CLINICAL STUDIES
Clinical Trials of THYROGEN as an Adjunctive Diagnostic Tool
Two prospective, randomized phase 3 clinical trials
were conducted in patients with well-differentiated thyroid
cancer to compare 131I whole body scans obtained
after THYROGEN injection to 131I whole body scans
after thyroid hormone withdrawal. A cross-over,
non-blinded design was used in both trials. Oral
radioiodine was given 24 hours after the second injection of
THYROGEN, and scanning was done 48 hours after the radioiodine
administration. Each patient was scanned first following
THYROGEN and then scanned after thyroid hormone withdrawal.
In both studies, the primary endpoint was the rate of
concordant scans (scan findings in agreement in a given patient
using each preparation method).
Study 1
(n=127) compared the diagnostic scanning following a THYROGEN
regimen of 0.9 mg IM daily on two consecutive days to thyroid
hormone withdrawal. In addition to body scans, Study 2
(n=229) also compared thyroglobulin (Tg) levels obtained after
THYROGEN to those at baseline 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. Patients who were included
in the Tg analysis were those who had undergone total or
near-total thyroidectomy with or without 131I
ablation, had < 1% uptake in the thyroid bed on a
scan after thyroid hormone withdrawal, and did not have
detectable anti-Tg antibodies. The maximum THYROGEN Tg
value was obtained 72 hours after the final THYROGEN injection,
and this value was used in the
analysis.
Diagnostic Radioiodine Whole Body Scan
Results
Study
1 enrolled 127 patients, 71% were female and 29% male,
and mean age was 44 years. The study included the
following forms of differentiated thyroid cancer:
papillary cancer (88%), follicular cancer (9%),
and Hurthle cell (2%). Study results are displayed in
Table 2.
In Study 2, patients with
differentiated thyroid cancer who had been thyroidectomized (n =
229) were randomized into one of two THYROGEN treatment
regimens: THYROGEN 0.9 mg IM daily on two consecutive days
(n = 117), and THYROGEN 0.9 mg IM daily on days 1, 4 and 7
(n = 112). Each patient was scanned first using THYROGEN,
then scanned using thyroid hormone withdrawal. The group
receiving the THYROGEN 0.9 mg IM x 2 regimen was 63%
female/27% male, had a mean age 44 years, and generally had
low-stage papillary or follicular cancer (AJCC/TNM Stage I
61%, Stage II 19%, Stage III 14%, Stage IV 5%).
The group receiving the THYROGEN 0.9 mg IM x 3 regimen was
66% female/34% male, had a mean age 50 years, and
generally had low-stage papillary or follicular cancer (AJCC/TNM
Stage I 50%, Stage II 20%, Stage III 20%, Stage IV
9%). The amount of radioiodine used for scanning was 4
mCi ± 10%, and scanning times were lengthened in some
patients to capture adequate images (30 minute scans, or 140,000
counts). Scan pairs were assessed by blinded readers.
Study results are presented in Table
2.
Table 2: Concordance of
Positive Thyroid Scans Following THYROGEN Treatment with
Scans Following Thyroid Hormone
Withdrawal
|
Number of Scan Pairs by
Disease
Category
|
Concordance of scan pairs between
THYROGEN scan and
thyroid hormone withdrawal
scan
|
Study 1 (0.9 mg IM qd
x2)
|
|
|
Positive for
remnant or cancer in thyroid bed
|
48
|
81%
|
Positive for
metastatic disease
|
15
|
73%
|
Total positive
withdrawal scans ,
|
63
|
79%
|
|
Study 2 (0.9 mg IM qd x
2)
|
|
|
Positive for
remnant or cancer in thyroid bed
|
35
|
86%
|
Positive for
metastatic Disease
|
9
|
67%
|
Total positive
withdrawal scans,
|
44
|
82%
|
Across the two clinical
studies, and scoring all false positives in favor of thyroid
hormone withdrawal, the majority of positive scans using
THYROGEN and thyroid hormone withdrawal were concordant.
The THYROGEN scan failed to detect remnant and/or cancer
localized to the thyroid bed in 17% (14/83) 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 29% (7/24) 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 anti-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 positive (≥ 2.5 ng/mL) in
69% (40/58) of patients after 2 doses of
THYROGEN.
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.
Among patients with
metastatic disease confirmed by a post-treatment scan or by
lymph node biopsy (35 patients), THYROGEN Tg was positive
(≥ 2.5 ng/mL) in all 35 patients, while Tg on thyroid
hormone suppressive therapy was positive (≥ 2.5
ng/mL) in 79% of these patients.
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.
Hypothyroid Signs and
Symptoms
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
1).
Figure 1: Hypothyroid Symptom Assessment
Billewicz Scale Diagnostic Indication 0.9 mg
THYROGEN® q 24 hours x 2 doses vs.
Thyroid Hormone Withdrawal
Phase
Clinical Trials of THYROGEN as an Adjunct to Radioiodine Therapy to Achieve Thyroid Remnant Ablation
A randomized prospective clinical trial compared the
rates of thyroid remnant ablation achieved after preparation of
patients with thyroid hormone withdrawal or THYROGEN. Patients
(n = 63) with low-risk, well-differentiated thyroid cancer who
underwent near-total thyroidectomy were made euthyroid after
surgery by receiving thyroid hormone replacement and were
subsequently randomized to a thyroid hormone withdrawal or
THYROGEN. Patients in the THYROGEN group received THYROGEN
0.9 mg IM daily on 2 consecutive days and radioiodine 24 hours
after the second dose of THYROGEN. Patients in the thyroid
hormone withdrawal group had the thyroid replacement withheld
until they became hypothyroid. Patients in both groups
received 100 mCi 131I ± 10% with the intent
to ablate any thyroid remnant tissue. The primary endpoint
of the study, was the rate of successful ablation, and was
assessed 8 months later by a THYROGEN-stimulated radioiodine
scan. Patients were considered successfully ablated if
there was no visible thyroid bed uptake on the scan, or if
visible, if uptake was less than 0.1%. Table 3
summarizes the results of this
evaluation.
Table 3: Remnant Ablation
in Clinical Trial of Patients with Well-Differentiated
Thyroid Cancer
Group60 per protocol patients with interpretable scan data. 95% CI for difference in ablation rates THYROGEN minus Thyroid Hormone Withdrawal, = 7% to 27%.
|
Mean Age
(Yr)
|
Gender (F:M)
|
Cancer Type
(Pap:Fol)
|
Ablation Criterion
(Measure at 8
Months)
|
|
|
|
|
Thyroid
Bed Activity <0.1%
|
No Visible
Thyroid Bed ActivityInterpretation by 2 of 3 reviewers. 95% CI for difference in ablation rates, THYROGEN minus Thyroid Hormone Withdrawal, = -31% to 9%. Abbreviations: fol = follicular, pap = papillary
|
Thyroid Hormone Withdrawal
(N=28)
|
43
|
24:6
|
29:1
|
28/28
(100%)
|
24/28
(86%)
|
THYROGEN (N=32)
|
44
|
26:7
|
30:3
|
32/32
(100%)
|
24/32
(75%)
|
The mean radiation dose to blood
was 0.266±0.061 mGy/MBq in the THYROGEN group and
0.395±0.135 mGy/MBq in the thyroid hormone withdrawal
group. Radioiodine residence time in remnant tissue was
0.9±1.3 hours in the THYROGEN group and 1.4±1.5 hours
in the thyroid hormone withdrawal group. It is not known
whether this difference in radiation exposure would convey a
clinical benefit.
Patients who completed
were followed up for a median duration of 3.7 years (range 3.4 to
4.4 years) following radioiodine ablation. Tg testing was
also performed.The main objective of the follow-up study was to
evaluate the status of thyroid remnant ablation by using
THYROGEN-stimulated neck imaging. Of the fifty-one patients
enrolled, forty eight patients received THYROGEN for remnant
neck/whole body imaging and/or thyroglobulin testing. Only
43 patients had imaging. 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%. All patients from both original treatment groups
who had scanning were found to still be ablated
.
Of 37 patients who were Tg–antibody
negative, 16/17 (94%) of patients in the former thyroid
hormone withdrawal group and 19/20 (95%) of patients in the
former THYROGEN group maintained successful ablation measured as
stimulated serum Tg 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.
Two large prospective
multi-center randomized studies compared THYROGEN to thyroid
hormone withdrawal using two different doses of radioactive
iodine in patients with differentiated thyroid cancer who had
been thyroidectomized. In both studies, patients were
randomized to 1 of 4 treatment groups: THYROGEN + 30 mCi
131I, THYROGEN + 100 mCi 131I, thyroid
hormone withdrawal + 30 mCi 131I, or thyroid
hormone withdrawal + 100 mCi 131I. Patients
were assessed for efficacy (ablation success rates) at
approximately 8 months.
The first study
(Study A) randomized 438 patients (tumor stages T1-T3, Nx, N0
and N1, M0). Ablation success was defined as radioiodine
uptake of <0.1% in the thyroid bed and stimulated
thyroglobulin levels of < 2.0
ng/mL.
The second study (Study B)
randomized 752 patients with low-risk thyroid cancer (tumor
stages pT1 < 1 cm and N1 or Nx, pT1 >1-2 cm and any N
stage, or pT2 N0, all patients M0). Ablation success was
defined by neck ultrasound and stimulated thyroglobulin of
≤ 1.0 ng/mL.
Results for both trials
are summarized below.
Table
4: Successful Remnant Ablation Rates in Study
A
95% CI of difference in ablation rate
(low-dose minus high dose): -10.2% to
2.6%
|
95% CI of difference in
ablation rate (THYROGEN - Thyroid Hormone Withdrawal): -6.0%
to 6.8%
|
|
THYROGEN
|
Thyroid Hormone
Withdrawal
|
Total
|
Low-dose
radioiodine
|
91/108
(84.3%)
|
91/106
(85.8%)
|
182/214
(85.0%)
|
High-dose
Radioiodine
|
92/102
(90.2%)
|
92/105
(87.6%)
|
184/207
(88.9%)
|
Total
|
183/210
(87.1%)
|
183/211
(86.7%)
|
366/421
(86.9%)
|
Table 5: Successful
Remnant Ablation Rates in Study
B
95% CI of difference in ablation rate
(low-dose minus high dose): -5.8% to
0.9% |
95% CI of difference in
ablation rate (THYROGEN minus Thyroid Hormone Withdrawal):
-4.5% to 2.2% |
|
THYROGEN
|
Thyroid
Hormone
Withdrawal
|
Total
|
Low-dose
radioiodine
|
160/177
(90.4%)
|
156/170
(91.8%)
|
316/347
(91.1%)
|
High-dose
Radioiodine
|
159/171
(93.0%)
|
156/166
(94.0%)
|
315/337
(93.5%)
|
Total
|
319/348
(91.6%)
|
312/336
(92.9%)
|
631/684
(92.3%)
|
Quality of Life
Quality of Life (QOL) was measured during both the
diagnostic study [
see Clinical Studies
(
14.1
)] and the
ablation of thyroid remnant study [
see Clinical Studies
(
14.2
)] 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 2). 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).
Figure 2: SF-36
Health Survey Results Quality of Life Domains Diagnostic
Indication
|