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From the Clinical Research Centers |
Division of Endocrinology, University of Colorado Health Sciences Center (B.R.H., E.C.R.), Denver, Colorado 80262; the Division of Endocrinology, University of Pisa (F.P.), 56124 Pisa, Italy; Klinik und Poliklinik fuer Nuklearmedezin der Universitaet Wuerzburg (C.R., M.L.), Wuerzburg D-97070, Germany; Service de Medecine Nucleaire, Institut Gustave Roussy (M.S.), Villejuif 94805; the Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine (P.W.L.), Baltimore, Maryland 21287; the Department of Medical Specialties, M. D. Anderson Cancer Center (S.I.S.), Houston, Texas 77030; the Division of Endocrinology, Sinai Hospital of Baltimore (D.S.C.), Baltimore, Maryland 21215; the Division of Endocrinology, Oregon Health Sciences University (K.E.G., M.H.S.), Portland, Oregon 97201; the Genetics Division, Brigham and Women’s Hospital (L.E.B.), Boston, Massachusetts 02115; the Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (M.C.S.), Bethesda, Maryland 20892; the Division of Endocrinology, Mount Sinai School of Medicine (T.F.D.), New York, New York 10029; the Department of Medicine, University of Chicago Medical Center (L.J.D.), Chicago, Illinois 60637; the Department of Internal Medicine, Ohio State University Health Sciences Center (E.L.M.), Columbus, Ohio 43210; the Thyroid Unit, Massachusetts General Hospital (G.H.D., D.S.R.), Boston, Massachusetts 02114; the Division of Nuclear Medicine, New York Hospital-Cornell Medical Center (D.V.B.), New York, New York 10021; Nuclear Medicine, University of Cincinnati Medical Center (H.R.M.), Cincinnati, Ohio 45267; Nuclear Medicine, Veterans Administration Medical Center (R.R.C.), San Francisco, California 94121; the Department of Medicine, University of Southern California (C.A.S.), Los Angeles, California 90033; Genzyme Transgenics Corp. (K.E.), Boston, Massachusetts 02139; and the Laboratory of Molecular Endocrinology, University of Maryland School of Medicine (B.D.W.), Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., University of Colorado Health Sciences Center, B151, 4200 E 9th Avenue, Denver, Colorado 80262.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recombinant human TSH (rhTSH) has been developed to facilitate monitoring for persistent or recurrent thyroid cancer without the attendant morbidity of hypothyroidism (7, 8, 9). Recent studies have shown that patients given rhTSH avoid the hypothyroid symptoms and signs seen with withdrawal of L-T4 therapy (10, 11). These studies also demonstrated that rhTSH stimulates radioiodine uptake in thyroid remnant tissue and metastatic disease. However, in the most recent study, radioiodine WBS after conventional thyroid hormone withdrawal generated superior scans compared with rhTSH scans in 29% of patients with positive scans (11). The superior scans observed with conventional L-T4 withdrawal were thought to be due in part to lower whole body radioiodine retention and shorter length of TSH elevation observed during rhTSH administration while patients were taking L-T4. The current study was designed to compare the effects of two different dosing regimens of rhTSH with conventional (levothyroxine) L-T4 withdrawal on radioiodine WBS. In addition, the likelihood of scans with suboptimal counts for adequate imaging was minimized by requiring uniform dosing of radioiodine and the acquisition of a minimum number of counts for scanning. Finally, serum Tg measurements after rhTSH stimulation were evaluated for disease detection when used alone and in combination with WBS.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS received rhTSH, and 226 patients completed the study. Written informed consent was obtained from each patient, and the protocol was approved by the institutional review board at each site. All but 1 patient had undergone a total or near-total thyroidectomy, and 83% had received prior radioiodine therapy. Patients who had received previous radioiodine therapy were enrolled at least 4 months after the last treatment. Within 7 days of entry into the study, a serum TSH level of 0.5 mU/L or less during thyroid hormone therapy (THT) was confirmed in each patient. None of the patients had a concurrent major medical disorder or received radiographic contrast agents that could interfere with radioiodine uptake. The use of a low iodine diet was specifically recommended, and a majority of investigators followed a low iodine protocol. Patients received the same diet instructions for both scans.
rhTSH
rhTSH (Thyrogen, Genzyme Corp., Cambridge, MA) was produced as previously described (7, 12). The biological potency was 4 IU/mg protein (Second WHO International Reference Preparation of human TSH for Bioassay 84/703).
Study design (Fig. 1
)
To evaluate dosing regimens of rhTSH, patients were randomized
into two study arms (Fig. 1). Patients in arm I received 0.9 mg rhTSH,
im, every 24 h for two doses (Fig. 1A). Twenty-four hours after
the second dose of rhTSH, 4 ± 0.4 mCi (148 ± 14.8
megabecquerels) radioiodine were administered orally, and a whole body
scan was obtained 48 h later. Whole body images were acquired with
a 
-camera after scanning for a minimum of 30 min or a minimum of
140,000 counts. Single (spot) images of body regions were acquired
after scanning a minimum of 10–15 min or after obtaining 60,000 counts
for a large field of view camera or 35,000 counts for a small field of
view camera. These specified conditions were required to account for
the differences in iodine retention between the euthyroid (rhTSH) and
hypothyroid (withdrawal) phases of the study (10). At least 2 weeks
after the second dose of rhTSH, patients were withdrawn from THT and
followed until adequate hypothyroidism (TSH, 
25 mU/L) was achieved. A
repeat dosage of 4 ± 0.4 mCi radioiodine was administered, and
WBS was again performed 48 h later. Patients in arm II of the
study received 0.9 mg rhTSH IM every 72 h for three doses (Fig. 1B). Twenty-four hours after the third dose of rhTSH, 4 ± 0.4 mCi
radioiodine were administered orally, followed by a whole body scan
48 h later. At least 2 weeks after the third dose of rhTSH,
patients were withdrawn from THT, and a repeat radioiodine WBS was
performed in the same manner as in arm I.
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Whole body 131I scans were independently
evaluated by three reviewers who were unaware of the order of the
scans. Scans were evaluated for technical quality (acceptable,
suboptimal, or inadequate) and were classified according to site of
uptake and number of lesions (Table 1).
The suboptimal or inadequate scans were further classified as poor scan
quality, count poor scans, blurred images, missing or unlabeled
markers, or other to better define why these scans were not acceptable.
The scan classification used for all analyses was the consensus of at
least two of the three independent reviewers. Sixty-five percent of
scans were given the same classification by all three reviewers, and
31% of scans were given the same classification by two of the three
reviewers. Four percent of scans were given different classifications
by all three reviewers. If the classification (e.g. 1, 2, or
3) or subclassification (e.g. 2A or 2B) assigned to each
scan for a patient was equivalent, the scans were considered
concordant. Scans were considered discordant if one scan was given a
higher classification or subclassification, and the higher rated scan
was considered superior. Furthermore, for concordant scans, the
reviewers were also asked if a difference in the number and
distribution of lesions between these concordant scans could
potentially change the clinical management of the patient. Scans were
performed with and without labeled markers (chin, thyroid cartilage,
sternal notch, xiphoid process, and iliac crest).
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Baseline serum Tg was measured during THT (TSH, 
0.5 mU/L).
Serum was obtained on the final day of rhTSH administration in each
arm, as well as 24 h, 48 h, 72 h, and 7 days after the
final dose of rhTSH (Fig. 1
). During the withdrawal phase, serum was
obtained on the day of radioiodine administration. All serum Tg assays
were performed in duplicate at one institution (University of Southern
California, Endocrine Services, Los Angeles, CA) using a RIA employing
CRM-457 standardization. The RIA had an analytical sensitivity of 0.2
ng/mL, a functional sensitivity of 0.5 ng/mL, and a reference range for
euthyroid subjects of 3–40 ng/mL (13). All samples collected from an
individual patient were tested in a single assay run. The basal serum
specimen for each patient was screened for the presence of Tg
antibodies using a quantitative RIA method with a detection limit of
1.0 IU/mL which was calibrated against the WHO First International
Reference Preparation 65/93 (Kronus, San Clemente, CA).
Measurements for rhTSH antibodies were performed in each patient at
baseline and during the hypothyroid phase before the administration of
radioiodine. Samples were analyzed by a validated enzyme-linked
immunoassay. Abnormal results were confirmed for antibodies by Western
blot analysis.
Hypothyroid symptoms and quality of life measurements
Hypothyroid symptoms and signs were assessed in each patient by the Billewicz scale (14), which is an observer-rated evaluation for 14 symptoms and signs of hypothyroidism. The SF-36 quality of life instrument is a validated self-administered scale (15). The Billewicz scale and SF-36 instrument were tested in each patient at three points in the study: at baseline on THT, after administration of rhTSH, and after withdrawal of thyroid hormone therapy on the day of radioiodine administration.
Statistical analysis
All statistical tests were two sided, and the significance
level (
) used was 0.050. Comparisons between the rhTSH- and
withdrawal-mediated scanning techniques were made using the sign test
and the continuously adjusted 95% confidence interval. Treatment arm
comparisons were made using the Fisher’s exact test. Comparisons of
serum Tg levels between groups (THT and rhTSH) were performed using the
Wilcoxon signed rank test. Comparisons of hypothyroid symptoms and
signs on the Billewicz scale and the SF-36 quality of life measures
between treatment groups were made using the Wilcoxon signed rank test
within each arm.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The characteristics of the 229 patients who received rhTSH are
shown in Table 2. With the exception of a
difference in mean ages (44 vs. 50 yr, between arms I and
II, respectively; P = 0.020), there were no significant
differences between patients receiving the two-dose and three-dose
regimens. Disease staging at initial therapy is also shown in Table 2,
which is different from radioiodine scan classification at the time of
the study (Table 1).
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Baseline serum TSH concentrations during THT were 0.08 ±
0.17 and 0.10 ± 0.13 mU/L in patients in arms I and II,
respectively. Maximal serum TSH concentrations were observed 24 h
after the final dose of rhTSH in both arm I (124 ± 59 mU/L) and
arm II (102 ± 44 mU/L). By comparison, mean serum TSH levels
during the withdrawal phase were 71 ± 40 and 69 ± 38 mU/L
at the time of radioiodine administration in arms I and II,
respectively. Patients in the rhTSH phase of arm I had elevated serum
TSH levels (25 mU/L) for approximately 4 days, whereas patients in
arm II had elevated levels for approximately 9 days.
Comparison of whole body radioiodine imaging after rhTSH administration and after thyroid hormone withdrawal
Of the 229 patients who received rhTSH, 226 completed the study,
and 220 had evaluable scans as determined by the independent reviewers.
Among these 220 patients, 195 (89%) had concordant scans, 8 (4%) had
superior rhTSH scans, and 17 (8%) had superior withdrawal scans (Table 3). There was no significant difference
in the number of superior rhTSH or withdrawal scans within either study
arm (arm I, P = 0.146; arm II, P =
0.581; all patients, P = 0.108) or between arms I and
II (P = 0.76).
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1) after 1 or both preparatory techniques.
Eighty-three patients (77%) had concordant scans, 8 (7%) had superior
rhTSH scans, and 17 (16%) had superior withdrawal scans (Table 3B).
There was no significant difference in the number of superior rhTSH or
withdrawal scans within either study arm (arm I, P =
0.146; arm II, P = 0.581; all patients,
P = 0.108) or between arms I and II (P
= 0.78).
Metastatic disease was defined as disease outside the thyroid bed on a
diagnostic or posttherapy scan, and/or an elevated serum Tg (10
ng/mL) during thyroid hormone withdrawal in the absence of a positive
diagnostic scan at the time of the study. Based on this definition, 49
patients (22%) had metastatic disease. Ten of these patients had an
elevated serum Tg as the only evidence of disease (16, 17, 18). Thirty-nine
patients (80%) had concordant scans, 2 (5%) had superior rhTSH scans,
and 8 (16%) had superior withdrawal scans (Table 3C). There was no
significant difference in the number of superior rhTSH or withdrawal
scans within either study arm (arm I, P = 0.375; arm
II, P = 0.375; all patients, P = 0.109)
or between arms I and II (P = 0.85). Scan results for
the 10 individual patients with disease outside the thyroid bed and
discordant scans are shown in Table 4. Of
the 8 patients with superior withdrawal scans, 5 had negative rhTSH
scans (Table 4A). Three of these patients with negative rhTSH scans had
thyroid bed uptake (class 1) after withdrawal scanning (patients 1, 5,
and 6). Neither of the rhTSH and withdrawal diagnostic scans
detected disease in the neck outside the thyroid bed in 1 patient
(patient 1) or pulmonary uptake (patients 5 and 6) seen on posttherapy
scanning. One of these patients (no. 5) had discordant scans at 48
h, but concordant scans when repeated at 72 h. One patient in each
arm of the study had markedly discordant diagnostic scan results
(patients 2 and 7), with no uptake after rhTSH and mediastinal or
pulmonary uptake after withdrawal, both of which were confirmed at
posttherapy scanning. Both patients had elevated serum Tg levels after
rhTSH stimulation (38.0 and 13.1 ng/mL, respectively).
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Maximum serum Tg levels were observed 3 days after the final rhTSH
injection in arm I and between 1–3 days after the final rhTSH
injection in arm II. Of the 229 patients enrolled in the study, 35
(15%) had detectable serum Tg antibodies. Patients who had undergone
previous ablation of thyroid tissue (<1% uptake in thyroid bed) and
had negative serum Tg antibodies were further studied. One hundred and
five patients had a serum Tg levels of 2 ng/mL or more after thyroid
hormone withdrawal. This serum Tg value was chosen because of the assay
sensitivity (0.5 ng/mL) and evidence that any detectable serum Tg
indicates the presence of thyroid tissue (19). Of these 105 patients,
91 (87%) had a serum Tg of 2 ng/mL or more after rhTSH stimulation,
and 52 (50%) had a serum Tg of 2 ng/mL or more during THT. Figure 2 shows a comparison of
serum Tg levels during THT, after stimulation with rhTSH, and after
thyroid hormone withdrawal in 58 patients in arm I (Fig. 2A) and 50
patients in arm II (Fig. 2B) with a baseline Tg of less than 2 ng/mL.
Median serum Tg levels were less than 0.5, 1.1, and 1.8 ng/mL during
THT, after rhTSH, and after hormone withdrawal, respectively, in arm I,
and were less than 0.5, 1.2, and 1.8 ng/mL, respectively, in arm
II.
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2) had Tg measurements during
THT, after rhTSH stimulation, and after thyroid hormone withdrawal. Tg
levels of 2 ng/mL or more and 5 ng/mL or more were used as cut-off
values for disease detection. Figure 3A
shows the percentage of positive Tg measurements at each cut-off level
for the 46 patients with radioiodine uptake in the thyroid bed. An
elevated Tg was detected on THT in 22% and 20% of patients at the 2
and 5 ng/mL cut-off levels, respectively, whereas 52% and 35% had
elevated Tg levels after rhTSH stimulation using these cut-off values.
In comparison, an elevated Tg was detected after thyroid hormone
withdrawal in 56% and 43% at the 2 and 5 ng/mL cut-off levels,
respectively. For patients with cancer outside the thyroid bed, an
elevated Tg level was detected during THT in 80% and 67% of patients
at the 2 and 5 ng/mL cut-off levels, respectively (Fig. 3B). In
comparison, an elevated Tg was detected after rhTSH stimulation in
100% and 97% of these patients with metastatic disease at these
cut-off values. An elevated Tg level was detected in all 30 patients
after thyroid hormone withdrawal at both cut-off values. The use of
rhTSH to stimulate Tg production from thyroid tumor cells increased
detection of radioiodine-concentrating disease over Tg levels measured
during THT alone.
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Combined use of rhTSH-stimulated Tg and WBS to detect thyroid remnant or cancer
The same 2 groups of patients described above were analyzed for
disease detection using the combination of serum Tg and WBS after rhTSH
stimulation (Fig. 4). The disease
detection rates in the 46 patients with thyroid bed uptake (class 1)
after thyroid hormone withdrawal or posttherapy scanning were 93% (43
of 46) and 91% (42 of 46) of patients after rhTSH using the 2 and 5
ng/mL Tg cut-off values, respectively. The disease detection rates in
the 30 patients with metastatic disease identified after thyroid
hormone withdrawal or posttherapy scanning were 100% after rhTSH at
both Tg cut-off values.
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Patients had essentially no symptoms or signs of hypothyroidism after rhTSH administration compared with thyroid hormone withdrawal. There were statistically significant differences between rhTSH administration and thyroid hormone withdrawal in both study arms for all 14 symptoms and signs of hypothyroidism on the Billewicz scale (P < 0.01). Patients reported significantly better quality of life scores (SF-36 instrument) after rhTSH administration compared with those after thyroid hormone withdrawal in areas including performance of physical activities, problems with daily activities as a result of physical health, bodily pain, and emotional problems (P < 0.01).
Adverse events
There were no significant differences in the rate of adverse events after rhTSH administration between the 2 study arms (P = 0.08). Headache was the most common event (9.2%) followed by nausea (6.1%) and asthenia (3.5%), which were usually mild and transient. No serious adverse events (life-threatening or requiring hospitalization) were related to rhTSH administration. Four patients had unrelated serious adverse events. Two patients in arm I had chest pain and palpitations 26 and 30 days after rhTSH administration, during the withdrawal phase. One patient in arm I had syncope 52 days after rhTSH administration on the eighth day of thyroid hormone withdrawal. One patient in arm II was hospitalized for nausea and vomiting, uncontrolled diabetes mellitus, and fever 26 days after rhTSH administration during the withdrawal phase. None of the patients developed antibodies to rhTSH, including 17 patients who had received multiple courses of treatment in previous studies.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a previous study (11), 71% of patients with positive diagnostic scans had an equivalent or superior scan with rhTSH, whereas 95% had equivalent or superior scans using the conventional withdrawal method. This difference was statistically significant in favor of the withdrawal method. The present study was designed to address a number of shortcomings in the previous study, most notably a significantly lower whole body retention of radioiodine after rhTSH stimulation compared with thyroid hormone withdrawal (10). Clearance of radioiodine is decreased by about one third during the hypothyroid withdrawal phase compared with the euthyroid rhTSH phase, leading to a 2-fold increase in whole body retention of radioiodine at 48 h after the radioiodine dose (20). To compensate for this difference, the present study used a slower scanning speed and minimum total count number for each image rather than scanning for a defined period of time, thereby minimizing potential count-poor scans after rhTSH administration. Furthermore, in the present study, we standardized the dosage of radioiodine to 4 ± 0.4 mCi. Using these methods, we found that 84% of patients with a positive diagnostic scan had an equivalent or superior scan with rhTSH, whereas 93% of the patients had an equivalent or superior scan after thyroid hormone withdrawal. The differences between the rhTSH and withdrawal scans were not statistically significant in either arm of the study, although more discordant scans were superior after thyroid hormone withdrawal. Moreover, we found no significant difference between the two dosing regimens of rhTSH, suggesting that the two-dose regimen is preferable due to the convenience of administration. Following these guidelines for patient preparation, radioiodine dosage, and scanning technique is important to obtain good quality whole body scans.
It has been suggested that even with the availability of rhTSH, conventional thyroid hormone withdrawal is still preferable for detection of residual tissue and cancer in most patients (21). This commentary accurately noted that in the previous study (11), 21 patients had discordant scans, and 18 of these scans were superior after thyroid hormone withdrawal. In the current study, using standardized radioiodine scanning dosage and scanning techniques, we found discordant scans in only 12 patients receiving 2 doses of rhTSH (arm I). Nine of these scans were superior after thyroid hormone withdrawal, and 3 were superior after rhTSH stimulation. Although this difference was not statistically significant, the trend still favored thyroid hormone withdrawal. However, measurement of serum Tg together with WBS after rhTSH greatly improved the detection of remnant tissue or cancer. Specifically, the combination of measuring serum Tg and WBS after rhTSH accurately identified 100% of patients with metastatic disease and 93% of patients with uptake limited to the thyroid bed. In fact, measurement of a serum Tg level alone after rhTSH stimulation predicted thyroid bed uptake in 52% of patients and metastatic disease in 100% of patients using a cut-off level of 2 ng/mL. These results are superior to those obtained while patients were taking THT alone, in which a serum Tg measurement predicted thyroid bed uptake in 22% of patients and metastatic disease in 80% of patients using a cut-off level of 2 ng/mL. Prediction of remnant thyroid tissue or thyroid cancer using serum Tg requires a sensitive and consistent Tg assay and the absence of serum antibodies to Tg. The specific Tg values used in this study may not be the same in other assays, and these values must be interpreted carefully.
As in the initial phase III study, the rhTSH scan was performed first in each patient, followed by the withdrawal scan. Recent studies have shown that scanning dosages of 131I can cause "stunning" of thyroid tissue, resulting in diminished uptake of a subsequent therapeutic dosage of radioiodine (22, 23). This effect is more pronounced with higher administered activities of 131I. In the present study, 96% of scans were either equivalent or superior after thyroid hormone withdrawal, suggesting that any contribution of stunning may have been small. The potential effect of stunning, however, cannot be excluded in the 4% of scans that were superior using rhTSH. Although the order of scans was not randomized, it was believed inappropriate to perform a withdrawal scan first, resume thyroid hormone therapy for 4–6 weeks, perform the rhTSH scan, and possibly withdraw thyroid hormone therapy again for 4–6 weeks in patients for whom a therapeutic dose of radioiodine was indicated.
In conclusion, rhTSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer recurrence. No significant differences were seen between the two and three dose rhTSH arms of the study, suggesting that the two-dose rhTSH regimen may be preferable due to ease of administration. As whole body retention of radioiodine is reduced by half in euthyroid patients receiving rhTSH, care must be taken to obtain adequate scans for interpretation, using a minimum number of total counts as a threshold. Patients in this study had essentially no hypothyroid symptoms during administration of rhTSH compared to thyroid hormone withdrawal, and concomitantly fewer effects on job performance, mood state, and general sense of well-being. The use of rhTSH provides an alternative to thyroid hormone withdrawal for patients undergoing evaluation for thyroid cancer persistence and recurrence.
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Acknowledgments |
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Footnotes |
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Received April 22, 1999.
Revised June 30, 1999.
Accepted July 7, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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R. J. Robbins and M. J. Schlumberger The Evolving Rol |
