Recombinant Human Thyrotropin in Thyroid Remnant Ablation with 131-Iodine in High-Risk Patients

Abstract

Background:

Most patients with well-differentiated thyroid cancer (WDTC) are first treated by total thyroidectomy followed by remnant ablation (RA) with ¹³¹I. There are less data regarding the efficacy of recombinant human thyrotropin (rhTSH) for patients with WDTC at high risk of relapse than for low-risk patients. This study compared the efficacies of rhTSH and thyroid hormone withdrawal (THW) to prepare patients at high risk of relapse for RA.

Methods:

Post-thyroidectomy patients with WDTC and complete tumor resection (n = 275) were studied. They were at high risk of recurrence (tumor size >4 cm and/or extrathyroidal extension [pT3] and/or lymph node metastases), and they did not have antithyroglobulin (Tg) antibodies. Group A (n = 77) received 0.9 mg rhTSH for 2 consecutive days followed by RA on day 3. The remaining 198 patients (group B) were prepared by THW for 4 weeks. Patients in groups A and B received 3.7 or 5.5 GBq ¹³¹I.

Results:

The groups were similar in terms of gender, age, histology, TNM (tumor–node–metastases) stage, ¹³¹I activity, and frequency of metastases on post-therapy whole-body scanning (RxWBS). Among patients without metastases on RxWBS, RA was successful (stimulated Tg <1 ng/mL and negative diagnostic whole body scan and neck ultrasonography) in 56 of 70 patients in group A (80%) and in 135 of 169 patients in group B (79.9%). Among patients with Tg >1 ng/mL immediately before RA, the comparable success rates were 68.4% and 67.4%, respectively. Among patients with metastases on the first RxWBS, no uptake was observed on the RxWBS 1 year later in 5 of 7 patients in group A (71.4%) and in 17 of 29 patients in group B (58.6%). The rhTSH stimulated serum Tg was <1 ng/mL in 3 of 5 and in 12 of 17 patients with a second negative RxWBS in groups A and B, respectively. Persistent disease (stimulated Tg >1 ng/mL and RxWBS continuing to show ectopic uptake) occurred in 2 of 7 patients in group A (28.5%) and in 12 of 29 patients in group B (41.3%).

Conclusions:

rhTSH is as effective as THW for RA in patients with WDTC who are at a high risk of relapse.

Introduction

M ost patients with well-differentiated thyroid cancer (WDTC) are first treated by total thyroidectomy followed by remnant ablation (RA) with ¹³¹I, and preparation with recombinant human thyrotropin (rhTSH) is widely used for this purpose. However, in the absence of contraindications to the development of hypothyroidism or inability of the patient to elevate his/her endogenous TSH, patients who are at a high risk of relapse are often preferentially prepared for RA by levothyroxine (L-T4) withdrawal (1 –5). Thus, there are fewer data regarding the efficacy of rhTSH to prepare patients for RA with high-risk compared with low-risk patients. In high-risk patients, micrometastases (mainly lymph node metastases) might be detected by whole-body scanning performed after administration of ¹³¹I (RxWBS) even after apparently complete tumor resection and in the absence of apparent disease (6). The efficacy of treatment of these metastases is also important for the choice of preparation for RA, but few studies have evaluated this aspect (6,7).

There are advantages of rhTSH over L-T4 withdrawal including prevention of symptoms and risks resulting from hypothyroidism, preservation of quality of life, and shorter absence from work. In addition, patients who are at high risk of relapse may particularly benefit from preparation with rhTSH, as they may be likely treated with higher doses of ¹³¹I. They generally receive a minimum of 3.7 GBq (100 mCi) ¹³¹I for remnant ablation (1). They, therefore, require hospitalization and, with higher doses, are more susceptible to the adverse effects of radioiodine (8 –12). An advantage of rhTSH over L-T4 withdrawal is some minimization of radiotoxicity (8,13) and a reduction in the duration of hospitalization (14).

The objective of the present study was to evaluate the efficacy of rhTSH compared with thyroid hormone withdrawal for RA in patients with WDTC who are at high risk of relapse.

Materials and Methods

Patients

A total of 275 consecutive patients with WDTC seen between August 2003 and August 2008 who had been treated with total thyroidectomy with complete tumor resection were studied. To be eligible for the study, their postoperative clinical examination and chest radiograph were negative for metastases, and they needed to be at high risk of relapse as judged by a tumor size >4 cm and/or extrathyroidal extension (pT3) and/or lymph node metastases (1,2,15,16). In addition, tests for antithyroglobulin antibodies (TgAb) needed to be negative. All patients signed a consent form approved by the Ethics Committee of our Institution.

¹³¹I therapy

Until 2006, since the use of rhTSH for ablation had not yet been approved in Brazil, only patients having a contraindication to hypothyroidism (17,18) were prepared with rhTSH (33/127 subjects). After the approval, preparation with rhTSH was offered to all patients. Acquisition of rhTSH was not feasible in 104 of 148 patients. Seventy-seven patients (group A) received 0.9 mg rhTSH for 2 consecutive days followed by ¹³¹I administration on the third day. L-T4 was discontinued 3 days before and 1 day after therapy (19) in the first 27 cases and continuously maintained (20) in the last 50 patients. The remaining 198 patients (group B) were prepared by L-T4 withdrawal for 4 weeks. TSH and Tg were measured immediately before ¹³¹I administration. Symptoms of hypothyroidism (21) were evaluated on the same occasion. The patients received 3.7 or 5.5 GBq (100 or 150 mCi) ¹³¹I without undergoing pretreatment diagnostic whole-body scanning (DxWBS). Hormonal therapy was reintroduced 48 hours after radioiodine administration in patients who underwent L-T4 withdrawal, and RxWBS was performed 7 days after ¹³¹I administration.

The subjects received instructions regarding limiting exposure to environmental iodine and using a low-iodine diet for 2 weeks before ¹³¹I therapy. For women of child-bearing potential, a negative serum human chorionic gonadotropin pregnancy test was required. The patients were told to drink a lot of water and, when presenting with intestinal constipation, were given a laxative to adequately eliminate ¹³¹I. The patients were advised to frequently chew gum, which was made freely available.

Outcome of ablation

Nine to 12 months after ablation, the patients without ectopic uptake on RxWBS were reevaluated by measurement of stimulated Tg, DxWBS (185 MBq ¹³¹I) and neck ultrasonography. Ablation was considered to be successful when the stimulated Tg level was <1 ng/mL, and neck ultrasonography and DxWBS showed no abnormalities (1,2,15). Also, 12 months after ablation, the patients with ectopic uptake on RxWBS received a second dose of ¹³¹I (3.7 GBq). Tg and TgAb were measured immediately before administration of ¹³¹I, and RxWBS was performed 7 days after administration of ¹³¹I.

Assays

Tg was measured by a radioimmunometric assay (ELSA-hTG; CIS Bio International), with a functional sensitivity of 1 ng/mL. TgAb was determined by a chemiluminescent assay (Nichols Institute Diagnostics [detection limit of 1 IU/mL and reference value of up to 2 IU/mL] or Immulite 2000 [detection limit of 20 IU/mL and reference value of up to 40 IU/mL]). Patients with TgAb were excluded.

Imaging methods

Ultrasonography was performed with a linear multifrequency 10-MHz transducer. All suspected lesions apparent on ultrasonography (22,23) were evaluated by ultrasonography-guided fine-needle aspiration biopsy.

Statistical analysis

Means were compared between groups by the Student's t-test or the nonparametric Mann–Whitney U-test. The Fisher exact test or χ ² test was used to detect differences in the proportion of cases. A p-value of <0.05 was considered significant.

Results

The characteristics of the patients in group A (rhTSH) and group B (L-T4 withdrawal) are shown in Table 1. The groups were similar in terms of gender, age, histology, TNM (tumor–node–metastases) stage, ¹³¹I activity, and frequency of metastases on RxWBS. Immediately before the administration of ¹³¹I, TSH was >30 mIU/L in all patients (group A: 100 ± 23 mIU/L vs. group B: 96 ± 26 mIU/L [p·ns]), and Tg was <1 ng/mL in 32/77 of group A (41.5%) and in 80/198 of group B (40.4%). Five or more of the 14 signs and symptoms of hypothyroidism (21) were observed in 128/198 (64.6%) patients of group B, but in none of the patients of group A, including those submitted to short-term L-T4 withdrawal (n = 27). Only two patients (2.6%) reported mild and transient adverse reactions to rhTSH (headache and nausea) during the period between the first injection and 1 week after the second application and responded to symptomatic medication. The results of the patients with and without metastases on RxWBS are separately presented.

Table 1.

Characteristics of the Patients of Groups A and B

	Group A (rhTSH; n = 77)	Group B (hypothyroidism; n = 198)
Subjects
Male	24 (31.6%)	61 (30.8%)
Age (mean, years)	49.2	50.6
Tumor characteristics
Papillary histologic type	70 (90.9%)	182 (91.9%)
T1N1	8 (10.4%)	20 (10.1%)
T2N1	8 (10.4%)	19 (9.6%)
T3N0	18 (23.3%)	41 (20.7%)
T3N1	43 (55.8%)	118 (59.6%)
¹³¹I therapy
Interval between thyroidectomy and ¹³¹I (days)	100 ± 13	105 ± 11
Activity of 3.7 GBq	30 (39%)	72 (36.3%)
Activity of 5.5 GBq	47 (61%)	126 (63.6%)
Metastases on RxWBS	7 (9.1%)	29 (14.6%)

rhTSH, recombinant human thyrotropin; RxWBS, post-treatment whole-body scanning.

Patients without metastases on RxWBS

Ablation was successful (stimulated Tg <1 ng/mL and negative DxWBS and neck ultrasonography) in 56 of 70 patients of group A (80%) and in 135 of 169 patients in group B (79.9%). Considering only patients with Tg >1 ng/mL immediately before ¹³¹I administration, the rates were 68.4% in group A (26/38) and 67.4% in group B (60/89). In group A, ablation was successful in 19 of 24 (79.1%) patients who discontinued L-T4 3 days before and 1 day after ¹³¹I and in 37 of 46 patients (80.4%) who were maintained on hormone therapy. The results of the first control assessment after ablation are shown in Table 2. Similar results were obtained for groups A and B, irrespective of the end point (stimulated Tg <1 ng/mL only, stimulated Tg <1 ng/mL and negative DxWBS, stimulated Tg <1 ng/mL and negative ultrasonography or negative DxWBS only).

Table 2.

Results Obtained for Groups A and B in the Control Assessment Including Patients Without Metastases on Post-Treatment Whole-Body Scanning

Results	Group A (rhTSH; n = 70)	Group B (hypothyroidism; n = 169)
Stimulated Tg <1 ng/mL	57 (81.4%)	137 (81%)
Negative DxWBS and ultrasonography	56 (80%)	135 (79.9%)
Negative DxWBS and positive ultrasonography	1 (1.4%)	0
Positive DxWBS and negative ultrasonography	0	2 (1.2%)
Stimulated Tg >1 ng/mL	13 (18.5%)	32 (19%)
Negative DxWBS and ultrasonography	9 (12.8%)	21 (12.4%)
Negative DxWBS and positive ultrasonography	2 (2.8%)	8 (4.7%)
Positive DxWBS and negative ultrasonography	1 (1.4%)	1 (0.6%)
Positive DxWBS and ultrasonography	1 (1.4%)	2 (1.2%)
Apparent disease	5 (7.1%)	13 (7.7%)

Negative DxWBS: absent ectopic uptake and uptake in the thyroid bed <0.3%; positive ultrasonography: lymph node metastases.

Tg, thyroglobulin; DxWBS, diagnostic whole-body scanning.

Considering patients of groups A and B together, 191 (80%) patients were ablated and 48 (20%) were not. When correlating ablation outcome with potential determining factors, we found that failure to ablate did not depend on gender, age, histology, TNM status, preparation (rhTSH or hypothyroidism), peak serum TSH values, or radioactive activity administered. Only Tg measured before ¹³¹I administration was associated with ablation success (105/112 [93.7%].Patients with Tg-ablation <1 ng/mL achieved complete ablation vs. 86/127 [67.7%] with Tg-ablation >1 ng/mL [p < 0.01]).

Patients with metastases on RxWBS

All 36 patients with metastases on RxWBS had serum Tg concentrations of >1 ng/mL immediately before the initial dose of ¹³¹I. Among the 6 patients of group A and 26 of group B with ectopic uptake on RxWBS suggestive of lymph node metastases, 5 and 22 patients, respectively, had corresponding suspicious lymph nodes (22,23) on ultrasonography and/or cervical and mediastinal computed tomography. Computed tomography revealed micrometastases in only 1 patient (group B) among those with pulmonary uptake on RxWBS (n = 4). None of the patients received additional treatment by surgery or external radiotherapy.

One year after ablation with ¹³¹I, no uptake was seen on the second RxWBS in 4 of 6 patients of group A (66%) and in 16 of 26 patients of group B (61.5%) with lymph node metastases. Stimulated Tg was <1 ng/mL (and negative TgAb) in 3 of 4 and in 12 of 16 patients with negative RxWBS, respectively. Persistent disease (stimulated Tg >1 ng/mL and RxWBS continuing to show ectopic uptake) was found in 2 of 6 patients of group A (33%) and in 10 of 26 patients of group B (38.4%). Among patients with pulmonary metastases, one patient of group A and one of group B had a negative RxWBS 1 year after ablation with ¹³¹I, with >70% reduction of stimulated Tg (still >1 ng/mL). Metastases persisted on RxWBS in two patients of group B. The results are shown in Table 3.

Table 3.

Results Obtained 1 Year After Ablation in Patients with Metastases on Post-Treatment Whole-Body Scanning

Results	Group A (rhTSH; n = 7)	Group B (hypothyroidism; n = 29)
Stimulated Tg <1 ng/mL	3 (42.8%)	12 (41.3%)
Stimulated Tg <1 ng/mL and negative RxWBS	3 (42.8%)	12 (41.3%)
Stimulated Tg >1 ng/mL	4 (57.1%)	17 (58.6%)
Stimulated Tg >1 ng/mL and negative RxWBS	2 (28.5%)	5 (17.2%)
Stimulated Tg >1 ng/mL and positive RxWBS	2 (28.5%)	12 (41.3%)
Positive RxWBS	2 (28.5%)	12 (41.3%)

Positive RxWBS: persistent ectopic uptake.

Discussion

Since DxWBS may occasionally reveal ectopic uptake even when stimulated Tg is low and neck ultrasonography is negative (24 –26), a combination of these three tests is recommended for assessment after ablation in patients who are at high risk of relapse. Patients with stimulated Tg <1 ng/mL (and negative TgAb) who have no ultrasonographic or DxWBS abnormalities are classified as “free of disease” (1,2,15). Therefore, we adopted this as a definition of ablation success. The results would not be different, however, if other criteria were applied such as stimulated Tg <1 ng/mL only, stimulated Tg <1 ng/mL and negative DxWBS, or stimulated Tg <1 ng/mL and negative ultrasonography or negative DxWBS only. In patients with ectopic uptake on RxWBS, a second radioiodine activity (3.7 GBq) was administered after 1 year, followed by a new RxWBS, and the disappearance of anomalous uptake and the behavior of Tg, that was positive at all times of ablation, were considered as response parameters.

In the present study, using an activity of 3.7 or 5.5 GBq ¹³¹I, preparation with rhTSH promoted complete ablation in 76% of high-risk patients. In most previous studies, only a small number of patients having extrathyroid invasion and/or lymph node metastases were prepared with rhTSH (8,13,20,27 –32). Although not reporting the individual results obtained for high-risk patients, in the study of Lee et al. (33), 40 of 69 patients (58%) were triiodothyronine (T3), 24 of 69 (34.8%) were N1a, and 91.3% achieved complete ablation with rhTSH. Using this preparation, ablation was successful in 85% of patients in stage N1 (n = 20) in the study of Tala Jury et al. (34) and in 89.4% of patients older than 45 years in stage T3–T4 and/or N1 (n = 66) in the study of Barbaro et al. (35). Finally, Tuttle et al. (36) reported the results of short-term follow up, a median of 2.5 years, in high-risk patients who were >45 years and stage T3–T4 and/or N1 (n = 107) prepared for ablation with rhTSH. There were 77.5% who were free of disease (Tg/T4 <1 ng/mL or stimulated Tg <2 ng/mL, negative DxWBS, and no apparent disease), and 7.5% had clinical recurrence. Another 9.3% had elevated Tg alone, and 5.6% had only uptake in the thyroid bed.

In the present study, the rate of complete ablation was the same for high-risk patients prepared with rhTSH or L-T4 withdrawal. A study enrolling patients in stage N1 showed successful ablation in 17 of 20 (85%) patients prepared with rhTSH versus 31 of 37 (83.4%) having L-T4 withdrawal (34). In another study, complete remission within a median follow-up period of 2.5 years was observed in 83 of 107 (77.5%) high-risk patients prepared with rhTSH versus 12 of 20 (60%) having L-T4 withdrawal for ablation (36). The rates of ablation achieved in these patients were similar to those reported for low-risk patients receiving the same preparation and an activity of 3.7 GBq ¹³¹I (7,8,20,30), thus demonstrating the efficacy of rhTSH in high-risk patients.

One of the aspects to be considered in high-risk patients is the higher likelihood that metastases are detected by RxWBS, even after apparently complete tumor resection and in the absence of apparent disease (clinical examination and simple radiography). This was observed in 13% of the patients in the present series. In this regard, it is relevant to know whether the preparation used for ablation of normal remnant tissue is also effective in destroying these metastases. Since high ¹³¹I activities (3.7–5.5 GBq) are administered to high-risk patients and since most persistent metastases are lymph node micrometastases, this tumoricidal effect seems likely. A small number of patients with pulmonary metastases were evaluated in this study and in another series (6), but the results regarding lymph node metastases detected by RxWBS can be added to those of previous studies (6,7) and demonstrate the efficacy of the activity administered for remnant ablation and, together with rhTSH, for persistent disease.

It is also relevant to know the overall rate of persistent/recurrent disease for the two preparations after administration of a similar ¹³¹I activity. In this regard, considering patients with and without ectopic uptake on RxWBS since this information will only be available after ablation, 7 of 77 (9.1%) patients prepared with rhTSH versus 25 of 198 (12.6%) submitted to L-T4 withdrawal had persistent/recurrent disease after 1 year; whereas elevated Tg alone was observed in 11 (14.3%) and 26 (13.1%) patients, respectively. These rates demonstrate the similar efficacy of the two preparations (36).

The use of rhTSH is particularly interesting in the case of high-risk patients. In addition to the traditional advantages of this preparation, other aspects should be emphasized. Since the minimum ¹³¹I activity recommended is 3.7 GBq (1), these patients are susceptible to the adverse effects of radioiodine (8 –12). Preparation with rhTSH results in lower radiation in blood (37), a fact indicating lower extrathyroid exposure to radiation and consequent lower radiotoxicity as demonstrated in recent prospective clinical trials (8,13). Thus, the consequences of radiotoxicity in patients receiving high ¹³¹I activity can be reduced by preparation with rhTSH (8,13,37). Also, due to the high activity of ¹³¹I, high-risk patients invariably require hospitalization for remnant ablation, and preparation with rhTSH has the advantage of reducing the length of hospital stay (14).

The present study was not randomized. However, the selection of patients for the use of rhTSH was not based on parameters known to influence the outcome of ablation, and the groups receiving the two preparations were similar. In addition, the patients originated from the same center. Thus, possible differences between groups in terms of therapeutic procedures and evaluation of the results, including the technique and the observer, are unlikely.

In conclusion, the results of this study suggest that, in patients with complete tumor resection and high risk of relapse, preparation with rhTSH is as effective as L-T4 withdrawal for remnant ablation after total thyroidectomy using an activity of 3.7 or 5.5 GBq ¹³¹I.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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Recombinant Human Thyrotropin in Thyroid Remnant Ablation with 131-Iodine in High-Risk Patients

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Patients

131I therapy

Outcome of ablation

Assays

Imaging methods

Statistical analysis

Results

Patients without metastases on RxWBS

Patients with metastases on RxWBS

Discussion

Footnotes

Disclosure Statement

References

¹³¹I therapy