Radioactive Iodine Uptake in Response to Recombinant Human Thyrotropin Stimulation for Thyroid Remnant Ablation in Patients with Differentiated Thyroid Cancer

The vast majority of differentiated thyroid tumours arise from
thyroid follicular epithelial cells; papillary cancer corresponds
to approximately 85% of cases, whereas about 12% of tumours
have follicular histology, including Hurthle cell carcinomas


Introduction
The vast majority of differentiated thyroid tumours arise from thyroid follicular epithelial cells; papillary cancer corresponds to approximately 85% of cases, whereas about 12% of tumours have follicular histology, including Hürthle cell carcinomas [1].
Initial therapeutic management aims to remove the primary tumour with as low surgery-related morbidity as possible [2].
Total thyroidectomy (TT) has been indicated as the primary surgical treatment option for nearly all differentiated thyroid lesions >1cm, independently of the presence of loco-regional or distant metastases [3]. When performing TT, the surgeon aims to remove as much thyroid tissue within the operative bed as possible.
However, in a significant number of patients, a small amount of of the patients who underwent TT due to differentiated thyroid cancer (DTC) [4]. Incomplete thyroid tissue removal may lead to the performance of radioactive iodine (RAI) therapy for TR ablation [5,6].
In general, RAIU measurements provide valuable information for the therapeutic management of DTC patients. Residual RAIavid disease can be detected, and TR uptake is evaluated through RAIU testing. As previously mentioned, RAIU data are employed, in combination with TxWBS findings and Tg levels, in the decisionmaking process regarding the need for RAI ablation. Interestingly, Holsinger et al. reported that post-operative RAIU <0.2% is associated with the highest likelihood of undetectable Tg levels after TT, resulting in an even smaller need for TR ablation [7].
Moreover, Zerva et al. reported that the ratio of Tg levels to RAIU values, during the immediate post-surgical period, can be used as a tool for the identification of patients with metastatic disease [8]. In these patients, higher initial RAI therapy doses may be selectively administered in order to obtain a better outcome. On the other hand, the tailoring of RAI activities based on RAIU values was not found more advantageous compared to the fixing dosing, in terms of the success of TR ablation [9][10][11]. A dose of approximately 1,110MBq (30mCi) is generally favoured over higher administered activities that may be considered only if a large TR is suspected [5].
In DTC patients considered to be at low risk of recurrence or mortality, previous management guidelines advocated selective performance of RAI ablation, due to its side-effects [3,6,12,13].
More recently, according to the American Thyroid Association (ATA) guidelines task force on thyroid nodules and DTC, TT may be performed in patients with tumour size 1-4 cm, but it is strongly indicated only in patients with tumour >4 cm, or gross extrathyroidal extension, or clinically apparent metastatic disease [5].
These recommendations are formulated in international centres of excellence; however, they may not be fully applicable in other institutions where TT remains the primary surgical procedure in DTC patients [14][15][16]. Therefore, especially in countries with few specialized thyroid cancer centres, such as Greece, RAIU measurements continue to have a significant role in making therapeutic decisions, in most patients with regard to the need for RAI ablation.
A goal thyroid-stimulating hormone (TSH) concentration of ≥30mIU/L is generally adopted in RAI therapy preparation, since TSH levels above this threshold are required for incompletely resected thyroid tissue to significantly concentrate 131I [17]. According to the recent ATA guidelines, preparation with recombinant human thyrotropin (rhTSH) stimulation is an acceptable alternative to thyroid hormone withdrawal (THW) for achieving TR ablation in ATA low-risk DTC patients, ATA intermediate-risk DTC patients, especially in those without extensive lymph node involvement, and DTC patients of any risk level with significant co-morbidity that may preclude THW prior to RAI administration.5 rhTSH preparation is also advocated for attaining TSH elevation in DTC patients, referred for RAI ablation, based on the European Association of Nuclear Medicine (EANM) guidelines [6]. In the present study, we aimed to investigate the presence of variations in RAIU measurements after either rhTSH preparation or THW in DTC patients referred for TR ablation, and to examine whether these potential discrepancies could influence the efficacy of TR ablation.

Methods
The influence of rhTSH preparation on RAIU measurements  (Table 1).   All patients started a low-iodine diet 2 weeks before RAI administration. In group A patients, thyroxine was withdrawn for 5 weeks prior to RAI treatment and was substituted by triiodothyronine administration during the first 3 weeks of thyroxine withdrawal. Triiodothyronine was withdrawn for at least 2 weeks before RAI therapy. RAIU was performed 2 days prior ablation, after an oral 131I administration of 2,220-2,960MBq (60-80μCi) (Figure 1). In group B patients, 131I was administered at the second day of rhTSH administration and RAIU was performed 24h later, at the day of ablation (Figure 2 [19]. On the other hand, TR RAIU can serve as a valuable tool for the evaluation of the completeness of resection and the prediction of individual recurrence risk [20]. Moreover, pretreatment measurement of thyroid bed RAIU contributes not only to the therapeutic management regarding the decision to either perform TR ablation or not, but also to the selection of RAI activity when tailoring dose according to RAIU values. This test may clearly maximise the degree of individualisation in therapeutic decisionmaking after TT, an advantage especially important in paediatric patients.6 Consequently, it is a useful tool, particularly in cases of suboptimal TR extent evaluation based on the surgical report or neck ultrasonography [21].
Traditionally, the decision regarding the administered activity for TR ablation could be made based on three different approaches: a. Empirical fixed doses.
b. Upper bound limits according to blood and whole-body dosimetry.
TR ablation can be performed successfully with RAI doses based on TxWBS neck uptake, although there are published data supporting a fixed-dose protocol.9,21 Nevertheless, RAIU-guided strategy has undoubtedly two important advantages over fixeddose protocols; unnecessary radiation exposure can be avoided and the occurrence of local side effects due to RAI administration is lower [22][23][24]. In our department, if RAIU is over 9.0% and there is no evidence of RAI-avid tissue outside the thyroid bed, we opt for lower activities of 30-40 mCi, instead of doses ranging between 80-120 mCi. In the present study eight group A patients had RAIU values >9 %, indicating a higher risk of side-effects in the postablation period. RAI therapy is generally safe; however, there is a risk for potential side-effects [25,26].  [27].
The efficacy of rhTSH-aided RAI therapy for TR ablation has been evaluated in several studies. It was reported to be equally effective to THW in recent meta-analyses [28,29]. In our study, ablation rates were optimal, both in rhTSH-prepared patients and in patients treated under hypothyroid state. Important advantages of rhTSH preparation have been reported in terms of quality of life and adverse effects during and after ablation, including fatigue, headache, sialadenitis, neck pain, taste loss, nausea, radiation gastritis, and bone pain.12 [30][31][32], Notably, rhTSH-aided TR ablation was linked to decreased irradiation to the patients. In particular, the specific absorbed dose to the blood was significantly lower in patients undergoing rhTSH preparation compared to those randomized to the THW group [33]. Lower red marrow absorbed dose was also reported [34]. Although rhTSH preparation significantly increases the overall cost of the treatment, the balance may be in favour of its use when the cost to the society due to hypothyroidism -associated loss of productivity (days off work) is taken into account [35,36].
Moreover, rhTSH may allow a shorter hospitalization length because of the faster RAI excretion, partially compensating its high cost [35][36][37]. Thus, based on a cost-effectiveness analysis, rhTSH preparation should be considered ''good value-for-money'' with the benefits to both patients and the society obtained at modest net cost [38]. Similar findings were reported for a non-western patient population [39].

Conclusion
RAI ablation continues to have an important role in the management of DTC patients since TT remains the primary therapeutic option for patients suffering from DTC in many countries, particularly in those where specialized thyroid cancer services are rare. We suggest that the pre-ablation TR estimation is helpful whenever RAI therapy is performed in non-specialized clinics. RAIU measurement represents a valuable tool for the assessment of the need for ablation, including the appropriate RAI activity. Based on our protocol, RAIU test is applicable even after rhTSH preparation which permits the performance of RAI therapy without the THW-related adverse effects. Although we showed that RAIU may be underestimated in rhTSH-prepared patients, compared to patients who underwent THW, the observed variations did not affect negatively the patient management; therefore, these variations were not found to influence the outcome of ablation therapy. Finally, our findings were in accordance to the previously published studies confirming the efficacy of RAI therapy after rhTSH preparation.