Title: Assessment of the Incremental Value of Recombinant TSH Stimulation before
FDG PET/CT Imaging to Localize Residual Differentiated Thyroid Cancer
S Leboulleux1, PR Schroeder2, NL Busaidy3, A Auperin4, C Corone1, HA Jacene5, ME
Ewertz2, C Bournaud1, RL Wahl5, SI Sherman3, PW Ladenson2 and M Schlumberger1.
1Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, University Paris
Sud-XI, Villejuif, France, 94805
2Department of Medicine, Division of Endocrinology and Metabolism, Johns Hopkins University School
of Medicine, Baltimore, MD, United States, 21201
3Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, Department of Endocrine
Neoplasia and Hormonal Disorders, The M. D. Anderson Cancer Center, Houston, Texas, United
4Department of Statistics, Institut Gustave Roussy, Villejuif, France
5Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine,
Johns Hopkins University School of Medicine, Baltimore, MD, United States, 21287
Short Title: Incremental value of rhTSH stimulation before FDG PET/CT
Precis: The use of rhTSH before FDG-PET/CT significantly increases the number of lesions detected
but lesions found only by rhTSH-PET contributed to treatment changes in 13% patients, among whom
only half were true-positive on pathology.
Key words: PET, PET/CT, FDG, fluorodesoxyglucose, thyroid cancer, recurrence, thyroglobulin
Word counts: abstract: 249 ; text: 3598
Number of tables: 3 ; Number of figures: 2, References: 38
This study was supported by an unrestricted grant from Genzyme. S.S., P.L. and M.S. S. received
lecture fees from Genzyme. HAJ., CC. received honoraria from Genzyme Corporation. S.L., P.R.S.,
N.L.B., A.A., M.E.E., C.B. R.L.W., have nothing to declare
ClinicalTrials.gov Identifier: NCT00181168
J Clin Endocrin Metab. First published ahead of print January 21, 2009 as doi:10.1210/jc.2008-1747
Copyright (C) 2009 by The Endocrine Society
PURPOSE: To assess prospectively the impact of recombinant human TSH (rhTSH)
administration on PET/CT imaging in differentiated thyroid cancer (DTC) patients who, after
primary treatment, had a suppressed or stimulated serum thyroglobulin >10 ng/mL and no
radioactive iodine uptake consistent with thyroid cancer on a whole body scan.
PATIENTS-METHODS: PET/CT was performed before (basal PET) and 24-48 hours after
rhTSH administration (rhTSH-PET) in 63 patients (52 papillary TC and 11 follicular TC).
Images were blindly analyzed by 2 readers. The proposed treatment plan was prospectively
assessed before basal PET, after basal PET and again after rhTSH-PET
RESULTS: One hundred and eight lesions were detected in 48 organs, in 30 patients. rhTSH
PET was significantly more sensitive than basal PET for the detection of lesions (95% vs.
81%, P=0.001) and tended to be more sensitive for the detection of involved organs (94% vs.
79%, P=0.054). However, basal PET and rhTSH PET did not have significant different
sensitivity for detecting patients with any lesions (49% vs. 54%, P=0.42).
Changes in treatment management plan occurred in 19% of the patients after basal PET.
Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in 8 patients,
among whom only 4 were true-positive on pathology (6%).
CONCLUSION: The use of rhTSH for FDG-PET/CT significantly increased the number of
lesions detected, but the numbers of patients in whom any lesion was detected were no
different between basal and rhTSH-stimulated PET/CT scans. Treatment changes due to
true positive lesions occurred in 6% of cases.
A large majority of differentiated thyroid cancer patients (DTC) are cured following
initial treatment, but 15% have persistent disease, most often located in the neck (1).
However, there is no identifiable tumor focus in many patients and the only abnormality is
persistently detectable serum thyroglobulin (Tg) levels. In such patients, imaging is
performed to localize residual disease, including neck ultrasonography, neck and chest
computed tomography (CT) scan, bone scintigraphy, and whole body scan (WBS) after the
administration of a high activity of radioiodine (2).
In recent years, 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) positron emission
tomography (PET) scanning became available in many centers. Thyroid cancer tissue is
often able to concentrate FDG, particularly when poorly differentiated and unable to
accumulate radioiodine (3-7). FDG PET was found to change treatment management plans
in 10 to 50% of patients undergoing scanning for the detection of thyroid cancer recurrence
In vitro studies showed increased FDG uptake in thyroid cells following thyrotropin
(TSH) stimulation (19-23). Several reports in patients with DTC have suggested that FDG
uptake in neoplastic foci increases following TSH stimulation obtained either during
withdrawal of thyroid hormone treatment or following recombinant humanized (rh) TSH
injections (10, 24-27). Both the intensity of FDG uptake measured with the maximum
standardized uptake value (SUVmax) and the number of lesions were reported to increase.
The benefits of TSH stimulation have not, however, been quantified in a large series of
patients. Furthermore, other studies comparing TSH-suppressed and rhTSH-stimulated
FDG-PET scans in different patients, rather than the same patients studied sequentially,
failed to find a difference in PET sensitivity (8, 28).
The aims of this prospective study were to evaluate the incremental value of rhTSH
administration before FDG PET scanning on the number of lesions detected and on the
changes in clinical management in a large number of patients with elevated serum Tg levels
with residual disease that was either not localized at all by other conventional imaging
techniques, or if some disease had been identified, was limited.
PATIENTS AND METHODS
The inclusion criteria for this study were: (i) papillary or follicular TC treated with total
thyroidectomy and radioiodine ablation, (ii) Tg level ? 10 μg/liter more than 1 year after initial
treatment, on thyroxine treatment or following TSH stimulation, obtained either during
thyroxine withdrawal or following rhTSH injections, (iii) no abnormal focus of uptake on a
radioiodine WBS performed within 12 months of the study after the administration of 150 to
3700 MBq (4 to 100 mCi) of 131I, (iv) no more than 3 known or suspected extra-cervical tumor
foci on conventional imaging, and (iv) age greater than 18 years. The exclusion criteria
included: (i) diabetes mellitus, (ii) thyroid withdrawal or rhTSH injections during the month
preceding the study, (iii) presence of Tg antibodies or a recovery test of less than 80%, (iv)
pregnancy or breast feeding, (v) TSH level above 0.5 mU/mL during thyroxine treatment, (vi)
known bone or cerebral metastases.
Patients first underwent a basal PET/CT during thyroxine treatment (whith a serum
TSH concentration <0.5 mU/L), and then a rhTSH (thyrotropin alfa, Thyrogen®, Genzyme
Corporation, Cambridge MA, USA) stimulated PET/CT. rhTSH-PET stimulation was
accomplished by intramuscular injections of 0.9 mg of rhTSH on 2 consecutive days.
In order to determine the optimal timing for rhTSH-PET, a pilot study was first
performed with rhTSH-PET performed 24 hours and 48 hours after the second rhTSH dose.
Subsequently, patients underwent only one PET/CT after rhTSH administration.
The treatment plan was prospectively assessed at three time points--before the
PET/CTs, after the basal PET/CT, and after the rhTSH-PET/CT--to determine whether the
use of rhTSH before PET/CT would lead to changes in management. The six categories of
potential subsequent treatment were: thyroid hormone suppression therapy alone, unilateral
± central neck surgery, bilateral ± central neck surgery, external beam radiation,
chemotherapy, or fine needle aspiration biopsy (FNAB). Any change in the management
strategy based on basal or rhTSH-stimulated PET/CT findings was noted.
The protocol was approved by each site’s institutional review board and/or
independent ethics committee. All patients provided written informed consent to participate in
Imaging was performed on a Discovery LS PET/CT scanner (GE Medical Systems,
Milwaukee, Wisconsin) at Johns Hopkins University (JHH), on a PET/CT Biograph LSO
system (Siemens Medical Solutions, Erlangen, Germany) at Institut Gustave Roussy (IGR)
and on a Discovery ST PET/CT scanner (GE Medical Systems, Milwaukee, Wisconsin) at
MD Anderson Cancer Center (MDACC).
PET/CT scanning was performed after an intravenous injection of 222 to 888 MBq
of FDG, followed by a mean 66 minute tracer uptake phase (range: 41-152). All patients
fasted for at least 6 h before FDG injection. Mean Capillary glucose was 5.5 mmol/liter
(range: 4.3– 7.7) in the 58 patients with available data.
For scanning, patients were positioned supine and head first on an in-line PET-CT
system with a single gantry and table and were allowed to breath quietly. Images from the
upper part of the thorax to mid-thigh level were obtained with arms raised above the head
followed by images from the top of the skull to the upper part of the thorax with arms along
CT parameters were set to 80 milliamperage-seconds (mAs) and 110 kilovolt peak
(kVp) at IGR, weight-adjusted for mAs and set to 140 kVp at JHH, and weight-adjusted for
both mA and kVp at MDACC. Slice thickness was 3.75 to 5 mm.
For PET scanning, four-minute emission acquisitions per FOV were obtained in three-
dimensional mode at IGR, five-minute emission acquisitions and three-minute emission