Neoplasms

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Thyroid Neoplasms

Thyroid Diseases

Hypothyroidism

Thyroid Cancer, Papillary

Adenocarcinoma, Follicular

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Papillary Thyroid Carcinoma

Thyroid Cancer, Follicular

All Drugs and Chemicals

Hormones

No reference therapy was given. All patients in this follow-up study received Thyrogen. Thyrogen 0.9 mg was administered intramuscularly (IM) in the buttock on 2 consecutive days.

For WBS and static neck imaging, each patient received 4 mCi (148 MBq) ± 0.4 mCi 131I PO.

Thyrogen (thyrotropin alfa for injection)

Medical Monitor

Patients diagnosed with thyroid cancer are commonly treated with surgery to remove their thyroid gland followed by radioiodine ablation to destroy any remaining parts of the thyroid gland that may have been missed during surgery. It is thought that ablation with radioiodine destroys normal remaining thyroid tissue as well as cancerous cells either in the thyroid area or at other sites.

Following successful treatment, patients are then monitored by their physicians at regular intervals with testing to detect any recurrence of thyroid cancer throughout the body. If thyroid cells are detected by these follow up tests, the physician will decide the best method to re-treat the patient.

In 2001-2003 Genzyme conducted a clinical study to test if Thyrogen® can be used to accomplish radioiodine ablation treatment. This study aimed to determine that the success rates of radioiodine ablation were comparable when patients were prepared for ablation with Thyrogen® while being maintained on their normal thyroid hormone therapy, or, alternatively, by thyroid hormone withdrawal. Thyroid hormone withdrawal commonly causes uncomfortable side effects for patients, and these might be avoided by the use of Thyrogen.

Eight months after the initial Thyrogen plus radioiodine treatment to achieve ablation, all patients in both groups were given Thyrogen® to test for any remaining thyroid tissue. The results of this testing showed that all patients (in both groups) had successfully achieved remnant ablation and had no detectable thyroid tissue remaining.

In order to confirm these remnant ablation results we will conduct follow up testing in this study for all patients that were enrolled in the previous study and we also will determine if their thyroid cancer has recurred. Only patients who completed this previous Thyrogen ablation study are eligible for entry into this study.

A New Study to Follow-up Thyroid Cancer Patients Who Participated in a Previous Study, Which Compared the Success of Destruction of the Thyroid Remnant Using Standard Treatment or Thyrogen.

Follow-up of Thyroid Cancer Patients From Study THYR-008-00 Who Received Thyroid Remnant Ablation Using Either the Hypothyroid or the Thyrogen Method.

Genzyme, a Sanofi Company

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Luca Giovanella, MD

Thyroidectomy followed by administration of large activities of 131-iodine (131I) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement during hypothyroidism (offT4-Tg), just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease. However, the Tg measurement cannot be used as a corresponding value for preablative offT4-Tg when rhTSH is used as stimulous before treatment. The present study was undertaken to evaluate if post-thyroidectomy Tg values, measured before rhTSH-stimulation and radioiodine administration, is of prognostic value in patients affected by DTC. We enrolled 28 patients with DTC and submitted to total thyroidectomy. Thyroxine (T4) treatment was started just after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation. Subsequently, T4 was stopped and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) was performed and neck radioiodine uptake (RAIU) measured. A significant relationship was found between onT4-Tg and both rhTSH-Tg and offT4-Tg. The onT4-Tg levels of 0.2 ng/mL or higher predicted PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively. Basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.

Introduction Total (or near-total) thyroidectomy followed by TSH-stimulated administration of large activities of 131-iodine (131I) is the treatment of choice for DTC \[1-3\]. The serum thyroglobulin (Tg) measurement during hypothyroidism, just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease \[4-8\]. Recently recombinant human TSH (rhTSH) showed to be safely employed instead of thyroxine (T4) withdrawal (offT4) to prepare patients for radioiodine ablation \[9-10\]. However, the Tg level are measured 48 hours after radioiodine administration when rhTSH is used as stimulation \[11\]. Consequently, due to the radioiodine-induced thyroid cells damage and Tg release, the Tg measurement would not have reliable predictive value in patients treated by rhTSH stimulation \[12\]. The present study was undertaken to evaluate if preablativeTg measurement under T4 treatment is of prognostic value and serves as surrogate marker of offT4-stimulated preablative Tg.

Patients and methods

Patients selection We retrospectively enrolled 28 consecutive patients affected by histologically proven DTC (23 papillary, 5 follicular) submitted to total thyroidectomy and central compartment lymph-node dissection. Thyroxine (T4) treatment was started immediately after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation as previously described \[13\]. Subsequently, T4 was stopped for 4 weeks and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) with radioiodine uptake (RAIU) calculation was performed according to a previously described protocol \[1\]. All non physiologic iodine uptake areas out of the thyroid bed were considered as positive findings \[14, 15\]. Patients with positive PT-WBS underwent specific treatment and personalized follow-up. Patients with negative PT-WBS immediately restarted T4 suppressive treatment. Final restaging was performed in all patients 12 months after the last treatment by neck ultrasound, onT4-Tg assay and both offT4-diagnostic WBS (DgWBS) and Tg assay (4 weeks T4 withdrawal; required TSH\>30 mUI/L). Clinical and pathological characteristics of selected patients were summarized in the Table 1.

Serum Tg assay and screening for interferences Serum Tg was assayed in duplicate by a specific high-sensitive IRMA assay (DYNOtest® Tg-plus, BRAHMS Diagnostica GmbH, Berlin, Germany) according to the producer' instructions. This method provided a sensitivity of 0.05 ng/mL and a functional sensitivity of 0.2 ng/mL \[16, 17\]. As previously published, preablative offT4 serum Tg values above 4.5 ng/mL and 3.2 ng/mL were considered as positive with respect to PT-WBS and 12 months restaging results, respectively \[8\]. Otherwise, offT4-Tg values higher than 0.2 ng/ml measured 12 months after thyroid ablation were considered positive for persisting/relapsing disease. \[18, 19\]. The presence of anti-thyroglobulin antibodies (AbTg) was screened by a specific radioimmunoassay (DYNOtest® anti-TGn, BRAHMS Diagnostica GmbH, Berlin, Germany) and by recovery test with a specific Tg-recovery buffer provided by the producer. Sera showing AbTg levels more than 60 U/mL and/or recover less than 80% or more than 120% were excluded from the study. Quality control was ensured by assaying two levels of control sera in each series, by re-assessing all sera showing a coefficient of variation exceeding 10% and by a bimonthly partecipation in the European inter-laboratory control OncocheckTM.

Statistics Quantitative data are expressed as mean ± SD. Differences between groups were assessed by two-tailed unpaired t-test. The relationship between variables was assessed by linear regression analysis. In order to allow statistical analysis the value of undetectable serum Tg expressed as \< 0.2 ng/nL was arbitrarily changed in 0.10 ng/mL. Statistical significance was defined by a p-value \< 0.05.

Ethics All diagnostic and therapeutic procedures were performed according to the regulations of the local ethics committee. Informed consensus was obtained from each patient.

Results The overall results are summarized in the Table I. Relationship Between Post-surgery onT4-Tg, rhTSH-Tg and offT4-Tg A significant positive relationship was found between onT4-Tg and both rhTSH-Tg (p\<.0001) and offT4-Tg (p\<0.0001) (Figure 1, A-B-C) as well as between rhTSH and offT4-stimulated Tg (p\<.0001).

Relationship Between Post-surgery Serum Tg and Thyroid Remnant Radioiodine Uptake (RAIU) Among 22 patients showing no DTC metastasis on PT-WBS the serum distribution of onT4-Tg, rhTSH-Tg and offT4-Tg was 0.342±0.402; 0.664±0.803 and 1.195±1.485 ng/mL respectively. Both rhTSH and offT4-stimulated Tg levels were related to RAIU (p \<.05 and \<.005, respectively) while no significant relationship was found between RAIU and onT4-Tg levels (Figure 1, D-E-F).

Relationship Between Post-surgery Serum Tg and PT-WBS results The patients with positive PT-WBS showed higher onT4-Tg (0.617±0.445 vs 0.341±0.402 ng/mL), rhTSH-Tg (2.150±1.249 vs 0.664±0.803 ng/mL) and offT4-Tg (4.417±2.136 vs 1.195±1.485 ng/mL) levels as compared with patients with negative scan. Among 14 patients with undetectable onT4-Tg (i.e. ≤0.2 ng/mL) none had positive PT-WBS neither recurrences at 12-months restaging. Additionally, none of these patients showed stimulated Tg values more than 0.4 ng/mL and 1.0 ng/mL after rhTSH stimulation and T4 withdrawal, respectively. Viceversa, among 14 patients with onT4-Tg levels more than 0.2 ng/mL, 6 had positive PT-WBS (onT4-Tg: 0.3 to 1.4 ng/mL) and 3 showed DTC recurrences at 12 months restaging (onT4-Tg: 0.9 to 1.7 ng/mL). Consequently, the onT4-Tg levels predicts PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively.

Discussion Many reports indicate the usefulness of Tg concentration measurement before radioiodine treatment to early detection of DTC relapse or metastasis \[4-8, 20, 21\]. Three factors determine Tg concentration in most clinical situations: thyroid cell mass, thyroid cell damage and activation of TSH receptors \[22\]. When Tg is measured before radioiodine ablation the effects of surgical damage are generally vanished and endogenous TSH levels are increased in all patients: consequently the thyroid remnant mass is the major determinant of the serum Tg concentrations \[23\]. However, the rhTSH-stimulated Tg cannot be used instead of preablative offT4-Tg when rhTSH is employed to prepare radioiodine ablation \[12\]. Therefore we evaluated the role of post-surgery onT4-Tg as surrogate prognostic marker. We choiced to suppress TSH levels in order to normalize the effect of TSH stimulation on thyroid remnants. Clearly, the TSH suppression reduced Tg levels: however, the high-sensitive Tg assays provide a good distinction between the lower limit of the euthyroid reference range and the functional sensitivity limit detecting small amounts of thyroid tissue even in the TSH-suppressed state (22, 23). We showed a significant positive relationship between post-surgery Tg measured during T4 treatment and after TSH stimulation. No relationship was found between RAIU (i.e. expression of remnant mass) and onT4-Tg, probably due the clustering of all Tg levels lower than 0.2 ng/mL (see statistics paragraph). However, undetectable onT4-Tg after surgery identifies patients free of metastasis at PT-WBS and without late recurreces during early 12-months follow-up. None of these patients showed a significant increase in both rhTSH and offT4-stimulated Tg before radioiodine ablation. This seems to indicate that the relationship between Tg expression and thyroid tissue mass is manteined even in TSH suppression state: Therefore undetectable serum onT4-Tg really identifies patients without significant thyroid tissue amount as well as stimulated Tg. All patients performed extracapsular total thyroidectomy in a dedicated thyroid surgery unit and the thyroid remnant, expressed as RAIU, was lower in our series than in others. This means that our data cannot directly translated to patients treated by more limited surgery. Globally, basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.

References

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OnT4-Thyroglobulin Assay Before rhTSH-Aided Radioiodine Ablation

Is the Thyroglobulin Measurement Under Thyroxine of Prognostic Value Before rhTSH-Aided Radioiodine Ablation in Differentiated Thyroid Carcinoma?

Oncology Institute of Southern Switzerland

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A New Study to Follow-up Thyroid Cancer Patients Who Participated in a Previous Study, Which Compared the Success of Destruction of the Thyroid Remnant Using Standard Treatment or Thyrogen.	NCT00295763	Differentiated ...	Thyrogen (thyro...	18 Years -	Sanofi
A New Study to Follow-up Thyroid Cancer Patients Who Participated in a Previous Study, Which Compared the Success of Destruction of the Thyroid Remnant Using Standard Treatment or Thyrogen.	NCT00295763	Differentiated ...	Thyrogen (thyro...	18 Years -	Sanofi
OnT4-Thyroglobulin Assay Before rhTSH-Aided Radioiodine Ablation	NCT00439127	Differentiated ...		-	Oncology Institute of Southern Switzerland
A New Study to Follow-up Thyroid Cancer Patients Who Participated in a Previous Study, Which Compared the Success of Destruction of the Thyroid Remnant Using Standard Treatment or Thyrogen.	NCT00295763	Differentiated ...	Thyrogen (thyro...	18 Years -	Sanofi

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