Is Empirical Radioactive Iodine Therapy Still a Valid Approach to Patients with Thyroid Cancer and Elevated Thyroglobulin?

Introduction

Originally, “empirical ¹³¹ I therapy” referred to the treatment of patients with differentiated thyroid cancer who had elevated thyroglobulin (Tg) after initial therapy, but no apparent disease on clinical examination, diagnostic whole-body scanning (DxWBS), or chest X-ray (1,2). At that time, WBS after ablation (WBS-ablation) was not always obtained and showed low sensitivity because of the presence of large thyroid remnants after less than total thyroidectomy. Since then, (i) WBS-ablation became a routine procedure and is now highly informative because only small thyroid remnants remain after total thyroidectomy; (ii) neck ultrasonography (US) was included in the follow-up of patients with thyroid cancer; (iii) DxWBS was no longer required in most patients; and (iv) computed tomography (CT) became more widely available. As a consequence of these changes, empirical ¹³¹I therapy was recommended for patients with elevated Tg and negative WBS-ablation, neck US, chest CT, and DxWBS (performed in selected cases) (3 –6).

The demonstration of the value of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in detecting metastases that are not visualized by other imaging methods has revived discussions on the indication for empirical ¹³¹I therapy. First, the recommendation was to perform ¹³¹I therapy, and only if posttherapy WBS (RxWBS) was negative would FDG-PET be necessary for the detection of iodine-negative metastases (3 –6). In view of the capacity of FDG-PET to detect metastases not visualized by other imaging methods such as US, CT, and DxWBS, and the fact that intense uptake of FDG is a predictor of poor response to treatment with ¹³¹I, the current recommendation is to first perform an FDG-PET and to restrict empirical ¹³¹I therapy to patients with negative FDG-PET (7 –10). However, the usefulness of empirical radioactive iodine therapy for patients with negative FDG-PET has also been questioned in recent years (11).

The objective of the present study was to evaluate the value of empirical ¹³¹I therapy in patients with elevated Tg after initial treatment, but with negative findings on WBS-ablation, neck US, chest CT, and FDG-PET.

Patients and Methods

We selected patients with papillary thyroid cancer (PTC) who submitted to total thyroidectomy followed by remnant ablation with ¹³¹I, in whom WBS-ablation did not reveal metastases and who had elevated Tg levels 8–12 months after ablation or during late follow-up. Included in the study were patients with basal Tg (without stimulation with endogenous or exogenous thyrotropin [TSH]) >2 ng/mL or Tg >5 ng/mL after stimulation with recombinant human TSH (Tg/rhTSH) or Tg >10 ng/mL after levothyroxine (L-T4) withdrawal for 4 weeks (4,5,8,9,12). These Tg concentrations were observed in 12 patients 9–14 months after ablation, and 12 other patients developed such levels during follow-up. In the latter cases (n=12), a Tg increase of >50% was required in addition to the above absolute values (11,13,14). Patients with documented structural recurrence before the study were excluded, and the patients were evaluated 36–120 months (mean 64 months) after initial remnant ablation.

All patients were first investigated by neck US and chest CT. FDG-PET/CT was performed in patients with negative US and CT. The final sample of this study consisted of patients whose FDG-PET/CT scan was also negative. These patients received an activity of 100 mCi ¹³¹I and were submitted to RxWBS.

For empirical therapy, ¹³¹I was given 24 hours after administration of the second rhTSH dose of 0.9 mg intramuscularly or after 4 weeks without L-T4; TSH was higher than 50 mIU/L in all patients. The administration of ¹³¹I was preceded by a low-iodine diet for 10–14 days. RxWBS was performed 7 days after treatment and was analyzed by at least two nuclear medicine professionals who had broad experience with this imaging method.

US was performed with a linear multifrequency 14 MHz transducer for morphological analysis (B-mode) and for power Doppler evaluation. US was defined as negative when it did not reveal suspicious lesions (15) or, if lesions were detected, when cytology and Tg measurement in the needle washout of US-guided fine-needle aspiration were negative. Chest and mediastinal CT was performed with 5-mm sequential sections. FDG-PET/CT was carried out after stimulation with rhTSH or L-T4 withdrawal for 4 weeks according to a recommended protocol (16).

Chemiluminescent assays were used for the measurement of Tg (Access Thyroglobulin Assay; Beckman Coulter, Fullerton, CA [functional sensitivity of 0.1 ng/mL]) and anti-Tg antibodies (Immulite 2000; Diagnostic Products Corporation, Los Angeles, CA [reference value of up to 40 IU/mL] or ARCHITET Anti-Tg; Abbott Laboratories, Green Oaks, IL [reference value of up to 4.11 IU/mL]).

Results

The characteristics of the patients are shown in Table 1. For ablation after thyroidectomy, 8 patients were prepared by administration of rhTSH and 16 by L-T4 withdrawal for 4 weeks; 6 patients received a low ¹³¹I activity (30 mCi) and 20 were treated with a high activity (100–200 mCi). All patients received an activity of 100 mCi for empirical ¹³¹I therapy, 20 of them after L-T4 withdrawal and 4 after the administration of rhTSH. Stimulated Tg measured immediately before empirical ¹³¹I therapy was >10 ng/mL in the former 20 patients (12–206 ng/mL, median 42 ng/mL) and >5 ng/mL in the latter 4 (6.5, 11, 23, and 71 ng/mL).

No ectopic uptake of ¹³¹I was seen in 23 patients, and mild uptake in the thyroid bed (<0.5%) was observed in 15 patients. Only one patient presented pulmonary metastases detected by RxWBS (a 49-year-old woman with tall-cell PTC, pT3N1M0, submitted to empirical therapy 48 months after ablation; Tg/rhTSH: 23 ng/mL).

During further short-term follow-up (12–48 months, mean 22 months), among the 12 patients in whom elevated Tg was detected 9–14 months after initial ablation, only 1 developed lymph node metastases diagnosed by a new US scan and the remaining 11 continued without detectable disease (a Tg reduction was observed in 6 patients, Tg levels remained stable in 3, and a Tg elevation was seen in 2). Among the 11 patients in whom an elevated Tg was observed during late follow-up, 1 had bone metastasis diagnosed by new CT and FDG-PET scans and the remaining 10 continued without detectable metastases (Tg levels remained stable in 8 patients and a Tg elevation was seen in 2).

Discussion

We first clarify the definition of “empirical ¹³¹I therapy” adopted in this study. First, we do not use this term for patients with metastases that could be detected on prior WBS. Second, minimal Tg elevations do not justify empirical therapy, and therefore only Tg concentrations >2, 5, and 10 ng/mL in the absence of TSH stimulation, post-rhTSH or during hypothyroidism, respectively, were considered (4,5,8,9,12). Third, empirical therapy concerns situations in which neck US, chest CT, and FDG-PET are all negative (7 –10).

If these criteria are observed, few patients are candidates for empirical ¹³¹I therapy. In the case of persistent disease after thyroidectomy, WBS-ablation often permits to detect disease (17). During follow-up, Tg is negative in most patients with negative WBS-ablation and continues to be undetectable for a long period (18 –20). On the other hand, in most patients with positive Tg levels who do not fulfill the criteria for empirical therapy, Tg becomes stable or declines (14,18 –20). In addition, US is a sensitive method for the detection of cervical metastases (19,21), CT shows high sensitivity in detecting pulmonary and mediastinal metastases (22), and FDG-PET is able to identify metastases that escape detection by US and CT as well as nonpulmonary distant metastases. Thus, the small number of patients included in this study is not a limitation, but rather reflects the fact that very few patients qualify for truly empirical therapy as defined above. In fact, the number of candidates for empirical ¹³¹I therapy was also small in two other series in which patients were evaluated with US and FDG-PET (11,22). In older series, when WBS-ablation was not a routine procedure, surveillance examinations typically consisted of DxWBS and chest X-ray, and US, CT, and FDG-PET were not performed in order to establish the indication for ¹³¹I therapy; for these reasons, these series tended to include larger numbers of patients. However, the results of these studies cannot be extrapolated to today's practice patterns.

In addition to being rarely indicated, the use of empirical radioactive iodine therapy has been questioned because it rarely detects pathological uptake (11), a fact that can be explained by two factors. First, by definition, WBS-ablation was already negative in these patients. Even without FDG-PET, some studies have shown that a second ¹³¹I administration does not reveal abnormal uptake in patients with negative WBS-ablation and US, despite persistently elevated Tg levels (19,23). Second, as mentioned earlier, the combination of US, CT, and FDG-PET shows high sensitivity (22).

Two other series also evaluated the use of empirical ¹³¹I therapy in patients with negative FDG-PET and reported similar results (11,22). In the series of Kim et al. (11), studying patients with negative WBS-ablation and elevated Tg during follow-up, empirical therapy did not reveal ectopic uptake of ¹³¹I in any of the 14 patients with a negative US, DxWBS, and FDG-PET. Moreover, Leboulleux et al. (22) detected iodine-accumulating metastases in only 1/12 patients with negative US and FDG-PET/CT. These studies were carried out at centers with large experience, and false-negative RxWBS results are therefore unlikely. In addition, there was only mild iodine uptake in the thyroid bed and no ectopic cervical uptake was observed in these patients submitted to empirical ¹³¹I therapy; that is, RxWBS was clearly negative, weakening the hypothesis that the results would be different if single-photon emission computed tomography/CT were performed (24 –28). We also do not believe that the results not favoring empirical therapy could be explained by the histological subtype of the tumors. Only conventional PTCs were included in the study of Kim et al. (11). The only cases in which ectopic uptake of ¹³¹I was not detected by FDG-PET in that study and in another series (22) were exactly tumors of the aggressive subtype. Thus, even if only patients with classic tumors that have higher iodine avidity were analyzed, RxWBS would be negative in all cases.

At our service, empirical ¹³¹I therapy is currently restricted to patients with documented progression of serum Tg, that is, a significant increase of Tg during late follow-up in relation to baseline levels after ablation, which is generally observed some years after WBS-ablation. In fact, similar cases were not studied by Kim et al. (11), and the patients in whom RxWBS showed iodine uptake not detected by FDG-PET/CT had progression of serum Tg in that study and in another series (22). Empirical ¹³¹I therapy restricted to patients with progression of serum Tg is consistent with the view that Tg elevation in sequential measurements is the best predictor of detectable metastases (13,14,19). The fact that these patients do not present clinically or radiologically apparent disease or FDG uptake, predictors of a better prognosis, leads us to delay the administration of ¹³¹I to situations where there is an increase of Tg. Furthermore, considering that few patients will present positive RxWBS and that there is no evidence showing that an activity of 100 mCi is more sensitive for the detection of disease (29), the administration of a lower activity, such as 30 mCi, to exclusively identify these exceptional cases may be an interesting approach. The adoption of these two measures for empirical ¹³¹I therapy would spare many patients from the unnecessary exposure to a high radioactive iodine activity.

We conclude that RxWBS rarely reveals disease in patients with elevated Tg after ablation, but with negative findings on WBS-ablation, US, CT, and FDG-PET. In this situation, empirical ¹³¹I therapy should be restricted to patients with documented progression of serum Tg levels.