life of ¹³¹I is shorter under rhTSH stimulation than it is under withdrawal. In contrast it is also known that the intrathyroidal ¹³¹I half-life is longer during rhTSH stimulation than during LT₄ withdrawal [8, 16, 17]. This can be explained by the relatively short duration of the rhTSH stimulus, which only results in a modest secretion of thyroid hormone-bound radioiodine. The ¹³¹I residence time between rhTSH stimulation and LT₄ withdrawal in normal cells does not differ however, as the thyrocytes’ ¹³¹I uptake tends to be lower after rhTSH stimulation than during LT₄ withdrawal [8, 16].

Physiology teaches us that ¹³¹I uptake is, at least in part, inversely related to iodine intake and the whole-body iodine pool, as stable iodine in a pharmacological sense works as a competitive ¹³¹I inhibitor. For this reason low-iodine diets have been employed for many years in preparing patients for ¹³¹I ablation [18–21]. Considering that, as stated before, iodine uptake tends to be lower under rhTSH than under withdrawal, it seems that in the case of rhTSH-stimulated ablation the need for reducing the whole-body stable iodine pool is even more important in order to maximize the therapeutic effect of the longer iodine retention under rhTSH. This may be especially true in areas with a high nutritional iodine intake. Consequently it is conceivable that the lower the ablative ¹³¹I activity used, the more important the reduction of stable iodine becomes. The studies by Barbaro et al. [6, 7], who performed ablation under rhTSH stimulation with an activity of only 1.1 GBq after patient preparation with a stringent diet as well as a so-called mini-withdrawal (i.e. the discontinuation of LT₄ for 4 days before ¹³¹I administration as it is a source of stable iodine), seem to prove that it is possible to effectively ablate patients using only 1.11 GBq when paying attention to the reduction of the whole-body iodine pool; the ablation success rates in the studies by Barbaro et al. were comparable with those in studies which used a higher ablative ¹³¹I activity. Furthermore, in a recently published study by Barbaro et al. [22] comparing stage-adjusted activities for rhTSH-stimulated ablation as well as several preparation regimes, it was shown that the whole-body pool of stable iodine, as measured by its urinary excretion, could be further reduced significantly by adding furosemide treatment to the preparation regime. In this study, patients pre-treated with furosemide showed a non-significant trend towards a higher success rate.

With only sparse literature to go by, it seems that the role of the reduction of the whole-body stable iodine pool before ablation certainly deserves further study—especially where it comes to measures such as the addition of a mini-withdrawal or furosemide therapy to the patient preparation procedure.

In conclusion, there are still (too) many open questions to definitively answer what activity is the lowest reasonably achievable activity for rhTSH-stimulated ¹³¹I ablation. There are however indications in the literature that lower activities of 1.85 GBq or, at least with special preparations such as an LT₄ mini-withdrawal and/or furosemide treatment, even 1.1 GBq are attainable. Whether 1.1 GBq ¹³¹I is also sufficient without such extensive patient preparation, or in patients with large thyroid remnants, remains subject to further study.