The application of a diagnostic activity of ¹³¹I immediately before radioiodine treatment may induce “stunning,” that is, reduced uptake or altered kinetics of ¹³¹I during subsequent radioiodine therapy, which may substantially impair the efficacy of that therapy and reduce the rate of successful ablation by as much as 50 % (Lassmann et al. 2004; Lundh et al. 2007, 2009; Verburg et al. 2009). Therefore, it is recommended not to use the diagnostic activities of ¹³¹I that are necessary for scintigraphy (more than 10–20 MBq) before ablation (Medvedec 2005). As an alternative, 24-h uptake measurements with smaller ¹³¹I activities (<10 MBq) may be performed to roughly estimate the mass of the thyroid remnant (Dietlein et al. 2007a, b). As an additional alternative to ¹³¹I diagnostic scanning, iodine-123 (¹²³I) WBS may be used. Because ¹²³I is a pure gamma emitter, it has the advantage of causing no stunning (Lundh et al. 2009). However, given its 13.2 h half-life, this relatively expensive radionuclide does not allow late scans (i.e., >24 h after ¹²³I administration) with low background activity. ¹²³I scintigraphy therefore is regarded less sensitive than ¹³¹I scanning. If ¹²³I is used for WBS, a 40–200 MBq activity must be applied.

Recently, positron emission tomography (PET) with 40–100 MBq of the radioisotope ¹²⁴I (half-life 4.2 days) has been tested as still another alternative for localization of thyroid remnants or for pretherapeutic dosimetry (Freudenberg et al. 2007). However, no systematic data are available up to now with respect to stunning, which at least hypothetically may be induced by ¹²⁴I, a positron—as well as a gamma—and beta-emitter.

Ablative radioiodine treatment demands serum TSH levels above 30 mU/l to induce sufficient radioiodine uptake in thyroid remnants or tumor tissue. Such TSH stimulation may be achieved by two different approaches:

When withholding levothyroxine replacement, some authors recommend giving patients shortlived triiodothyronine (T3, pharmacological half-life approximately 10 h) for one or—at most—2 weeks immediately after surgery or—when thyroid hormone withdrawal (THW) is undertaken later in the post-surgical course, after levothyroxine (T4, pharmacological half-life approximately 10 days) has been discontinued.

A randomized prospective Phase III study in mainly low-risk patients proved that a standard activity of 3.7 GBq ¹³¹I induced comparable ablation rates of approximately 90 % after endogenous (TSH >25 mU/l after THW) or after exogenous TSH-stimulation (two consecutive daily i.m. injections of rhTSH, 0.9 mg). These rates were obtained when successful ablation was defined as the combination of radioiodine neck uptake <0.1 % on a diagnostic WBS and of serum Tg < 2 ng/ml under rhTSH stimulation at 8 ± 1 months after ablation (Pacini et al. 2006b). In the meantime, the long-term follow-up of patients included in this prospective phase-III trial proved the equal efficacy of radioiodine ablation prepared by recombinant TSH as compared for thyroid hormone withdrawal (Elisei et al. 2009). On the other hand, a nearly 400-patient retrospective analysis from the Memorial Sloan-Kettering Cancer Center (Tuttle et al. 2008a), which also used large activities of ¹³¹I and included a higher risk study population than the Phase III trial, found that, with a median 2.5 years of follow-up, rhTSH- and withdrawal-aided ablation were associated with statistically not different, low rates of clinical recurrence or persistent thyroid bed scintigraphic uptake, as well as statistically similar time to recurrence. This led the American Thyroid Association (Cooper et al. 2009), the European Society for Medical Oncology (Pacini et al. 2010) and the European Association for Nuclear Medicine (Luster et al. 2008) to recommend preparation of radioiodine ablation with recombinant TSH because of its equal effectivity but lower rate of side-effects. In 2009, the European Medicine Agency (EMEA) expanded the indication for rhTSH in combination with 3.7 GBq ¹³¹I from “low risk (pT1-2, N0, M0) patients” to patients after near-total or total thyroidectomy of differentiated thyroid cancer tumor stages pT 1–4, N 0–1, M0.

Recently, Tuttle et al. from the Memorial Sloan Cancer Institute, New York showed in a retrospective study that radioiodine had similar therapeutic (tumoricidal) effects on small volume I-131 with metastatic disease in both locoregional lymph nodes and pulmonary parenchyma (Tuttle et al. 2010).

Advantages of ablative radioiodine treatment under recombinant TSH were avoidance of hypothyroid morbidity and hence, improved quality of life, and lower radiation exposure of extrathyroidal compartments due to lesser (−35 % on average) radioactivity in the blood. The latter finding can be explained by non-disturbed renal clearance of radioiodine in the euthyroid state (Hanscheid et al. 2006; Luster et al. 2003; Loffler et al. 2003). As a consequence of decreased whole-body radiation exposure, a lower risk for secondary cancers after radioiodine therapy (see below) must be taken into account, at least hypothetically.

According to model calculations from a societal perspective by Mernagh et al. (2006), the use of rhTSH rather than THW led to a gain of 0.05 quality adjusted life years (QALYs) per course, which was caused by shorter missed worktime and an extrapolated lower rate of secondary neoplasia. The additional cost associated with this increase in QALY, calculated as an incremental cost-effectiveness ratio (ICER), amounted to 958 euros per QALY, which suggests that preparation of ablative radioiodine therapy by rhTSH is cost-efficient, given the generally accepted cost-effectiveness threshold, an ICER of 45,000 euros/QALY, for new interventions. In addition, short-term hypothyroidism secondary to T4 withholding after thyroidectomy leads to disturbances of lipid metabolism and increased arteriosclerotic risk (Duntas and Wartofsky 2007).

Some authors recommend performing a “mini-withdrawal” of levothyroxine a few days before the two rhTSH injections, and a few days after radioiodine administration, to reduce the supply of stable iodine provided by thyroid hormone medication (100 μg of levothyroxine contain approximately 65 μg of iodide). A study by Barbaro et al. (2003) compared urinary iodine excretion after rhTSH stimulation and continued T4 medication versus after rhTSH stimulation and thyroid hormone “mini-withdrawal.” Iodine excretion was significantly lower after “mini-withdrawal” (47.2 ± 4.0 μg/l versus 76.4 ± 9.3 μg/l, P = 0.019). The ablation success rate after 1 year was even slightly higher after rhTSH-aided ablation with short-term thyroid hormone withdrawal as compared to stimulation with traditional THW (81.2 % versus 75.0 %). In contrast, Tala Jury et al. were unable to find a relationship between urinary iodine excretion and the success rate of rhTSH-aided ablation (Tala Jury et al. 2010).

If the remnant dose (in Gy) cannot be projected and an individualized activity therefore cannot be calculated for a given patient, standard fixed ¹³¹I activities between 1 and 3.7 GBq are recommended for THW-aided ablation, whereas a standard fixed activity of 3.7 GBq has been used for rhTSH-aided ablation. Within the “bandwidth” of 1 and 3.7 GBq ¹³¹I, higher activities seem to coincide with higher success rates (Hackshaw et al. 2007). A recent prospective, randomized, controlled investigation (Pilli et al. 2007) suggests that rhTSH-aided ablation with 1.85 GBq of ¹³¹I may achieve a statistically non-inferior ablation success rate to that seen with rhTSH-aided ablation using 3.7 GBq, even in the presence of node metastases. Two prospective trials (Barbaro et al. 2003, 2006), but not another (Pacini et al. 2002), suggest equivalent ablation success rates with rhTSH-aided versus withdrawal aided ablation using 1.1 GBq; the latter study by Pacini is best disregarded for the comparison between rhTSH and levothyroxin withdrawal as the I-131 activity was administered at a later than recommended timepoint after rhTSH administration. Further studies are desirable to increase the duration of follow-up that has been reported for rhTSH-aided ablation.

The amounts of radioactivity for successful ablation strongly depend on the completeness of previous surgery. Especially in countries such as Germany, where approximately 50 % of DTC patients are diagnosed “by chance” coincidentally after routine thyroid surgery for endemic nodular goiter, thyroid remnants usually are relatively large, so that even treatment activities of 3.7 GBq of ¹³¹I may not be sufficient for complete ablation of the remnant. If the 24-h uptake of a (low) diagnostic activity of ¹³¹I exceeds 20 %, the patient should be remitted to the surgeon for complete thyroidectomy. In the case of R1 resections, aggressive DTC subtypes or other high-risk features, even higher standard therapeutic activities of up to 7.4 GBq ¹³¹I can be administered without special precautions.

If radioiodine activities above 7 GBq are considered for ablative treatment, dosimetric approaches should be used to estimate the radiation dose to the blood, to ensure that this dose does not exceed 2 Gy, the traditionally accepted safety threshold to avoid serious myelotoxicity (Hanscheid et al. 2006; Benua et al. 1962; Lassmann et al. 2008; Flux et al. 2010).

At least in the situation of ablation therapy it is most often not possible to calculate target doses to the remnant using the MIRD formalism because of the difficulty to determine the remnant volume after surgery (Salvatori and Luster 2010). On the other hand, even in patients with advanced disease the relatively simple method to limit the radiation dose to the blood proved to be safe and effective (Verburg et al. 2010).

It is strongly recommended to avoid iodine-containing drugs (e.g., X-ray contrast media, reagents for disinfection, ophthalmic agents, amiodarone, iodide medication), food or food additives with high iodine content (e.g., seaweed, kelp multivitamin and trace element combinations) in the weeks preceding radioiodine ablation. A low-iodine diet with <50 μg iodine per day no seafood or iodized salt is recommended for 2–3 weeks (Cooper et al. 2009; Pacini et al. 2005; Maxon et al. 1983) before radioiodine treatment to improve radioactive iodine uptake in thyroid remnants or metastases.

In nearly 70 years of experience many studies, especially those with long-term follow-up, have shown that radioiodine ablation or therapy leads to considerable clinical benefits in the sense of a reduced recurrence and death rate in DTC patients. We will highlight some of the more important studies here.

Mazzaferri and Jhiang (1994) showed that in long-term follow-up the recurrence rate was reduced from about 40 % in patients without radioiodine treatment to 10 %, whereas the death rate was reduced from 9 to 0 %. Similarly in a study by Hay et al. (2002) the long-term recurrence rate was reduced from about 25 % to about 10 % whereas thyroid cancer mortality was decreased by half. Handkiewicz-Junak et al. (2007) were able to show a reduction in long-term recurrence rates from >60 % without to about 5 % with radioiodine therapy; in a meta-analysis of literature Jarzab et al. (2005) were able to determine a relative risk for recurrence of 5.8 for those who did not receive radioiodine treatment compared to patients who did.

A large meta-analysis of the literature by Sawka et al. (2004) definitively showed that studies on the efficacy of I-131 treatment in thyroid cancer patients require a long follow-up. As can be seen in Table 3, it is only after at least 10 years of follow-up that any benefit of I-131 treatment can be proven with statistical significance. This is important to remember, as most studies in DTC do not achieve such a long follow-up. In this 2004 review by Sawka, it could not yet definitively be proven that I-131 treatment was actually beneficial to all patients.

In a further, updated meta-analysis published in 2008, Sawka et al. (2008b) tackled another difficult problem. Due to the very good prognosis of DTC patients, it is almost impossible to attain a sufficiently long-term follow-up for analysis of tumor specific mortality. Especially in low-risk patients, this would require a time-span of observation that far exceeds the length of the average physician’s career. Therefore, Sawka et al. used a surrogate measure of prognosis in order to analyze the efficacy of I-131 ablation in patients: they performed a pooled analysis of several studies reporting the later subsequent incidence of distant metastases between patients who did receive I-131 therapy and those who did not. In a pooled analysis of 2,263 patients (see Table 4) they demonstrated a small but statistically significant reduction in the risk for developing distant metastases of −2 % (95 % confidence interval: −1 to −4 %; P = 0.0005) (Sawka et al. 2008b). This significant improvement in a substitute measure can be interpreted as an improvement of the prognosis of patients after I-131 ablation.

Radioiodine therapy is therefore clearly able to alter prognosis in DTC patients for the better. In fact, the response to radioiodine ablation may even be a more powerful indicator of prognosis than the initial clinicopathological stage. Verburg et al. (2010) were able to show that after successful radioiodine ablation there were no differences anymore in both recurrence and death rates between patients who were classified as low risk or high risk according the the ETA classification. Another study by Verburg et al. (2005) showed that there was a dramatic difference in both disease-free survival (87 % in case of successful ablation versus 49 % if ablation was unsuccessful) and thyroid cancer-related mortality (7 % versus 22 %) between patients in whom radioiodine ablation was successful and those in whom the treatment was unsuccessful. These findings solidly support the concept of restaging according to treatment success which was first proposed by Tuttle et al. (2008b).

Whereas radioiodine ablation often leads to great success in patients without distant metastases, the picture is looking somewhat different in patients with distant metastases. Although some patients, especially those younger than 45 years of age at the time of diagnosis, may still achieve a stable partial or even complete remission after radioiodine therapy, in many, especially older, patients distant metastases often respond poorly to radioiodine treatment or even fail to accumulate radioiodine at all. Especially in the latter case, the role of radioiodine therapy is extremely limited and other therapy modalities will have to be considered.