Pharmacodynamics

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It has comparable biochemical properties to the human pituitary TSH. Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

In patients with thyroid cancer, a near-total or total thyroidectomy is usually performed. Thyroidectomy is usually followed by radioiodine treatment to remove any remnant of normal thyroid tissue and microscopic residues of malignant tissue. Prior to radioiodine remnant ablation, serum TSH elevation is necessary to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH may be achieved by withholding of synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary thyroid stimulating hormone; or by administration of thyrotropin in the setting of synthetic thyroid hormone administration. After remnant ablation, patients are placed on synthetic thyroid hormone supplements to replace endogenous hormone and to suppress serum levels of TSH in order to avoid TSH-stimulated tumor growth. Thereafter, patients are followed for the presence of remnants, or of residual or recurrent cancer, by thyroglobulin (Tg) testing, usually with radioiodine imaging. This follow-up testing is most effective when conducted under TSH stimulation, achieved either by thyroid hormone withdrawal or administration of thyrotropin. Thyroid hormone withdrawal results in hypothyroidism with subsequent elevation of endogenous pituitary TSH; when thyrotropin is used, patients remain on thyroid hormone suppressive therapy and are euthyroid.

Pharmacokinetics

The pharmacokinetics of Thyrogen were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose. Mean peak concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours). The mean apparent elimination half-life was 25 ± 10 hours. The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.

Clinical Trials

Clinical Trials of Thyrogen as an Adjunctive Diagnostic Tool

Two phase 3 clinical trials were conducted in 358 evaluable patients with well-differentiated thyroid cancer to compare 48-hour radioiodine (131I) whole body scans obtained after Thyrogen to whole body scans after thyroid hormone withdrawal. One of these trials also compared Tg levels obtained after Thyrogen to those on thyroid hormone suppressive therapy, and to those after thyroid hormone withdrawal. All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL.

Only successfully ablated patients (defined as patients who have undergone total or neartotal thyroidectomy with or without radioiodine ablation, and with < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal) without detectable anti-thyroglobulin antibodies were included in the Tg data analysis. The maximum Thyrogen Tg value was obtained 72 hours after the final Thyrogen injection, and this value was used in the analysis (see DOSAGE AND ADMINISTRATION).

Diagnostic Radioiodine Whole Body Scan Results

Table 1 summarizes the scan data in patients with positive scans after withdrawal of thyroid hormone from the diagnostic phase 3 studies:

Table 1: Scan Data in Patients with Positive Scans

Across the two clinical studies, the Thyrogen scan failed to detect remnant and/or cancer localized to the thyroid bed in 16% (20/124) of patients in whom it was detected by a scan after thyroid hormone withdrawal. In addition, the Thyrogen scan failed to detect metastatic disease in 24% (9/38) of patients in whom it was detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal

In Tg antibody negative patients with a thyroid remnant or cancer as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan (after thyroid hormone withdrawal or after radioiodine therapy), the Thyrogen Tg was ≥ 2.5 ng/mL in 69% (40/58) of patients after 2 doses of Thyrogen, and in 80% (53/66) of patients after 3 doses of Thyrogen. Across both dosage groups, 45% had a Tg ≥ 2.5 ng/mL on thyroid hormone suppressive therapy.

In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of Thyrogen and 94% (62/66) of patients after 3 doses of Thyrogen.

Thyrogen Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning in Patients with Confirmed Metastatic Disease

Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen Tg was ≥ 2.5 ng/mL in all 35 patients while Tg on thyroid hormone suppressive therapy was ≥ 2.5 ng/mL in 79% of these patients.

In this same cohort of 35 patients with confirmed metastatic disease, the Thyrogen Tg levels were below 10 ng/mL in 27% (3/11) of patients after 2 doses of Thyrogen and in 13% (3/24) of patients after 3 doses of Thyrogen. The corresponding thyroid hormone withdrawal Tg levels in these 6 patients were 15.6 – 137 ng/mL. The Thyrogen scan detected metastatic disease in 1 of these 6 patients (see INDICATIONS AND USAGE, Considerations in the Use of Thyrogen).

As with thyroid hormone withdrawal, the intra-patient reproducibility of Thyrogen testing with regard to both Tg stimulation and radioiodine imaging has not been studied.

Clinical Trials of Thyrogen as an Adjunct to Radioiodine Therapy to Achieve Thyroid Remnant Ablation

A randomized prospective clinical trial comparing the rates of thyroid remnant ablation achieved after preparation of patients either with hypothyroidism or Thyrogen has been performed. Patients (n = 63) with low-risk well-differentiated thyroid cancer underwent near-total thyroidectomy, then were equally randomized to the Hypothyroid group (serum TSH > 25 μU/mL) or thyroxine replacement (Euthyroid group; serum TSH < 5 μU/mL). Patients in the Euthyroid group then received Thyrogen 0.9 mg IM daily on two consecutive days, and then radioiodine 24 hours after the second dose of Thyrogen. All patients received 100 mCi ¹³¹I ± 10% with the intent to ablate any thyroid remnant tissue. The primary endpoint of the study, which was the success of ablation, was assessed 8 months later by a Thyrogen-stimulated radioiodine scan. Patients were considered successfully ablated if 4728 (09/08) there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1%. Table 2 summarizes the results of this evaluation.

Table 2: Results from the Remnant Ablation Clinical Trial

The mean radiation dose to blood was 0.266±0.061 mGy/MBq in the Euthyroid group and 0.395±0.135 mGy/MBq in the Hypothyroid group (p < 0.0001). Radioiodine residence time in remnant tissue was 0.9±1.3 hours in the Euthyroid group and 1.4±1.5 hours in the Hypothyroid group. It is not known whether this difference in radiation exposure would convey a clinical benefit.

A follow-up study was conducted on patients who previously completed the initial study. The main objective of the follow-up study was to confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-up of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyroglobulin testing was also performed.

Sixty-one male and female thyroidectomized patients who participated in the original study (Table 2) were planned for inclusion in this follow-up study. Fifty-one patients were enrolled in this study; 48 received Thyrogen for remnant neck/whole body imaging and/or Tg testing (three patients underwent the collection of medical history portion of the study but did not undergo stimulated neck/WB scanning or testing). Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1% (Table 3).

Table 3: Summary of Thyroid Remnant Ablation During the 3.7-Year Follow-Up of Patients Treated in the Initial Study

Of note, 9 patients (distributed similarly in both treatment groups: 5 former Hypothyroid and 4 former Euthyroid patients) received 131I (approximately 100 mCi (3.7 GBq) or more) during the period between the end of the initial study and the initiation of this follow-up study. When considering only the patients who did not receive radioiodine during the period between studies, 100% of patients in both treatment subgroups (15 former Hypothyroid and 22 former Euthyroid patients) were successfully ablated according to the predefined study criteria.

Successful ablation also can be inferred when the Thyrogen-stimulated serum Tg level is < 2 ng/mL, although a lower Tg level might also be used as a criterion by some experts. The presence of antithyroglobulin antibodies can render results of thyroglobulin assays uninterpretable. A total of 17 patients in the former Hypothyroid group and 20 patients in the former Euthyroid group had antithyroglobulin antibody levels < 5 units/mL. Of these patients, 16/17 (94%) of patients in the former Hypothyroid group and 19/20 (95%) of patients in the former Euthyroid group had stimulated serum thyroglobulin levels of < 2 ng/mL.

No patient had a definitive cancer recurrence during the 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patient had possible cancer recurrence (although it was not clear whether this patient had a true recurrence or persistent tumor from the regional disease noted at the start of the initial study), and 2 patients could not be assessed.

In summary, in this study and its follow-up study, Thyrogen was noninferior to thyroid hormone withholding for elevation of TSH levels as adjunctive therapy to radioiodine for postsurgical ablation of remnant thyroid tissue.

Several publications describe studies or series of patients in which Thyrogen was used as an adjunct to radioiodine for the ablation of thyroid remnant tissue. Some publications^1-4 found comparable rates of remnant ablation whether patients were prepared using hypothyroidism or Thyrogen, whereas another publication⁵ found that hypothyroidism had a better rate of success than Thyrogen, although in that study the radioiodine was administered 48 hours rather than 24 hours after the second dose of Thyrogen. Follow-up for 2.5 years of patients undergoing ablation at Memorial Sloan-Kettering has shown that use of Thyrogen results in a low rate of tumor recurrence that is comparable to the rate seen after use of withdrawal from thyroxine.⁶

Quality of Life

Quality of Life (QOL) was measured during both the diagnostic study and the ablation of thyroid remnant study, using the SF-36 Health Survey, a standardized, patient-administered instrument assessing QOL across eight domains measuring both physical and mental functioning. In the diagnostic study and in the remnant ablation study, following Thyrogen administration, little change from baseline was observed in any of the eight QOL domains of the SF-36. Following thyroid hormone withdrawal in the diagnostic study, statistically significant negative changes were noted in all eight QOL domains of the SF-36. The difference between treatment groups was statistically significant (p < 0.0001) for all eight QOL domains, favoring Thyrogen over thyroid hormone withdrawal (Figure 1). In the remnant ablation study, following thyroid hormone withdrawal, statistically significant negative changes were noted in five of the eight QOL domains (physical functioning, role physical, vitality, social functioning and mental health). The difference between treatment groups was statistically significant (p < 0.05), favoring Thyrogen over thyroid hormone withdrawal.

FIGURE 1 : SF-36 HEALTH SURVEY RESULTS
QUALITY OF LIFE DOMAINS DIAGNOSTIC INDICATION

Hypothyroid Signs and Symptoms – Diagnostic Indication

Thyrogen administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale. Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p < 0.01) (Figure 2).

FIGURE 2 : HYPOTHYROID SYMPTOM ASSESSMENT BILLEWICZ SCALE
DIAGNOSTIC INDICATION
0.9 mg Thyrogen® q 24 hours x 2 doses

REFERENCES

1 Robbins RJ, Tuttle RM, Sonenberg M, Shaha A, Sharaf R, Robbins H, Fleisher M, Larson SM. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin. Thyroid 2001; 11:865-869.

2 Robbins RJ, Larson SM, Sinha N, Shaha A, Divgi C, Pentlow KS, Ghossein R, Tuttle RM. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002; 43:1482-1488.

3 Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P, Pasquini C, Piazza F, Caciagli M, Mariani G. Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: Effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 2003; 88:4110-4115.

4 Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, Elisei R, Pinchera A. Ablation of thyroid residues with 30 mCi 131I: A comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab 2002; 87:4063-4068.

5 Pacini F, Ladenson P, Schlumberger M, Driedger A, Luster M, Kloos RT, Sherman S, Haugen B, Corone C, Molinaro E, Elisei R, Ceccarelli C, Pinchera A, Wahl RL, Leboulleux S, Ricard M, Yoo J, Busaidy E, Delpassand E, Hanschied H, Felbinger R, Lassmann M, Reiner C. Radioiodine Ablation of Thyroid Remnants after Preparation with Recombinant Human Thyrotropin in Differentiated Thyroid Carcinoma: Results of an International, Randomized, Controlled Study. J Clin Endocrinol Metab 2006; 91:926- 932.

6 Brokhin M, Robbins R, Omry G, Martorella A, Fleisher M, Tuttle RM. Recombinant human TSH (rhTSH)-assisted radioactive iodine remnant ablation (RRA) achieves very low short term clinical recurrence rates which are not significantly different than traditional thyroid hormone withdrawal (THW). Abstract # 232, American Thyroid Assn., 2006.

Last reviewed on RxList: 8/8/2012
This monograph has been modified to include the generic and brand name in many instances.