Wu 2019

Thyroid
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© Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2018.0598
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Title page
I-124 PET/CT versus conventional radioiodine imaging in

This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
differentiated thyroid cancer: a review
Di Wu, MD1,2
1
MedStar Health Research Institute, 6525 Belcrest Rd #700, Hyattsville, MD 20782
I-124 PET/CT versus conventional radioiodine imaging in differentiated thyroid cancer: a review (DOI: 10.1089/thy.2018.0598)
2
Nuclear Medicine Research, MedStar Washington Hospital Center, 110 Irving St NW, Suite
GA60D, Washington, DC 20010(address)
Downloaded by Macquarie University (Caul) from www.liebertpub.com at 08/28/19. For personal use only.
Di.Wu2@Medstar.net
Dorina Ylli, MD, PhD1,3
1
3
Division of Endocrinology, MedStar Washington Hospital Center, 110 Irving St NW, Suite
Thyroid
2A72, Washington, DC 20010
Dorina.Ylli@medstar.net
S. Layla Heimlich 4
4
William. B. Glew, MD, Health Sciences Library, MedStar Washington Hospital Center, 110
Irving St NW, Washington, DC 20010
Layla.Heimlich@medstar.net
Kenneth D. Burman, MD 3
3
Kenneth.D.Burman@medstar.net
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Leonard Wartofsky, MD 3
3
Leonard.Wartofsky@Medstar.net
Douglas Van Nostrand, MD 1,2

1
2
Division of Nuclear Medicine, MedStar Washington Hospital Center, 110 Irving St NW,
Suite GA60F, Washington, DC 20010 (address)
Douglas.Van.Nostrand@Medstar.net
Corresponding authors
Di Wu
Thyroid
wudi_823@yahoo.com
Douglas Van Nostrand, MD, FACP, FACNM
Director, Nuclear Medicine Research
Professor of Medicine, Georgetown University School of Medicine
MedStar Health Research Institute
MedStar Washington Hospital Center

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1Division of Nuclear Medicine
2Division of Endocrinology
Suite GA60F
110 Irving Street, N.W. Washington, D. C. 20010

Office: 202-877-0300
Fax: 202-877-6066
E-mail: douglas.van.nostrand@medstar.net
douglasvannostrand@gmail.com
Running title: I-124 PET/CT versus I-131detection

Keywords: I-124 PET/CT, I-131 scan, I-123 scan, differentiated thyroid cancer, detection
Disclosures
Thyroid
Douglas Van Nostrand: Speaker and consultant for Jubliant Draximage.
No competing financial interests exist for the remaining authors.
Acknowledgements
This study was underwritten by grants from grateful patients.

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Abstract (250 words)
Background: Studies report a wide spectrum of I-124 PET/CT sensitivity and
specificity in the detection of differentiated thyroid cancer (DTC) lesions. This study
reviews the lesion detection rate of pretherapy I-124 PET/CT in different patient
populations and further analyzes the factors necessary for a better detection on I-124
PET/CT.
Methods: A literature search was performed using multiple different databases

(MEDLINE, EMBASE, Northern Lights and handsearching) covering 1996 to April 2018. Two
reviewers reviewed and extracted study data for I-124, I-123 and I-131 scans in DTC.
Results: This review includes four retrospective and ten prospective studies in
which 495 DTC patients underwent I-124 and I-131 imaging; no studies made comparisons
to I-123. In the reports that compared I-124 PET/CT to diagnostic I-131scans, there were a
total of 72 patients in whom120 lesions were detected on I-124 imaging, whereas only 52
were detected on diagnostic I-131 scans. In publications that compared I-124 to
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posttherapy I-131scans in 266 patients, 410 lesions were detected with I-124 PET, whereas
390 were detected on posttherapy I-131 scans. Based on I-124 PET/CT in six studies, TNM
staging was revised in 15-21% of patients and disease management was altered in 5-29%
of patients.
Conclusion: I-124 PET/CT is able to identify a greater number of foci compared to

diagnostic I-131 scans. I-124 PET may have better detection compared to post-therapy I-
131 scans in patients who are I-131 therapy naïve, have less aggressive pathology, or do
not have disseminated lung metastases. Additional metastatic lesion detection by I-124
PET may have significant clinical impact in the management of patients prior to I-131
therapy in some patients.
Keywords: I-124 PET/CT, I-131 scan, I-123 scan, differentiated thyroid cancer, detection
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Introduction
Iodine-124 positron emission tomography (PET), performed with or without
diagnostic computed tomography (CT)1, has higher spatial and contrast resolution
compared to conventional planar diagnostic radioiodine scans in patients with
differentiated thyroid cancer (DTC) (1). Some studies have found that I-124 PET/CT is
useful in the identification and anatomic localization of focal disease, which is critical to
optimal management of patients with differentiated thyroid cancer (DTC). Several studies
have evaluated the lesion detection rate of I-124 PET as compared to radioiodine
diagnostic or post-therapy scans in cohorts of patients with different disease burden and
treatment stage. However, these data are conflicting. Santhanam et al. (2) reviewed the
literature on I-124 PET/CT versus post-therapy I-131 scans, identified eight articles, and
performed meta-analysis on five of the articles. They concluded that I-124 PET/CT is not
only a sensitive tool to diagnose radioiodine avid DTC lesions, but also detects a small
number of new lesions that are not visualized on the post-therapy I-131 scan.
This review expands the search parameters and includes further 1) a comparison of
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the diagnostic ability of I-124 PET versus low-activity I-123/I-131 diagnostic planar scans
and/or single photon emission computed tomography (SPECT) scans, 2) a comparison of
the diagnostic ability of I-124 PET/CT to the reference standard outlined in each article,
instead of only the post-therapy I-131 scan, 3) an assessment of I-124 PET/CT detection
with individual lesion- and patient-based analysis, 4) a review of the impact of I-124 PET
imaging on staging and management, and 5) a discussion of the possible reasons for the
wide variation in the detection rate of I-124 PET/CT reported in the literature.
Methods
A. Literature search
A comprehensive literature search was performed in April 2018 on
MEDLINE/PUBMED, EMBASE and Northern Lights to assess the clinical evidence for I-124
PET or PET/CT diagnostic accuracy in assisting the localization and management of
locoregional and distant metastases in patients with differentiated thyroid cancer. Search
1
The abbreviations of PET/CT and PET used in this review are those used by the original
authors in their respective articles, and unfortunately it is not always clear whether an
author using the abbreviation PET/CT meant a PET scan with attenuation (i.e., low dose) CT
or a diagnostic (i.e., high dose) CT.
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terms included 124I, 131I, 123I, radioactive iodine, radioiodine, thyroid carcinoma, thyroid
cancer, thyroid tumor. The reference lists from relevant studies and Google Scholar were
also searched. The parameters included English articles and English abstracts with no date
limits. This review only included studies that directly compared I-124 scans with either
diagnostic I-123/I-131 planar or SPECT scans or post-therapy I-131 scans. Figure 1 shows
the PRISMA diagram.
Four retrospective (3-6) and ten prospective studies (7-16) were identified for
systematic review. Two reviewers (DW, DY) verified the study eligibility and extracted the
data. Any disagreements were resolved by consensus.

B. Method of comparison
We evaluated the diagnostic ability of I-124 PET/CT when referenced to the
standard outlined in each article. The imaging tests evaluated were (i) I-124 PET or PET/CT,
(ii) diagnostic I-123/I-131 scan performed as planar whole-body scan (WBS) or SPECT or
SPECT/CT, and (iii) post-therapy I-131 scans performed as planar whole-body scan (WBS)
or SPECT or SPECT/CT. The standard of reference (i.e. the metrics used to characterize foci
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of uptake as DTC) were those outlined in the methods section in the respective
publications. Hence, the standard of reference varied and may have included various
imaging studies, cytopathology, changes in serum thyroglobulin levels, and/or physician
consensus. The post-therapy I-131 scan may not necessarily be part of the reference
standard for a publication. This analysis was performed based on individual lesions (lesion-
based) and patients (patient-based). Due to considerable variation in the reference
standard between articles, no meta-analysis was performed. Apart from the reference
standard, the reviewed articles were also heterogenous based on the patient cohort
selection (risk group, histology, treatment history), the radioiodine activities administered
for imaging, the TSH stimulation method (rhTSH or THW), the imaging method (diagnostic
scan versus posttherapy scan, whole-body scan versus SPECT/CT, PET versus PET/CT), the
timing of I-124 PET imaging relative to I-131 therapy (pretherapy or intratherapeutic), the
I-124 administration route ( IV or oral), the days of I-124 PET imaging, etc. The specific
topics reviewed are listed in Table 1.
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Review
This systematic review includes 14 publications in which 495 DTC patients underwent I-
124 PET imaging and had the PET results compared to radioiodine imaging. Specifically,
112 DTC patients had diagnostic I-123/I-131 imaging (Table 2), and 403 DTC patients had
post-therapy I-131 imaging (Table 3). Twenty of these patients had both planar diagnostic
and post-therapy I-131 scans for comparison (7).
A. Detection of I-124 PET compared to diagnostic I-123/I-131 imaging

Five studies consisting of 112 patients evaluated the clinical diagnostic value of I-
124 PET compared to diagnostic I-131 planar WBS or SPECT imaging. No studies compared
I-124 PET to I-123 diagnostic scans.
In 2008, Phan et al. (7) prospectively compared I-124 with planar I-131 WBS in 20
advanced DTC patients with histologically proven extrathyroidal tumor growth (T4), extra-
nodal tumor growth or distant metastasis (M1). All patients received post-operative I-131
therapy 4 months prior to the diagnostic I-131 WBS and I-124 PET. Of the 11 patients with
I-124 uptake, 8 patients (73%) did not have any corresponding foci of I-131 uptake on
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planar WBS. In the three patients who had uptake on both the I-124 and diagnostic I-131
scan, the uptake was more clearly visible on the I-124 PET than on the diagnostic I-131
scan, and more lesions were also identified on the I-124 PET in 2 patients.
The superiority of I-124 PET images relative to I-131 planar whole-body imaging
was further demonstrated by Van Nostrand et al. (8) in 25 adult patients with metastatic
DTC. Each scan was categorized as positive or negative for metastasis, and foci were
correlated with other diagnostic imaging studies when available. I-131 WBSs were positive
in 6/10 (60%) I-124 PET/CT positive patients. A total of 97 positive foci were identified on
either I-124 or I-131. I-124 identified 49 positive foci not identified on I-131, and I-131
identified one positive focus not identified on I-124. In patients who are positive on both I-
131 and I-124, 67% (4/6) of the patients had a greater number of positive foci detected on
I-124 images than on the I-131 images. Another 4 patients were positive on I-124 PET/CT
but were negative on I-131 WBS. Only one patient had one additional positive focus on I-
131 WBS that was not seen on the I-124 images; however, this focus has not been
confirmed as either a metastasis or a false-positive. The difference between the number of
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foci detected with I-124 versus I-131 was statistically significant using binomial regression
(p<0.0001).
Van Nostrand et al. (17) further compared I-131 diagnostic WBS and I-124 PET/CT
grouped by THW versus rhTSH preparation in 40 patients. Of these patients, 24 were
prepared with rhTSH and 16 with THW. Under rhTSH stimulation, 7/24 (29%) patients were
positive on I-124 PET/CT versus 1/24 (4%) on I-131 WBS. Under THW, 10/16 (63%) patients
were positive on I-124 PET/CT versus 10/16 (63%) on the I-131 WBS, of which 8/10 (80%)
were positive on both scans after THW. Also, a greater number of foci was detected on
THW and the largest number of lesions was detected on I-124 PET/CT: 117 lesions on THW
I-124, 58 lesions on THW I-131, 17 lesions on rhTSH I-124, and two lesions on rhTSH I-131
imaging. Even though no statistical difference was detected between the THW and rhTSH
groups for age, sex, serum thyroglobulin, TSH, urine iodine, histology and previous I-131
therapies, there may be a bias towards employing THW in more advanced DTC patients.
However, no individual patient-based or lesion-based analysis was available for further
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calculations.
Lee et al. (10) further prospectively evaluated the diagnostic I-131 WBS and I-124
PET/CT when compared with 18F FDG PET/CT in a selected group of patients with
stimulated thyroglobulin levels >9 ng/ml but had no pathological lesions on a prior post-
therapy I-131 WBS, neck ultrasound, chest x-ray or cytology. All 19 patients were negative
on the diagnostic I-131 WBS, but five patients had uptake on the I-124 PET/CT. All of the
four true positive I-124 PET/CT patients were restaged and disease management was
modified in one patient who was disease-free at last follow-up. The results of I-124 PET/CT
versus 18F FDG PET/CT are discussed under section heading I-124 PET and 18F FDG PET.
Finally, in a conference abstract, Abdel-Nabi et al.(6) prospectively demonstrated in

eight post-therapy DTC patients the detection rate of I-124 PET/CT and diagnostic I-131
WBS in structurally evident disease. None of the diagnostic I-131 WBS were positive;
however, I-124 PET/CT scans were able to localize metastatic lesions in 3/8 (38%) patients.
No lesion-based description was available.
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No comparison was available in the literature for any form of I-123 imaging, or
diagnostic I-131 SPECT imaging, and there were no studies on I-131 therapy naïve patients.
In summary, these articles uniformly show that I-124 PET is a better diagnostic tool
compared to diagnostic planar I-131 WBS in radioiodine non-naïve patients.
B. Detection of I-124 PET compared to post-therapy I-131 imaging

Ten studies were identified that compared I-124 PET to post-therapy I-131 planar
WBS or SPECT imaging in a total of 403 patients. The following articles are discussed
separately in four categories based on patient cohort: I-131 therapy naïve cohort, I-131
therapy non-naïve cohort, mixed I-131 therapy cohort, and Tg positive/imaging negative
cohort.
a. In I-131 therapy naïve patients
In 2004, Freudenberg et al. (11) demonstrated the value of I-124 PET and PET/CT
compared to post-therapy I-131 WBS. All twelve patients were positive (i.e., had at least
one positive lesion) on the post-therapy I-131 WBS, I-124 PET, and I-124 PET/CT. However,
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I-124 PET/CT identified more lesions than I-131 WBS in 9/12 (75%) patients. Overall, I-124
PET/CT visualized more lesions (69 foci) compared to I-124 PET (60 foci), while post-
therapyI-131 WBS identified the least (50 foci). The lesion detection rate was 100%, 87%,
and 83% for I-124 PET/CT, I-124 PET, and post-therapy I-131 WBS, respectively. The I-124
PET/CT fusion display did not reveal additional lesions relative to separately reported I-124
PET and CT readings, but the CT provided identifiable anatomical structures in the I-124
PET imaging (11). A limitation of their study is that six patients had serum Tg<1 ng/ml in
absence of antibodies, inadequate TSH stimulation, urine iodine >150 µg/L and/or I-131
uptake >10% in the thyroid bed. If these six patients were excluded from the analysis, the
lesion detection rate would be 100%, 79%, and 58% for I-124 PET/CT, I-124 PET, and post-
therapy I-131 WBS, respectively. They showed that I-124 PET/CT is more useful than I-124
PET and post-therapy I-131 WBS in advanced DTC patients.
In another study, Capoccetti et al. (12) compared I-124 PET/CT and post-therapy I-
131 WBS in 67 post-surgical patients who underwent initial I-131 therapy. Although the
overall diagnostic accuracy of I-124 PET/CT could not be calculated from the information
provided, the I-124 PET/CT and the I-131WBS were in total agreement (i.e., number, site
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and extent of disease) in 58/67 (87%) patients, which included the same number of thyroid
remnants (182 foci) in 58/67 (87%) patients and the same number of lymph nodes (63 foci)
in 21/67 (31%) patients. In discordant cases, I-124 PET/CT detected more pathological foci
(which were mainly than post-therapy I-131 WBS in 5/67 (7.5%) patients. Conversely, the
WBS detected more pathological foci than I-124 PET/CT in 4/67 (5.9%) patients, and these
included additional thyroid remnants, lymph nodes, and disseminated lung metastases.
Additional lesions found on I-124 PET/CT upstaged 11/67 (16%) of patients and modified
management in 2/67 (3%) of all evaluated patients.
b. In mixed cohort of I-131 therapy naïve and non-naïve patients

In a retrospective study by de Pont et al.(3), the diagnostic accuracy of I-124 PET/CT
was compared to planar I-131 WBS and SPECT/CT. Twenty consecutive patients underwent
planar I-131 WBS, low-dose CT attenuated I-131 SPECT , and high-dose CT attenuated I-124
PET/CT. Five of these patients had previous I-131 therapies with a cumulative activity of
2.78-14.99 GBq (75–405 mCi). In the patient-based analysis, one additional patient had
uptake on the I-124 PET/CT compared to I-131 SPECT/CT; however, this paratracheal
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remnant was not seen by other imaging modalities. In the lesion-based analysis, I-124
PET/CT identified 57 (92 %) of a total of 62 foci, I-131 SPECT/CT 50 (81%), and I-131 WBS
39 (63 %). On further analysis, 13 patients did not have adequate TSH stimulation >30
mIU/L and/or serum Tg level >5 ng/ml (TSH stimulation unknown) at the time of I-124
administration. If these patients were removed from the analysis, then I-124 PET/CT
detected one additional DTC lesion compared to I-131 SPECT/CT; and if the Tg was >10
ng/ml, then 3/3 (100%) were positive on I-124 PET/CT when I-131 SPECT/CT was positive.
In two patients, the tumor stage was changed based on I-124 PET/CT findings. This study
showed that I-124 PET/CT is predictive not only of post-therapy I-131 planar WBS but also
of I-131 SPECT/CT for lesion detection and staging differentiated thyroid carcinoma.
In a cohort of 106 post-operative I-131 therapy naïve and 31 I-131 therapy non-
naïve patients who received a cumulative activity of 1-47 GBq (37-1739 mCi) of I-131,
Ruhlmann et al. (16) reported a high level of agreement between I-124 PET/CT and post-
therapy I-131 WBS and SPECT/CT. Seven patients had poorly differentiated carcinoma.
Sixty-one of the 137 (45%) patients were positive both on the 25 MBq (0.68 mCi) I-124
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PET/CT imaged at 24 h and 120 h and on the 1.0–10.0 GBq (27-270 mCi) I-131 WBS and
SPECT/CT imaged at 5-10 days or both. Of the 61 patients, 59 (97%) patients were positive
on I-124 PET/CT and 60 (98%) patients were positive on post-therapy I-131 imaging. The
true positive was defined as positive on both I-124 and I-131, which was 95% (58/61),
while 76 patients had no uptake on both scans. In the lesion-based analysis, a total of 227
metastatic lesions were found, of which I-124 PET/CT detected 223 (98%) and I-131
imaging detected 225 (99%); the level of agreement between I-124 PET/CT and I-131
imaging was 97% (221/227). They observed that a diagnostic activity of I-124,
approximately 1% of the therapeutic activity of I-131, may be sufficient to achieve a high

level of agreement between I-124 PET/CT and I-131 WBS, including SPECT/CT. Ruhlmann
et al. suggested that due to the high level of agreement, I-124 PET/CT is adequate in the
detection of radioiodine avid metastases and has much lower radiation exposure
compared to I-131 post-therapy scans.
Gulec et al.(13) reported a prospective study in patients who did or did not have
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prior I-131 therapy and demonstrated that I-124 PET/CT imaging had high lesion detection
sensitivity and offered the additional advantage of quantitation. In the lesion-based
analysis of the 15 patients enrolled, a total of forty-six lesions were identified by I-124, I-
131, and/or 18F FDG PET/CT, of which the individual scans identified 37, 28, and 16 of the
lesions, respectively. I-124 PET/CT clearly demonstrated superior imaging by identifying
22.5% more foci of radioiodine avid lesions than I-131 imaging and by providing better
anatomical detail of remnant thyroid tissue.
c. In I-131 non-naïve patients

Phan et al. (7) showed in patients who had been previously treated with I-131 that
out of the 11 patients positive on the post-therapy I-131 WBS , 9 (82%) patients showed
uptake on the I-124 PET. Two patients had uptake only on the I-124 PET scan with no
anatomical correlate confirmed by neck ultrasound, 18F-FDG PET or MRI, whereas two
other patients showed only uptake on the post-therapy I-131 WBS of which one was
confirmed by MRI but not 18F-FDG PET. Seven patients were negative on both scans. After
excluding five patients with undetectable serum Tg (<0.3 ng/ml) after thyroid hormone
withdrawal, then all seven (100%) patients who had positive post-therapy I-131 WBS were
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also positive on I-124 PET scans. The I-124 PET scans in this group of patients adequately
detected metastatic lesions also seen on post-therapy I-131 scans in previously I-131
treated patients.
The superiority of I-124 PET/CT scan as compared to post-therapy I-131 WBS at 72

h was shown by Pettinato et al. (9) in 26 post-therapy patients treated with dosimetrically-
guided activities of 1.95-11.46 GBq (53-310 mCi) of I-131. In this study, I-124 PET/CT
images correlated with every post-therapy I-131 WBS and showed a superior image quality
due to the better resolution and lesion detectability of PET/CT compared to WBS. Fifteen
patients were positive, and 11 patients were negative on both scans. Of note, both
patients with tall cell variant and one with Hürthle cell were negative on both scans, and
more discussion of histology is summarized under section heading I-124 PET in various DTC
histology. Although a total of 34 lesions were measured for dosimetric analysis on 13 of
the 15 I-124 PET/CT positive patients, no individual lesion-based analysis was available for
further evaluation.
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However, in a retrospective review of seven I-131 post-therapy patients with

elevated serum Tg, Lammers et al. (5) showed poor sensitivity of I-124 PET/CT in detecting
post-therapy I-131 positive metastases. The reasons for poor sensitivity may be due to
patients not receiving low-iodine diet, and five of the seven patients were prepared with
rhTSH injections. Two patients had Hürthle cell cancer. Out of the six patients with a
positive post-therapy I-131 WBS, only one patient (1/6 [17%]) was also positive on the I-
124 PET/CT scan, and this patient was a true positive based on CT.
d. In patients with positive serum thyroglobulin levels and negative imaging

From a prospective study, Khorjekar et al. (14) performed a retrospective study of
twelve patients with elevated serum thyroglobulin levels, negative diagnostic I-131/I-123
scan, negative I-124 PET/CT scan, subsequent “blind” I-131 therapy, and subsequent post-
therapy I-131 scan. Of twelve patients, ten patients had abnormal uptake on the post-
therapy I-131 scan, results in a false negative rate of 83% in this select patient population.
Hence, there may be a subgroup of patients with negative diagnostic radioiodine (I-123, I-
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131 or I-124) imaging who may still benefit from I-131 therapy; however, outcomes of the
“blind” I-131 therapy was not evaluated.
This was further supported by a prospective multicenter observational cohort study

by Kist et al. (15). Seventeen post-therapy DTC patients with biochemical evidence of
recurrence but negative neck ultrasound were enrolled. The patients underwent rhTSH-
stimulated I-124 PET/CT imaging and a THW-stimulated “blind” I-131 therapy to test the
hypothesis that negative I-124 PET/CT can predict negative post-therapy I-131 WBS. Their
results showed only 5 (56%) I-124 PET/CT scans were positive on the nine positive post-
therapy I-131 scans. In all of the 8 patients with negative post-therapy I-131 scans, the I-
124 PET/CT scans were also negative. Of the twelve I-124 PET/CT scans with no pathologic
uptake, the false-negative rate was 33% (4/12). Lesion-based analysis showed that the
post-therapy I-131 WBS revealed 14 lesions versus 8 on I-124 PET/CT. Of note, one patient
with disseminated lung metastasis was positive on the post-therapy I-131 scan but
negative on I-124. Kist et al. demonstrated that rhTSH-stimulated I-124 PET/CT was not
Thyroid
adequate to avoid futile “blind” I-131 therapy because of its high false-negativity rate
(33%; 4/12) in the patient-based analysis. If I-124 PET/CT guided the decision whether or
not to administer “blind” I-131 therapy in this select group of patients, then 44% (4/9) of
patients would have been denied potentially beneficial I-131 therapy.
C. I-124 PET/CT in thyroglobulin <5 ng/ml

Among the reviewed articles, a total of ten patients had undetectable serum Tg
levels <0.3 ng/ml (3, 7, 11). In these patients, I-124 PET detected lesions in 2/5 patients
with negative diagnostic I-131 scan (7). I-124 PET/CT was concordant or better than the
post-therapy I-131 scan in 9/10 patients (3, 7, 11) in whom one patient had more lesions
detected on I-124 PET/CT.
A total of ten patients had serum Tg 0.3-2 ng/ml (3, 7, 11, 15), of whom I-124 PET
was concordant with the diagnostic I-131 scan in 2/2 patients and was concordant with or
better than the post-therapy I-131 scan in 9/10 patients. Three patients had more lesions
detected on I-124 PET/CT than on the post-therapy I-131 scan.
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Of the seven patients with serum Tg ranging from 2.1-5.0 ng/ml (3, 7, 11, 15), I-124
PET detected more lesions in two patients compared to the diagnostic I-131 scan and was
concordant with or better than the post-therapy I-131 scan in 6/7 patients. Two patients
had more lesions detected on the I-124 PET/CT than the post-therapy I-131 scan.
Therefore, even at undetectable or very low serum Tg levels, I-124 PET/CT has
better lesion detection that diagnostic I-131 scan and is concordant or better than the
post-therapy I-131 scan in most patients.

D. I-124 PET/CT in pediatrics

In this review, there are eight reported cases of I-124 PET/CT imaging in children
and adolescents. I-124 is typically orally administered to adult patients at an activity of
18.5-284.9 MBq (0.5-7.7 mCi) as capsule or as liquid, whereas children have been
reportedly administered 18.5-92.5 MBq (0.5-2.5 mCi) in the published literature. However,
none of these reports included a comparison to I-131 scans. The largest report is by
Freudenberg et al. (18) in which four patients aged 11-15 years received 22.2-25.9 MBq
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(0.6-0.7 mCi) of I-124 and were imaged at 25 h. Although the investigators did not
compare I-124 PET/CT to I-131 imaging, this quantitative PET dosimetry study concluded
that a standard adult I-124 PET/CT dosimetry protocol appears to be safe and informative
in pediatric DTC patients, but Freudenberg et al. did not further elucidate how informative
I-124 PET/CT was.
There are no extensive studies on the utility of I-124 and the activities used in
pediatrics. However, these studies did report the I-124 activities used in their pediatric
patients. Other case reports of pediatric use of I-124 are by Hobbs et al. (19) in which an
11-year-old girl received 92.5 MBq (2.5 mCi) of I-124, Lee et al. (10) in which a 15-year-old
boy received 74 MBq (2 mCi) of I-124, and Lammers et al. (5) in which a 17-year-old female
received 40.7 MBq (1.1 mCi) of I-124. Further studies are needed in pediatrics.
E. Change in staging and management based on I-124 PET

A total of six studies evaluated the effects I-124 PET on tumor staging or clinical
management (Table 4). Four of the six studies reported altered TNM tumor staging in 15-
21% of patients based on the I-124 PET detection of additional metastatic lymph nodes or
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distant metastasis (3, 10-12), and four of six studies reported altered disease management
in 5-29% of patients (10, 11)). Further studies are warranted to evaluate the value of I-124
in altering tumor staging and disease management.
F. Potential factors for different detection rates across studies

From the above discussions of various patient groups, significant variability exists in
the reported results, and we submit that this is due to many confounding factors. Several
of these are discussed below.

a. TSH stimulation method for I-124 PET/CT
The method of stimulating the patient’s TSH in preparation of scanning may be an

important factor. For example, Van Nostrand et al.(17) showed that more patients were
positive on I-124 PET/CT after THW (63% [10/16]) than after rhTSH (29% [7/24]). Also, a
greater number of foci was detected on THW than rhTSH I-124 PET/CT (117 versus 17
lesions). In addition, de Pont et al. (3) reported a smaller percentage of discordant results
between I-124 PET/CT and post-therapy I-131 scanning in patients who were prepared
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with THW compared to rhTSH. In their study, partial or complete discordance was seen in
43% (6/14) of patients who underwentTHW and 67 % (4/6) of patients who received
rhTSH. Wu et al. (20) reported one patient with diffuse lung metastasis who underwent
two sets of I-124 PET/CT scans performed 2 months apart. In this patient, no discrete
nodular uptake was seen on the I-124 PET/CT under rhTSH stimulation, but two of the
largest nodules were seen after THW. Therefore, it is also important to specify whether
different TSH stimulation methods were used to compare I-124 PET/CT and I-131 scans
(15).
In kinetic studies of lesional absorbed dose to administered activity ratio (LDpA)

with I-124-PET/CT under rhTSH and THW stimulation, the mean LDpA under THW was
almost twice that of rhTSH (51.8 Gy/GBq in 66 iodine-avid metastases versus 30.6 Gy/GBq
in 71 iodine-avid metastases) (21). Even though this difference (21.2 Gy/GBq; 95% CI, +51
to -9 Gy/GBq) was not statistically significant, the trend is that rhTSH has a lower LDpA
than THW in metastatic lesions. However, this study was a comparison between two
different groups of patients. A study by Plyku et al. (22) compared LDpA within the same
Page 16 of 44
16
patients in which three patients underwent THW and rhTSH I-124 PET/CT at least one
month apart. They found that the absorbed dose per unit administered activity was
higher in the THW study than in the rhTSH study. The ratios of the average tumor
absorbed dose after THW compared to rhTSH ranged from 1.4 to 27.
Given the above differences between rhTSH versus THW in I-124 PET/CT imaging,
this could be a possible explanation for the poor detection rate of I-124 PET/CT when
compared to post-therapy I-131 scans in some studies. For example, in the study by Kist et
al., all patients received rhTSH stimulation for I-124 PET/CT, but received THW for post-
therapy I-131 scan (15).
b. Administered activity of I-124 and I-131
Most studies administered 74 MBq (2 mCi) of I-124 for diagnostic imaging. One
case report administered an activity as low as 15 MBq (0.4 mCi) of I-124 (23), while
activities as high as 222-284.9 MBq (6-7.7 mCi) of I-124 were used in a case series (1). Due
Thyroid
to the limited literature and wide heterogeneity between studies, no definitive conclusion
can be made regarding administered activities of I-124. Future studies are warranted to
evaluate the effect of different I-124 activities on image quality. Furthermore, in this
review, the diagnostic I-131 scans were performed with 37–74 MBq (1-2 mCi) of I-131.
However, the range of I-131 activity administered prior to the post-therapy I-131 scans
ranged widely from 1 GBq (27 mCi) (16) to 20 GBq (541 mCi) (4). Therefore, we need to be
cautious when directly comparing the lesion detection rate of post-therapy I-131 scans
between each publication.
The stark difference in the amount of prescribed activity to obtain I-124 PET/CT and
post-therapy I-131 scans may be one of the reasons for lower lesion detection rate on I-
124 PET/CT in selected subgroups of DTC patient, such as in patients previously treated
with I-131 and in patients with more aggressive pathologies. The major effect of the
prescribed activity on the quality of radioiodine imaging has been shown by a Wells et al.
(24) publication where the post-therapy I-131 scan may be positive in as many as 25% to
80% of patients with a negative diagnostic radioiodine scan. Furthermore, Khorjekar et
al.(14) has shown that up to 83% (10/12) of DTC patients with a negative diagnostic I-124
Page 17 of 44
17
PET/CT may still have a positive post-therapy I-131 scan. With all other imaging
parameters constant, a higher prescribed activity usually yields a higher lesion detection
rate (25). Therefore, further studies are needed to evaluate the lesion detection rate of I-
124 PET/CT in selected subgroups of DTC patients utilizing higher I-124 activities than the
currently used 74 MBq (2 mCi).
c. I-124 PET/CT scan initiation time and acquisition time

The rate of lesion detection varies by the day of I-131 imaging after administration
of I-131 (26), so likewise, the I-124 PET/CT scan will also have varying rates of detection
when imaged at different time points after administration of I-124. Wu et al. (20)
evaluated 14 sets of 5 time points (2 h, 24 h, 48 h, 72 h and 96 h) for 13 DTC patients highly
suspected of metastatic disease. They found that a total of 37 lesions suspicious for
metastasis were identified on I-124 PET/CT, of which eight were seen on the 2 h scan, 22
at 24 h, 30 at 48 h, 28 at 72 h, and 27 at 96 h. The 48 h scan yielded a significantly greater
number of distant metastases. As further support that 48 h may be the optimal imaging
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time, Pettinato et al. (9) and Gulec et al. (13) showed that the 48 h I-124 PET/CT images
correlated well with post-therapy I-131 WBS.
In regard to duration of acquisition, the majority of studies in this review had

similar PET acquisition times of 4-5 min per bed position. Only Pettinato et al. imaged 3 to
4 bed positions with a duration of 15 min each. Lee et al. had an acquisition time of 3 min
per bed frame. Kist et al. did not specify their acquisition time. Although comparisons
between acquisition times should be made, there are too many confounding factors
between these studies to make a fair conclusion. Future studies are warranted to compare
administered I-124 activity, time of imaging from administration of I-124, and image
acquisition times for I-124, I-123, and I-131.
d. I-124 PET/CT in I-131 therapy naïve versus non-naïve patients

A factor that may affect the detection rate of I-124 PET/CT in the literature is
whether the study included only I-131 therapy naïve patients, only non-naïve patients, or a
mixed group of patients. In the reviewed studies, I-124 PET was either performed in post-
Page 18 of 44
18
surgical patients as initial evaluation, or performed in I-131 treated patients suspected of
recurrent or metastatic disease.
For comparison of the lesion detection rate of I-124 PET/CT to diagnostic

radioiodine scanning between naïve versus non-naïve patients, there was no study that
just looked at naïve patients. All five diagnostic I-131 scan studies were performed in I-131
therapy non-naïve cohorts (6-8, 10, 17). These five studies uniformly showed that I-124
PET/CT is better than diagnostic radioiodine scanning in non-naïve cohorts.

We observe that compared to the I-131 therapy naïve cohorts, the lesion detection
rate of I-124 PET/CT in cohorts of non-naïve patients with suspected or known advanced
disease is lower (5, 14, 15). Studies in cohorts of only I-131 therapy naïve patients that
compared I-124 PET to post-therapy I-131 scans included the work by Freudenberg et
al.(11) and Capoccetti et al.(12); studies that analyzed a heterogeneous cohort included
the one by de Pont et al.(3), Ruhlmann et al.(16), and Gulec et al.(13). This observation
may be due to a relative increase in the proportion of dedifferentiated thyroid cancer cells
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in metastatic lesions as previous I-131 therapies eradicated radioiodine sensitive

differentiated cells or as disease progression towards poorly differentiated variant or
anaplastic transformation. However, the clinical utility of I-124 PET/CT in I-131 therapy
naïve patients may be low due to the lower incidence of distant metastasis in I-131 naïve
patients. Until the higher cost of I-124 per MBq or mCi decreases (13), it may be more
economical to perform I-123/I-131 diagnostic scans in the initial patient assessment, and
to perform I-124 PET in patients with suspected recurrent and metastatic disease.
e. I-124 PET in various DTC histology

Few studies reported on aggressive variants of thyroid cancer (5, 9, 12, 16).
However, of those that did report the histology, the trend was that I-124 PET/CT imaging
may be less useful in aggressive histologies with increased false negatives on I-124 PET
images. Of these studies, Pettinato et al. (9) reported that in three tall cell variant PTC and
one Hürthle cell cancer 4/4 were negative on I-124 PET/CT and 3/3 were negative on the
post-therapy I-131 WBS. Lammers et al. (5) reported one Hürthle cell cancer that was false
negative on I-124 PET/CT. Capoccetti et al. (12) reported 4 Hürthle cell carcinomas, as well
Page 19 of 44
19
as 1 clear cell, 1 tall cell and 3 sclerosing variant PTC, and Ruhlmann et al. (16) reported 7
poorly differentiated thyroid carcinomas, but no individual data were available. As I-124
PET/CT is not widely available and the number of patient studies is small, future studies
should also separate the results of patients by histology.
f. I-124 PET in patients with disseminated lung metastases

I-124 PET may have poor performance in the detection of disseminated miliary lung
metastases. In four such patients who had a positive diagnostic or post-therapy I-131 WBS,
Kist et al. (15), Capoccetti et al. (12) and Gulec et al. (13) reported that all four cases were
negative on I-124 PET/CT. Freudenberg et al.(4) retrospectively analyzed 70 consecutive

patients with advanced DTC and found that only 1/7 patients with disseminated lung
disease had visible uptake on I-124 PET . However, this may be due to confounding factors
such as low I-124 activity or time of imaging as discussed previously. In this study,
disseminated iodine-avid lung metastases were defined as lung metastases positive on
post-therapy I-131 WBS but negative on thoracic CT. In a quantitative analysis of the lung-
Thyroid
to-background (L/B) I-124 uptake ratios, there was a significant difference in the L/B ratio
between disseminated lung metastases and the control group (0.92±0.31 vs. 0.41±0.13;
p<0.001). Freudenberg et al. (27) suggested that the L/B ratio in I-124 PET is a useful tool
for early detection of disseminated lung metastases and can be done as part of I-124 PET
dosimetry. However, the L/B ratio should not be used alone due to overlapping scores.
Despite the non-diagnostic quality of the attenuation CT, Freudenberg et al. states that an
independent interpretation of the attenuation CT is important to improve the detection of
disseminated lung metastasis on I-124 PET/CT. Additional methods to improve the
detection of disseminated lung metastasis on I-124 PET/CT is needed.
g. I-124 PET in 18F FDG PET positive patients

A higher percentage of 18F-FDG PET positive patients in the study cohort can
decrease the I-124 PET positivity in patients; however, a positive 18F-FDG PET scan does
not exclude positive I-124 PET uptake. The presence of FDG PET uptake is not mutually
exclusive with the presence of I-124 PET uptake: 23/31 lesions in Freudenberg et al.(11),
23/76 lesions in Freudenberg et al.(28), 7/46 lesions in Gulec et al.(13) and 1/1 lymph node
lesion in the study by de Pont et al.(3) were I-124(+)FDG(+) out of the true positive lesions
Page 20 of 44
20
based on the study reference standard. In these four articles, a total of 54/155 lesions had
both positive I-124 PET and 18F FDG PET uptake.
Based on the articles in this review, some patients with a negative I-124 PET scan
and positive 18F FDG scan [I-124(-)/FDG(+)] may still be amenable to I-131 therapy. Lee et
al. (10) and Freudenberg et al. (28) showed that 4/4 patients with I-124(-)/FDG(+) lesions
treated with I-131 alone achieved regression. Interestingly, the regression achieved was as
long as 9-22 months. Therefore, I-124(+)/FDG (+) or I-124(-)/FDG (+) scans should not
automatically preclude a further attempt at I-131 treatment.
Future studies should be considered to compare the 18F-FDG SUVs in this subgroup
of negative diagnostic radioiodine scans to help distinguish patients who may still benefit
from I-131 treatment to those who are truly radioiodine refractory. Moreover, future
studies can evaluate the utility of both I-124 PET and 18F-FDG PET in providing additional
diagnostic localization of metastasis in patients who have negative I-123/I-131 diagnostic
scans, and in helping to make I-131 treatment decisions.
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Discussion
This report is a comprehensive review of the clinical diagnostic value of I-124 PET as
compared to conventional diagnostic and post-therapy radioiodine scans. In comparison
to a previous systematic review by Santhanam et al.(2) that evaluated five studies in the
meta-analysis; we reviewed a larger number of studies — five diagnostic studies and ten
post-therapy studies. The scope of this review has been expanded to include low-dosage
diagnostic I-123/I-131 scans as the reference standard since the radioisotope activities
(e.g., 37 MBq or 2 mCi) used are comparable to the low activities used in I-124 PET
imaging. Diagnostic radioiodine scans were included in this review because they are
recommended by the ATA guidelines to identify radioiodine avid lesions in select groups of
patients during follow-up (29). This report is more inclusive of published data as it is
difficult to reconcile the heterogeneous reported patient cohorts and distinct institutional
radioiodine scan protocols. Therefore, this review included both radioiodine naïve and
post-therapy patients; the latter groups of patients were excluded in the previous review
(2). In addition, this report determined the diagnostic accuracy of I-124 PET by individual
Page 21 of 44
21
lesion analysis. Hence, studies with insufficient data for patient-based analysis were still
included if they had sufficient data for lesion-based analysis, and vice versa. Finally, we
reviewed the impact of I-124 PET on cancer staging and management.
Lesion detection rate on I-124 PET is significantly greater compared to planar

diagnostic I-131 scans and may have better detection compared to post-therapy I-131 in
patients who are I-131 therapy naïve, have less aggressive pathology, or do not have
disseminated lung metastases. Likewise, in a preliminary study by de Pont et al. (3), the
lesion detection rate on I-124 PET/CT was better than posttherapy I-131 SPECT/CT.
However, further comparison with SPECT/CT is warranted.
Moreover, the low diagnostic activities of I-124 PET have less side effects than a
diagnostic 1.11 GBq (30 mCi) exploratory scans (30) or the posttherapy scans obtained
after higher therapeutic activities of I-131. The radiation exposure of 5–10 mSv from the
administration of 50–100 MBq (1.4-2.7 mCi) of I-124 compares favorably with the 60 mSv
after receiving 1000 MBq (27 mCi) of I-131(31).
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Furthermore, the presence of FDG PET uptake is not mutually exclusive with the
presence of I-124 PET uptake and should not automatically preclude further I-131 therapy.
However, I-124 PET/CT has a lower detection rate in patients previously treated with I-131
and in patients with more aggressive pathologies. This suggests that diagnostic studies
with higher radioiodine activities such as a 1.11 GBq (30 mCi) (30) or a “blind” I-131
therapy may help in lesion detection. In addition, 18F-FDG PET might have increased
diagnostic utility in these patients for lesion detection.
More research has been focused on I-124 lesional dosimetry using PET/CT to
quantify I-131 uptake in each lesion (22, 32). Lesional dosimetry can help determine
whether a sufficient radiation dose can be delivered to a lesion for a specific administered
activity of I-131, as well as helping to quantify whether or not there is an increase in
radioiodine uptake after administration of new medications such as MAPK/ERK kinase
(MEK) or MEK-like inhibitors or other chemotherapeutic agents (33, 34). The use of I-124
PET will gain even more utility as more targeted medications are being developed for DTC
and more knowledge is gained from kinetic studies.
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Future directions
Future research should, among others, address the following topics:
 Comparison between I-124 PET/CT and I-131 SPECT/CT.

 Optimize the imaging techniques to improve image quality for I-124 PET/CT,
such as I-124 activity, time of imaging, duration of image acquisition, and decay
of I-124, I-123 and I-131.
 Evaluate the diagnostic value of I-124 PET/CT in various disease staging risk
groups.
 Comparison of I-124 PET/CT and 18F FDG PET/CT in patients with negative
diagnostic I-123/I-131 scan to help differentiate which patients may still benefit
from I-131 treatment to those who are truly radioiodine refractory.
 Evaluate whether additional lesion detection on I-124 PET/CT leads to altered
management and/or therefore improved long-term outcomes.
Conclusions
Thyroid
I-124 PET imaging is superior to diagnostic I-131 planar imaging in identifying a

greater number of metastatic foci of differentiated thyroid cancer. There is significant
heterogeneity between the ten studies included in this analysis using I-124 in a total of 403
patients on I-124 PET/CT compared to post-therapy I-131 scans. Some of the detection
rate variability between studies may be explained by many confounding factors such as
the method of TSH stimulation, scan initiation time, thyroid cancer histology, presence of
disseminated lung metastasis, and 18F-FDG positivity. However, despite the variability and
confounding factors, I-124 PET is a superior alternative to conventional diagnostic
radioiodine scans and is an option to help determine in advance which patients may
benefit from I-131 therapy. Furthermore, the presence of FDG PET uptake is not mutually
exclusive with the presence of I-124 PET uptake and should not automatically preclude
further I-131 therapy. More studies on I-124 PET/CT are warranted in order to compare it
to I-123/I-131 planar imaging, SPECT/CT imaging and 18F-FDG PET/CT, assessing detection
in various disease staging risk groups, and optimizing I-124 PET/CT imaging.
Page 23 of 44
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Disclosures
Douglas Van Nostrand: Speaker and consultant for Jubilant Draximage.

No competing financial interests exist for the remaining authors.
Funding
This study was underwritten by charitable donations from patients.
Acknowledgements
Thanks to Helen Ann Epstein Brown (Virtua), Christine Neilson (Health Sciences Library,
University of Manitoba), Catherine Arnott Smith (University of Wisconsin-Madison iSchool)
for assistance with the literature search methodology.
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Page 24 of 44
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Table 1. Categories Reviewed
124
G. I PET vs diagnostic 123I/131I imaging
124
H. I PET vs post-therapy 131I imaging.
131
e. I therapy naïve patients.
f. Mixed cohort of 131I therapy naïve and non-naïve patients.
131
g. I non-naïve patients.
h. Patients with positive serum thyroglobulin levels and negative imaging.
124
I. I PET/CT in thyroglobulin <5 ng/ml.
124
J. I PET/CT in pediatrics.
K. Change in staging and management based on 124I PET.
L. Potential factors for different detection rates across studies
a. TSH stimulation method for 124I PET/CT
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124
b. I administered activity
124
c. I PET/CT scan initiation time and acquisition time
124
d. I PET/CT in 131I therapy naïve vs non-naïve patients
124
e. I PET in patients with various DTC histology
124
f. I PET in patients with disseminated lung metastases
124
g. I PET and 18F-FDG PET
Page 30 of 44
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Table 2. Sensitivity and specificity of I-124 PET/CT and diagnostic I-131 imaging in
differentiated thyroid cancer lesion detection.
Time Iso TSH No. By lesion By patient

betwe top stim of
en e ulati foci Neg
Activit
No. admin an on Im det ativ
Aut y and Standar

of istrati d agi ect e
hor, admin Sens Spe Sens d of
pat on of im ng ed pre
yea istrati itivit cifici itivit referen

ien I-124 agi tim dicti
r on y ty y ce
ts and I- ng e ve
route
131 me valu
tho e
d
Pha 20 3 days I- THW 37 – 72 4/1 22.2 NA 27.3 52.9 18 true
Thyroid
n (I-131 13 or 74 h 6 % % % lesions
200 on 1 rhTS MBq (4/1 (3/1 (9/1 based
8 Day 1, wh H (1-2 8) 1) 7) on
(7) I-124 ole mCi), standar
on bo oral d of
Day 4) dy referen
sca ce:
n diagnos
I- 74 24 16/ 77.7 NA 81.8 47.1 tic and
12 MBq h 16 % % % postthe
4 (2 (14/ (9/1 (8/1 rapy I-
PE mCi), 18) 1) 7) 131
T intrav WBS,
enous US, CT,
MRI
and/or
Page 31 of 44
31
cytologi
cal
investig
ation
(fine
needle
aspirati
on
cytolog
y).
Van 25 10 I- 8 37–74 48 48/ 48.5 NA 63.6 77.8 I-131 or
Nos days 13 THW MBq h 97 % % % I-124
tran 1 17 (1-2 (47/ (7/1 (14/ uptake
d wh rhTS mCi), 97) 1) 18) categor
201 ole H oral ized as
Thyroid
0 bo residual
(8) dy thyroid
sca tissue/
n metast
I- 62.9 48 96/ 99% NA 90.9 93.3 asis in
12 MBq h 97 (96/ % % the
4 (1.7 (on 97) (10/ (14/ neck/b
PE mCi), e 11) 15) ed,
T/C oral pat most
T ien likely
t at distant
24 metast
h) asis or
definite
distant
Thyroid
2
Lee
201
(10)
19
10
on
on
124
Day
FDG
Day 2
and I-
(I-131
9 days
n
I-
I-
dy
12
13
bo
wh
before ole
sca
19
THW
(2
74
74
mCi)
MBq
MBq
h
h
24
48
e
0,
5/5
neg
ativ
NA
NA
NA
NA
%
NA
44.4
%
%
3)
(4/1
64.3 by
tic
, if
red
asis
was
were
were
30.7 True-
other
ified).
e, foci
uptake
metast
proven
studies
. When
ed with
gic FDG
availabl
conside
patholo
diagnos
or I-124
positive
positive
(unspec
correlat
imaging
histolog
32
Page 32 of 44
Thyroid
Page 33 of 44
on
11)
Day
T
4
PE
T/C
(2
oral
mCi),
stimulating hormone, WBS, whole-body scan.

)
(4/9
4)
(9/1
y,
ues.
Abbreviations: THW, thyroid hormone withdrawal; rhTSH, recombinant human thyroid-
y, or
other
cytolog
techniq
imaging
33
Page 34 of 44
34
Table 3. Lesion detection of I-124 PET/CT and posttherapy I-131 imaging in differentiated thyroid cancer.
Author, N Time Isotope TSH Activity Imagi No. of Lesion-based analysis Patient-based Standard
eviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
year o. between and stimulat and ng foci analysis of

of administra imaging ion administra time detect Sensitiv Positiv Negati Sensitiv Negati reference
pt tion of I- method tion route ed ity e ve ity ve per each
s 124 and I- predict predict predict article
124 PET/CT versus conventional radioiodine imaging in differentiated thyroid cancer: a review (DOI: 10.1089/thy.2018.0598)
131 ive ive ive

value value value
de Pont 20 1 day post I-131 14 THW 1110-7728 120h 39 62.9% NA NA 94.4% 66.7% Consensu
2013 (3) (I-131 on whole 6 rhTSH MBq (30- (5 (39/62) (17/18) (2/3) s, high
Day 3 body 209 mCi) day) dose CT,
before I- scan US with
124 on I-131 50 80.6% NA NA 94.4% 66.7% cytology,
Day 4) SPECT/C (50/62) (17/18) (2/3) MRI
Thyroid
T and/or
I-124 20-28 MBq 24h, 57 91.9% NA NA 100% 100% FDG
PET/ (0.54-0.77 96h (57/62) (18/18) (2/2) PET/CT
high mCi), oral
Page 35 of 44
35
dose CT
Freudenb 12 Not I-131 11 THW 3000 MBq 5-8 60 84.1% ( 96.7% NA 100% - Consensu
erg specified whole 1 rhTSH (81 mCi) day 58/69) (58/60) (12/12) s, clinical
2004 (11) (I-124 body data,

before I- scan other
131) I-124 84±15 24h 60 87% 100% NA 100% - imaging
PET MBq (60/69) (60/60) (12/12) studies, I-

I-124 (2.27±0.41 70 100% 98.5% NA 100% - 124
PET/CT ), oral (69/69) (69/70) (12/12) PET/CT,
CT, US, 5-
8 day I-
131
postthera
py scan
Freudenb 70 Not I-131 THW 3-20 GBq 6-9 NA NA NA NA NA NA Dissemina
Thyroid
erg 2008 specified whole (81-541 day ted

(4) (I-124 body mCi ) iodine-
before I- scan avid lung
131) metastas
Page 36 of 44
36
es were
I-124 24±2 MBq 24h NA NA NA NA 14.3% 91.3% defined

(63/69) as lung
PET/CT (0.65±0.05 (1/7)

mCi), oral metastas
es
positive
on I-131
WBS but
negative
on
thoracic
CT.
Gulec 15 Not I-131 13 THW 3.7-11.1 5-7 28 70% NA 33.3% NA NA Positive
2016 (13) specified whole 2 rhTSH GBq (100- day (28/40) (6/18) on I-124
(I-124 body 300 mCi) and/or I-
Thyroid
before I- scan 131,

131) I-124 74 MBq (2 2h, 37 92.5% NA 66.6% NA NA regardles
PET/CT mCi), oral 4h, (37/40) (6/9) s of FDG
48h,7 PET/CT
Page 37 of 44
37
2h, and
96h serum Tg.
Refer to
Table 1 in
reference
13
Khorjekar 12 I-131 5 THW Unspecifie 5–7 NA NA NA NA NA NA Semi-

2014 (14) whole 7 rhTSH d day quantitati
body dosimetric ve
scan ally-guided grading
activity scale
I-124 63.9 MBq 2h, NA NA NA NA NA 16.7%
PET/CT (1.7 mCi), 24h, (2/12)
oral 48h,
72h,
Thyroid
96h
Kist 17 Not I-131 17 THW 5.5-7.4 1 14 91.7% 78.6% NA 88.9% 87.5% 12 true
2016 (15) specified whole GBq (149- week (11/12) (11/14) (8/9) (7/8) lesions
(I-124 body 200 mCi) based on
Page 38 of 44
38
before I- scan standard
131) (+SPECT/ of
CT) reference
Prethera 17 74 MBq (2 24h, 8 33.3% 50% NA 44.4% 66.7% : I-131

py I-124 rhTSH mCi), 96h (4/12) (4/8) (4/9) (8/12) WBS
PET/CT intravenou (SPECT/C
I-124 s 8 57.1% NA NA 44% 62% T)

PET/CT (8/14) (4/9) (8/13)
(5
patients
perform
ed after
I-131
therapy)
Lammers 7 Not I-131 2 THW 5.55 or 7.4 7 day NA NA NA NA 100% 100% I-131
Thyroid
2014 (5) specified whole 7 rhTSH GBq (150 (6/6) (1/1) therapy
(I-124 body or 200 whole
before I- scan mCi) body
131) I-124 40 MBq 24h, NA NA NA NA 16.7% 16.7% scan,
Thyroid
Page 39 of 44
2014 (9)
Pettinato
26
Not
(I-124
before I-
specified
scan
body
I-131
whole
PET/CT
7 rhTSH
19 THW
s
1953-
11455
310 mCi)
MBq (53-
(1.1 mCi),
intravenou
72h
96h
NA
NA
NA
NA
(1/6)
100%
(15/15)
(1/6)
100%
I-131
when
with no
and US.
CT, MRI
PET/CT,
Positive
d serum
(11/11) on I-124
Tg levels
al results
and FDG-
e anti-Tg,
stimulate
>2 ng/mL
detectabl
available,
histologic
PET/CT or
39
Page 40 of 44
40
131) I-124 74 MBq (2 4h, NA NA NA NA 100% 100% postthera
PET/CT mCi), oral 24h, (15/15) (11/11) py scan.
48h,
72h
Phan 20 1 day prior I-131 THW or 5550 MBq 10 day 15 77.8% 93.3% NA 90.9% 77.8% Diagnosti
2008 (7) (I-124 on whole rhTSH (150 mCi) (14/18) (14/15) (10/11) (7/9) c and
Day 4 body postthera

before I- scan py I-131-
131 on I-124 74 MBq (2 24h 16 77.8% 87.5% NA 81.8% 47.1% WBS, US,
Day 5) PET/CT mCi), (14/18) (14/16) (9/11) (8/17) CT, MRI
intravenou and/or
s cytologica
l
investigat
ion (fine
Thyroid
needle
aspiration
cytology,
FNAC).
Thyroid
Page 41 of 44
n
Ruhlman
2016 (16)
7
13
Not
131)
(I-124
before I-
specified
T
neck
body
I-124
I-131
whole
PET/CT
SPECT/C
scan and
133
THW
4 rhTSH
oral
mCi)
(27-270
1-10 GBq
20.2-28.5
0.77 mCi),
day
24h,
5-10
MBq (0.55- 120h

223
225
27)
27)
98.2%
99.1%
(223/2
(225/2
NA
NA
NA
NA
95.2%
98.4%
(59/61)
(60/61)
97.4%
98.7%
(76/78)
.
one
124 at
Consensu
I-131 or I-
timepoint
(76/77) s, positive
41
Page 42 of 44
42
Table 4. Change in cancer staging or management by I-124 PET imaging.
First Author n Clinical significance of I-124 PET/CT No. of Explanation

Year patients
journal affected
Appropriate change in management based on I-124 PET*
Capoccetti (12) 67 TNM upstaging prior to I-131 therapy 16% (11/67) Detection of unknown lymph node involvement in 12%
2009 (8/67) and distant metastases in 4% (3/67).

Q J Nucl Med Mol Improved anatomical localization even when 3% (2/67) I-124 PET/CT was able to distinguish between lymph
Imaging the same number of lesions were detected node involvement versus thyroid remnant.
by I-131 posttherapy whole body scan
de Pont (3) 20 TNM upstaging (not visualized by I-131 15 % (3/20) Detection of unknown lymph node involvement in 10%
2013 posttherapy whole body scan + SPECT/CT) (2/20) and distant metastases in 5% (1/20).
Eur J Nucl Med
Mol Imaging
Thyroid
Freudenberg (11) 12 TNM upstaging 16.7% Detection of unknown primary tumor extension in 8%
2004 (2/12) (1/12) and lymph node involvement in 8% (1/12)
Eur Radiol Change in management – additional surgery 8% (1/12) Additional surgery for lymph node metastasis
Freudenberg (19) 28 Change in management - reduced I-131 18% (5/28) Confirmed disease-free status in 3 patients, and non-
Page 43 of 44
43
2007 therapy activity functional disease in 2 patients.
Nuklearmedizin Change in management – increased I-131 25% (7/28) I-124 PET dosimetry findings allowed patients to
treatment activity receive I-131 activities above the standard empiric

activity.
Change in management - early multimodal 25% (7/28) Other treatment modalities for non-functional disease
therapy for non-avid disease in 2 patients; additional neck surgery for inadequate
radioiodine uptake in locoregional disease for 5

patients.
Change in management – altered sequence 7% (2/28) Local therapy for large bone metastasis prior to I-131
of multimodal therapy treatment
Lee** (10) 19 TNM upstaging 21% (4/19) Disease management was modified in 1 (5.3%)
2012 Change in management - surgery 5% (1/19) Additional surgery for lymph node metastasis with
Korean Med Sci high activity I-131 treatment
Inappropriate change in management based on I-124 PET*
Kist (15) 17 rhTSH-stimulated I-124 PET/CT is not suited 29% (5/17) Due to the high false negative rate (38%; 5/13), I-124
Thyroid
2016 to avoid futile blind I-131 therapy PET/CT would have withheld potentially beneficial I-
J Nucl Med 131 therapy.
*Whether the change in management was appropriate or not was based upon the original article.
** Lee et al. includes combined data with FDG PET/CT positive patients.
Thyroid
Figure Legends
Figure 1. PRISMA diagram.

44
Page 44 of 44

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Thyroid

I-124 PET/CT versus conventional radioiodine imaging in

differentiated thyroid cancer: a review

Dorina Ylli, MD, PhD1,3

2A72, Washington, DC 20010

2A62, Washington, DC 20010

Douglas Van Nostrand, MD 1,2

Douglas Van Nostrand, MD, FACP, FACNM

Director, Nuclear Medicine Research

Professor of Medicine, Georgetown University School of Medicine

MedStar Health Research Institute

MedStar Washington Hospital Center

110 Irving Street, N.W. Washington, D. C. 20010

Running title: I-124 PET/CT versus I-131detection

Douglas Van Nostrand: Speaker and consultant for Jubliant Draximage.

No competing financial interests exist for the remaining authors.

This study was underwritten by grants from grateful patients.

Methods: A literature search was performed using multiple different databases

Conclusion: I-124 PET/CT is able to identify a greater number of foci compared to

data. Any disagreements were resolved by consensus.

A. Detection of I-124 PET compared to diagnostic I-123/I-131 imaging

Finally, in a conference abstract, Abdel-Nabi et al.(6) prospectively demonstrated in

B. Detection of I-124 PET compared to post-therapy I-131 imaging

b. In mixed cohort of I-131 therapy naïve and non-naïve patients

approximately 1% of the therapeutic activity of I-131, may be sufficient to achieve a high

c. In I-131 non-naïve patients

The superiority of I-124 PET/CT scan as compared to post-therapy I-131 WBS at 72

However, in a retrospective review of seven I-131 post-therapy patients with

d. In patients with positive serum thyroglobulin levels and negative imaging

This was further supported by a prospective multicenter observational cohort study

C. I-124 PET/CT in thyroglobulin <5 ng/ml

post-therapy I-131 scan in most patients.

D. I-124 PET/CT in pediatrics

E. Change in staging and management based on I-124 PET

in altering tumor staging and disease management.

F. Potential factors for different detection rates across studies

of these are discussed below.

The method of stimulating the patient’s TSH in preparation of scanning may be an

In kinetic studies of lesional absorbed dose to administered activity ratio (LDpA)

therapy I-131 scan (15).

b. Administered activity of I-124 and I-131

c. I-124 PET/CT scan initiation time and acquisition time

In regard to duration of acquisition, the majority of studies in this review had

d. I-124 PET/CT in I-131 therapy naïve versus non-naïve patients

For comparison of the lesion detection rate of I-124 PET/CT to diagnostic

PET/CT is better than diagnostic radioiodine scanning in non-naïve cohorts.

in metastatic lesions as previous I-131 therapies eradicated radioiodine sensitive

e. I-124 PET in various DTC histology

f. I-124 PET in patients with disseminated lung metastases

negative on I-124 PET/CT. Freudenberg et al.(4) retrospectively analyzed 70 consecutive

g. I-124 PET in 18F FDG PET positive patients

reviewed the impact of I-124 PET on cancer staging and management.

Lesion detection rate on I-124 PET is significantly greater compared to planar

However, further comparison with SPECT/CT is warranted.

 Comparison between I-124 PET/CT and I-131 SPECT/CT.

I-124 PET imaging is superior to diagnostic I-131 planar imaging in identifying a

Douglas Van Nostrand: Speaker and consultant for Jubilant Draximage.

No competing financial interests exist for the remaining authors.

This study was underwritten by charitable donations from patients.

Positron Emission Tomography Imaging in the Management of Patients with

2. Santhanam P, Taieb D, Solnes L, Marashdeh W, Ladenson PW 2017 Utility of I-124

PET/CT in identifying radioiodine avid lesions in differentiated thyroid cancer: a