Vannostrand2018 PDF

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© Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2018.0048
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Radioiodine Refractory Differentiated Thyroid Cancer: Time to
Update the Classifications
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.
Douglas Van Nostrand, MD
Director, Nuclear Medicine Research
MedStar Health Research Institute and Washington Hospital Center

Radioiodine Refractory Differentiated Thyroid Cancer: Time to Update the Classifications (DOI: 10.1089/thy.2018.0048)
Downloaded by Thomas Jefferson University from www.liebertpub.com at 08/24/18. For personal use only.
Corresponding author:
Suite GA60F
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110 Irving Street, N.W.
Washington, DC 20010
(202) 877-0300
Douglas.Van.Nostrand@medstar.net
douglasvannostrand@gmail.com (preferred)
Running Head
Radioiodine Refractory DTC
Key words
Radioiodine refractory, 131I, Radioiodine therapy, differentiated thyroid cancer,

Classifications
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ABSTRACT
The management of aggressive and progressing metastatic differentiated thyroid cancer
(DTC) is very difficult, and the determination as to when such patients are refractory to 131
I therapy (e.g. radioiodine refractory) is problematic and controversial.
Objective:
The objective of this review is to discuss 1) the present major classifications of radioiodine
refractory disease in DTC, 2) factors that should be considered before designating a
patient’s DTC as radioiodine refractory, 3) potential approaches and caveats to help

manage and minimize a patient’s exclusion from an 131I therapy that may have potential
benefit in patients with aggressive and progressing metastatic DTC, 4) next steps for
revision of the classifications of radioiodine refractory DTC, and 5) areas for future
research.
Summary
To date, the classifications of radioiodine refractory DTC, although very useful, are
not sacrosanct especially in the context of individualized patient management, and merely
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because a patient meets one or more of the various classifications, one should not
consider by definition, fiat, or de facto that that a patient’s DTC is radioiodine refractory.
Rather, each patient should be individually managed with a good understanding of the
limitations of the various classifications and potential approaches to help manage that
patient. With awareness of the suggestions and caveats discussed herein and with
assessment of the many other factors that affect the patient’s specific clinical situation,
the managing physician can deliver appropriate individualized patient care. A multi-
organizational committee should be established as a standing committee to supervise and
assist in the update of the classifications of radioiodine refractory DTC including
discussions of their limitations.
Conclusion
Classifications how to define radioiodine refractory disease will continue to evolve as
1) more studies are published, 2) managing physicians better understand the limitations
and confounding factors of present classifications, and 3) new agents either increase or
re-establish I-131 uptake.
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INTRODUCTION
131
I is one of the most important treatment options for patients with distant
metastatic DTC, and when a patient no longer responds to 131I treatment (i.e., radioiodine
refractory), additional therapeutic options are available including tyrosine kinase inhibitors
(TKIs). Although most physicians will agree that a patient who is radioiodine refractory
should not receive any further 131I treatment, the actual classification of a patient as
radioiodine refractory is problematic and controversial. In order to determine when a

patient will no longer respond to 131I, multiple classifications have been described to
categorize a patient as radioiodine refractory to spare the patient from the possibly
untoward effects of an 131I treatment with little to no benefit. However, the classifications
of radioiodine refractory DTC need to be updated. This is important because patients who
have aggressive and progressing metastatic DTC have access to a diminishing set of
therapeutic options, and I would submit that no treating physician has the intent of
inappropriately eliminating a treatment option that has the possibility of achieving a
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reasonable period of progression-free survival with acceptable side effects. The objective
of this article is to review the following: 1) the development of the major classifications of
radioiodine refractory DTC, 2) multiple present classifications of radioiodine refractory
DTC, 3) the supporting sources and literature of those classifications, and 4) the limitations
of those classifications. This review closes proposing 1) next steps for updating the
classifications of radioiodine refractory DTC, 2) potential approaches and caveats to help
manage and minimize a patient from being excluded from an 131I therapy that may have
potential benefit, and 3) future areas for research.
The Development of Classifications of Radioiodine Refractory DTC

First, I respectfully acknowledge and compliment the many individuals from many
institutions and committees for their pioneering time and energy in the initial
development of classifications to help better determine which patients with DTC are and
are not radioiodine refractory [1,2].
One of the initial efforts to classify radioiodine refractory disease was by an international
panel of experts in September 2010 during the 14th International Thyroid Congress in Paris,
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France [1]. Attendees were a member of at least one of the following organizations: the
American Thyroid Association (ATA), the European Thyroid Association, Latin American
Thyroid Society, and the Asia Oceania Thyroid Association. Funding was provided by Bayer
HealthCare Pharmaceuticals, and the authors affirmed that the content was not influenced
by the sponsor. The panel classified radioiodine refractory DTC (Supplement Table 1) and
stated that the situation became more problematic when there were mixed responses to
131
I. A subsequent international panel of experts gathered in September 2012 in Pisa, Italy
with their classification published in 2014 (Supplement Table 2) [2]. In addition, they
proposed an algorithm as follows: “Once one or more metastatic lesions fail to take up
radioactive iodine and continue to grow, these patients are considered refractory and
radioactive iodine treatment is abandoned. For such patients, alternative systemic therapy
is considered when both the tumour burden is substantial and tumour progression is
documented” [2]. The above panel in Pisa was conducted by SciStrategy Communications
and supported by Bayer HealthCare Pharmaceuticals. The two classifications from the
two panels have frequently been referenced by other articles discussed below, and these
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panels represent primary initial sources for classifications of radioiodine refractory DTC.
Tuttle et al. [3] in 2014 proposed definitions of radioiodine refractory DTC (Supplement
Table 3). The authors advise that “. . . while not definitively classifying a patient as being
completely refractory to RAI, the . . . clinical factors [Supplement Table 4] make it much less
likely that RAI therapy will achieve a clinically significant therapeutic response.”
Sacks et al. [4] classified radioiodine refractory DTC (Supplement Table 5). Of note,
the lack of radioiodine avidity after even a diagnostic radioiodine scan in one or more
lesions was considered radioiodine refractory disease. Sacks et al. further stated that
“Generally speaking, we recommend that the definition of RAI–refractory DTC be based on
clinical evidence or on imaging data showing at least one lesion that does not take up RAI
and thus encompasses both truly refractory disease as well as resistant disease [4].”
In early 2016, the ATA published their 2015 guidelines classifying radioiodine
refractory disease in Recommendation 91 (Supplement Table 6) [5].
The classifications for radioiodine refractory in the prescribing information for
sorafenib (Nexavar®) [6] and lenvatinib (Lenvima®) [7] are also available in Supplement
Tables 7 and 8, respectively.
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Distilled Classifications
The distilled classifications are noted in Table 1.

Literature Support for Classifications
The literature supporting the cited classifications are limited to a few citations
[1,2,8]. Although not all citations will be discussed herein, key references in the ATA
guidelines comprise Schlumberger et al. [2], which is the report of the 2012 panel, and
Brose et al. [1], the report of the 2010 panel. Both are frequently cited in other articles.
Vaisman et al. [Error! Bookmark not defined.], who were also referenced, provide some
citations in support of the classifications, but the support offered by these citations is
limited. Of note, however, Vaisman et al. [9] discuss more extensively than the ATA some
of the limitations to be considered when classifying a patient’s DTC as radioiodine
refractory. Durante et al. [8] propose that patients should be treated until the
disappearance of any uptake or until a cumulative 131I activity of 22 GBq (600 mCi) had
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been administered. The single administered prescribed activity was typically 3.7 GBq (100
mCi). However, Durante et al. [8] report that 4% of patients achieved negative diagnostic
131
I scans with a cumulative activity higher than 22.2 GBq (600 mCi). Although this finding
has been taken to suggest that a patient who has received over 22.2 GBq (> 600 mCi) of
131
I most likely is radioiodine refractory DTC, I would draw from the finding that this
classification is not sacrosanct and that a better classification would be whether there is an
adequate and durable response, which I discuss later. As with many of the articles
involving controversial areas of the management of DTC, there are no good prospective
studies, and each study has its own limitations. As an example, the retrospective study by
Durante et al. [8] used dual probe rectilinear scanners for imaging from 1971 until 1994.
This is understandable, but this inferior camera technology is still a limitation Sabra et al.
[10] state that despite radioiodine-avid disease, 131I therapy is ineffective in achieving a
cure in most patients. Sabra et al. [11] have also been referenced regarding patients with
negative diagnostic scans and positive-post-therapy scans that would most likely be
radioiodine refractory. However, 44% (12/27) of patients with DTC, negative “properly –
conducted” diagnostic scans, and positive post-therapy scans had stable cross-sectional
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imaging after 131I therapy. Whether this is due to the therapeutic effect of the 131I therapy
or the patient’s natural course of their disease is not known, but this result would argue
against the statement by the ATA that “. . . Patients with measurable disease with an
absence of 131I uptake on subsequent diagnostic WBS may also be considered refractory
because even when uptake is seen on post-therapy scan, it will likely have limited benefit.”
The remaining 56% of patients studied by Sabra et al. [11] demonstrated structural disease
progression with empiric activities, and the authors concluded, “. . . in this small subset of
patients with persistent progressive disease despite a positive-post-therapy RAI scan

argues that treatments other than repeated empiric 131I dosing be strongly considered.” I
have emphasized empiric and submit that this was not necessarily an argument that the
patients were radioiodine refractory, but rather another possibility is insufficient empiric
131
I activity. Half of the patients received an 131I activity of < 5.55 GBq (150 mCi).
Limitations of the Cited Classifications
Before discussing the limitations of the classifications, I would like to emphasize

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that I am in full agreement that any patient who meets one or more of the above
classifications has a significantly higher likelihood of being radioiodine refractory than a
patient who does not meet one of these classifications. I also agree with the statement
that when a patient is truly radioiodine refractory, then that patient should not receive any
further 131I. However, the issue is when is the patient truly radioiodine refractory, and I
do not believe that the current classifications are necessarily sufficient evidence for
establishing radioiodine refractory disease. In addition, and most importantly, I believe
that authors of recent articles discussing the various proposed classifications of
radioiodine refractory DTC are not necessarily discussing in sufficient detail the factors and
limitations of the classifications that have been previously considered [1,3]; in some
articles, in fact, discussion of the factors and limitations have been completely eliminated
[12,13 ,14, 15,16,17]. This in turn—intended or unintended—tends to reinforce the notion
that these classifications are somehow cast in stone. Thus, I view with concern the
gradual abandonment of limiting factors as a vital part of the context within which we
discuss the classifications of radioiodine refractory DTC. The mere fact that those authors
choose to ignore these factors in their work does not convey the classifications are based
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on evidence. Creditably, some authors, for example Tuttle et al. [3] and Cabanillas et al.
[18], continue to discuss at least some of the limitations. Accordingly, the discussion of
these factors and limitations of the classifications of radioiodine refractory disease is one
of the main objectives of this article.
Although physicians in academic settings and at large institutions may routinely
treat patients with aggressive and progressing metastatic DTC, many patients are managed
by physicians who only treat several such patients a year, if that, and it is difficult for these
physicians not only to stay up to date with the various guidelines, but also to stay up to
date regarding the limitations of the classifications of radioiodine refractory disease.

Without detailed discussion of the limitations, the classifications—again, intended or
unintended—may be accepted at face validity. In this section, therefore, I discuss selected
classifications that appear in one form or another in the various articles, guidelines, and/or
prescribing information. I further thrash out why these classifications are not infallible and
why, therefore, they should not be used in such a manner as to confer certainty that the
patient’s DTC is radioiodine refractory. Finally, although it is inevitable and appropriate
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that research studies produce and require strict classifications, such classifications are
again not sacrosanct. Thus, with an absence of a clear understanding of their limiting
conditions, such classifications are only conditionally appropriate for the management of
individualize care.
CLASSIFICATION 1: Malignant/metastatic tissue does not concentrate radioiodine

on a diagnostic radioiodine scan.
Although a negative diagnostic radioiodine scan definitely increases the likelihood
that the patient’s metastases are radioiodine refractory, this classification is problematic
for many reasons. Wells et al. [19] reviewed 12 articles and reported her institutional
experience. She showed that in patients with a negative diagnostic radioiodine scan, the
post-131I therapy scan may be positive in as many as 25% to 80% of patients (see Table 2)
[20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]. As already discussed above, I believe that the
2015 ATA Guidelines [5] discount this finding without merit by stating “[P]atients with
measurable disease with an absence of 131I uptake on subsequent diagnostic [whole body
scans] may also be considered refractory because even when uptake is seen on post-
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therapy scan, it will likely have limited benefit.” The problem is that the authors do not
amplify or even discuss the many factors that affect a diagnostic radioiodine scan; they
simply leave the inference that a negative diagnostic scan despite the presence of a
positive post-131I therapy scan is essentially prima facie evidence for radioiodine refractory
disease. This, however, is not the case. Sanctioning the classification of a patient with
measurable disease and negative diagnostic scan even with a positive post-therapy scan as
radioiodine refractory disease may inappropriately eliminate a potential useful treatment
in a patient who is typically running out of options. In the wide spectrum of patients who
may have negative radioiodine scans and positive thyroglobulins, I am again speaking of
patients with aggressive and progressing metastatic DTC. In fact, the statement of “. . .
even in the presence of a [positive] post-therapy scans . . .” argues that the patient with a
negative diagnostic radioiodine scan may in fact be radioiodine responsive. In short, there
are factors that may affect whether the radioiodine diagnostic scan succeeds in detecting
radioiodine-avid metastatic disease; these factors, therefore, deserve to be addressed, but
they rarely are.
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The factors that can affect whether a diagnostic radioiodine scan will detect
metastatic disease include categories of preparation, prescribed activity, and imaging
technique.
First, preparation is paramount and, as already noted in the 2015 ATA guidelines [5],
excessive intake of recent stable iodine (127I) (e.g., contrast, amiodarone, kelp, etc.) may
result in a negative diagnostic radioiodine scan by blocking the uptake of the radioiodine in
the metastases. However, I submit that other than a history from the patient of no recent
iodine load, some facilities do not confirm that there has been no recent excessive iodine
load with either a spot urine iodine measurement, spot urine iodine/creatinine ratio, or a
24-hour urine iodine collection. Although a recent article by Vassaux et al. [31] presents
data that may indicate that the measurements of urine iodine levels may not be accurate,
until this is confirmed, I believe this is reasonable to measure urinary iodine
concentrations. Likewise, Vaisman et al. [9] note that it is also important to assure
adequate elevation of the patient’s TSH after thyroid hormone withdrawal. A physician
could inappropriately classify a patient’s DTC with a negative diagnostic radioiodine scan
as radioiodine refractory if the TSH is not appropriately elevated. One might just assume
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an assurance that the patient has not had an excessive intake of stable iodine and that the
TSH is elevated sufficiently, but this is not necessarily the case. Based on personal
experience, I have observed that a large number of practices do not check urine for
excessive iodine load nor TSH levels after thyroid hormone withdrawal.
Second, regarding the prescribed activity of radioiodine, not all radioiodine
diagnostic scans are created equal. Radioiodine scans may be performed with 7.4 – 185
MBq (0.2 to 5 mCi) of 123I or even higher activities of 131I, which can make a significant
difference [32]. Specifically, the higher the prescribed activity with all other parameters
constant, the higher the detection rates of radioiodine-avid metastases, thereby reducing
the likelihood that that patient is falsely classified as non-radioiodine avid, and hence,
radioiodine refractory. With the hope for future approval of 124I, the literature already
has demonstrated the superiority of this positron-emitting isotope of iodine and the use of
positron emission cameras to deliver images that are superior for the detection of radioiodine-
avid metastatic disease relative to planar and SPECT-CT single photon isotopes (e.g., 123I and
131
I) [33]. However, demonstrating that a metastatic lesion is radioiodine-avid on an 124I scan
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is not in and of itself indicative that it will be responsive to an 131I therapy.

Third, in regard to techniques, this classification assumes that all imaging
procedures for radioiodine imaging are the same. They are not. One should not
automatically assume that a patient is radioiodine refractory because malignant metastatic
tissue, either measurable or non-measurable, does not concentrate radioiodine. A list of
several techniques that enhance the detection of radioiodine-avid lesions is shown in
Table 3, and a full discussion of these techniques with examples as well as a discussion of
how these techniques improve detection are available elsewhere and are not within the
scope of this review [34]. But imaging technique matters!
In summary, a negative diagnostic radioiodine scan is not a sufficient finding to
confirm a classification of radioiodine refractory disease for either measurable or non-
measurable disease. Although all of us believe we deliver quality radioiodine scanning, we
may not do this all of the time in every instance. However, even if a facility is delivering
quality radioiodine scanning and preparation and imaging technique are excellent,
negative diagnostic radioiodine scans cannot be taken as a foolproof data for the
classification of radioiodine refractory disease.
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CLASSIFICATION 2: Malignant tissue does not concentrate radioiodine on a post-
131
I therapy scan.
When malignant tissue is not visualized on a post-131I therapy scan, the patient’s
malignant tissue is indeed most likely radioiodine refractory, and, for many years, this
classification has been one of the best findings to correctly characterize the patient’s
malignant tissue as non-radioiodine-avid, hence, radioiodine refractory. However, this is
not necessarily reliable in all instances, and the managing physician should be aware of the
limitations. As discussed earlier, assuring the quality of the imaging technique is very
important to maximizing the sensitivity of a radioiodine diagnostic scan as well as the post-
131
I therapy scan, and, for the post-131I therapy scan, one of the most critical issues is the
time of imaging the patient after the administration of the therapeutic 131I. Specifically,
Salvatori et al. [35], Hung et al. [36], Lee et al. [37], Chong et al. [38], and Kodani et al. [39]
have reported on the detection of metastases on post-131I therapy scans based on the time
of the scanning from administration of the therapeutic activity, and the data strongly
support that the timing can make a difference in detection of radioiodine-avid metastases.
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Salvatori et al. [35] reported that if the patient was scanned at an earlier or later
time after the administration of an 131I therapy, one may falsely conclude that a
metastasis is radioiodine non-avid when in fact it is radioiodine avid. Salvatori et al. [35]
reported on 134 patients evaluated with two sequential whole-body scans performed
three and seven days after 131I therapy. Late scans provided more information compared
to early scans in 12% (16/134) of patients, and early scans visualized more information
than late scans in 7.5% (10/134) of patients. Again, the fact that the post-131I therapy
scan has radioiodine uptake is not indicative that the patient will respond to 131I therapy.
However, a negative post-131I therapy scan does not necessarily mean that the patient is
non-radioiodine-avid and could not benefit from a (partial) response.
In regard to similar studies, Hung et al. [36] evaluated 239 patients and three
sequential scans were performed on days 3 or 4, days 5 or 6 , and days 10 or 11. Of 122
lesions observed, 28% (18/63) of lymph nodes, 17% (7/41) of lung metastases, and 16%
(3/18) of bone metastases were missed on the late images on 10-11 day scans, and 5% of
remnant tissues were missed on the late images on the 10-11 day scan. They concluded,
“[E]arlier imaging is necessary and important for detection of metastatic lesions in
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patients with DTC.” Lee et al. [37] evaluated 81 patients with two sequential whole-body
scans on three days and 10 days after 131I therapy of which 5% (4/81) of patients had five
additional lesions identified on the delayed scan. The five lesions were located in the lung
(2), cervical lymph nodes (2), and the thyroid bed (1). Of eight patients with increased Tg
levels > 10 ng/ml with negative early scans, the delayed scan identified three patients
with additional lesions. Chong et al. [38] evaluated 52 patients with lung and bone
metastases with early (three days) and delayed (seven days) scans. For lung and bone
metastases, 22% (10/45) and 33% (5/15) were not observed on the early scans, but were
detected on delayed scanning. Kodani et al. [39] evaluated 24 patients with DTC who had
early (day 3) and delayed (7 to 9 days) scans performed and demonstrated that for lung
metastases, 29% (2/7) were only seen on the delayed scan, and for bone metastasis, 20%
(1/5) were only seen on the delayed scan.
Thus, even if a lesion is not visualized on a post-131I therapy scan that does not
mean that the patient is radioiodine refractory. In a later section, I propose potential
approaches to manage these patients.
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In summary, radioiodine imaging technique is also important for post-131I therapy

scans, and for this scan, the interval of the scanning after the 131I therapy can fail to reveal
as many as 12% of patients that have radioiodine uptake. When there is radioiodine
uptake, there is the possibility of a response to an 131I therapy when an appropriate
amount of therapeutic 131I activity is administered, and although the likelihood of a
reasonable therapeutic response is again definitely and significantly reduced, these
patients with aggressive and progressing metastatic DTC should have this potential
treatment option explored. Since a patient with a negative radioiodine diagnostic scan
and either a positive or negative post-131I therapy scan has obviously already been
treated with a “blind” 131I therapy, the key metric becomes progression, which I consider
later. However, for those patients with negative diagnostic radioiodine scans, which
many authors consider a conclusive classification of radioiodine refractory disease,
consideration of a “blind” 131I therapy is an option (discussed later). In short, a negative
post-131I therapy scan is not corroborative evidence of either non-radioiodine-avid
disease or radioiodine refractory disease. Further research is warranted.
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CLASSIFICATION 3: The tumor tissue loses the ability to concentrate radioiodine
after previous evidence of radioiodine-avid disease.
The problem with this classification is that the discussions typically and
ambiguously do not assert whether they are speaking about diagnostic radioiodine
scanning or post-131I therapy scanning. and I submit that for many authors, it does not
matter whether or not it is diagnostic or post-131I therapy. The limitations of both
diagnostic radioiodine scanning and post-131I scanning have been discussed earlier in
Classification 1 and 2 respectively, and as this classification is written should not be a

classification, and if it is, it should have a detail discussion of the limitations.

CLASSIFICATION 4: Radioiodine is concentrated in some lesions but not in others.
By this classification, if a patient has four bone lesions, and three bone lesions have
radioiodine uptake but one lesion does not, then some physicians classify this patient’s
DTC as radioiodine refractory and 131I is not considered an option. However some or many
lesions may still benefit from 131I therapy. For example, why couldn’t the physician potentially treat
the non-functioning bone metastases with targeted treatment options (e.g., surgery,
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radiofrequency ablation, cryotherapy, embolization, external radiation therapy) and then

treat the other three bone metastases with 131I? After members of the ATA and the
reviewers commented on the draft of the 2015 ATA guidelines, the authors of the 2015
ATA guidelines subsequently discussed this context within the text. However, the
guidelines still preface, “While these patients technically meet the definition of RAI
refractory disease, they may benefit from a combination of RAI therapy for the majority of
the lesions and direct therapy for those few lesions that do not concentrate RAI.” Rather
than trying to technically defend the definition of radioiodine refractory as correct, which is
not appropriate for some of the lesions, I propose that one should simply identify the
limitation of that classification. In addition, I submit that the usage of the term,
classification, category or criteria, is preferably over the term, definition. To quote Jay
Heinrichs’ definition of the term definition, it is “Words used to turn opinion into truth [40].”
Classification 5: Metastatic disease progresses despite significant concentration of
radioiodine.
This is one of the most useful—perhaps the most useful—of all classifications.
However, simply stating this as a “definition” or even as a “classification” of radioiodine
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refractory disease is not sufficient. With this classification six important factors of
progression must be considered and should always be discussed. But they frequently are
not discussed. Also in full disclosure, these factors are certainly not original or novel in this
review. The factors are: What therapeutic prescribed activity 131I was administered? What
are the metrics used to determine response? What are the criteria of those metrics to
determine response, stabilization, or progression? What was the duration of the response?
What were the adverse effects, and what was the benefit-to-side-effect ratio?
Unfortunately, when this classification appears as written above, the implication—again

intended or unintended—may be any progression at any time with any therapeutic activity
of 131I equals radioiodine refractory disease. When this classification is then promulgated
in subsequent articles without the accompaniment of the necessary details, physicians
can—and do—take the ”definition” to be definitive and sacrosanct. As discussed earlier,
while physicians in academic settings may be routinely treating these patients and know
these questions, physicians who may treat only of few such patients a year may not be
aware of the limitations of the classifications and assume that any progression at any time
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with any therapeutic activity of 131I equals radioiodine refractory disease. Neither in
publication nor in training should this classification be disseminated without discussion of
the aforementioned six factors.
The first factor is the amount of prescribed activity of 131I administered for the
therapy, which may be important. Was the amount of prescribed activity of 131I
administered as an empiric prescribed activity of 3.7 GBq (100 mCi), 5.55 GBq (150 mCi),
7.4 GBq (200 mCi) or a dosimetrically-guided prescribed activity that could be much
higher? Although controversy remains regarding the effectiveness of empiric prescribed
activity versus dosimetrically-guided activity[44,4344,45], which is beyond the scope of
this article, one of the core fundamentals of radiation therapy is that the physician must
deliver enough radiation absorbed dose to achieve the objectives of cure, stabilization, or
palliation. If the physician lowers the prescribed activity, it is intuitive that the lower
activity will deliver lower radiation absorb dose to the metastasis, which in turn increases
the likelihood that the radiation absorb dose delivered will not reach the necessary
absorbed dose threshold to achieve the desired objective. This is fundamental radiation
therapy planning. Thus, if patients have aggressive and progressing metastatic DTC after
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131
I therapies of perhaps 3.7 GBq (100 mCi) prescribed activity of 131I for each
administration every three or six months, then that may not be the reflecting radioiodine
resistant disease, but rather be the result of a radioiodine resistant physician.

The second and third factors are the metrics for response and the change of those
metrics to determine response, stabilization, or progression. Some of the articles address
the metrics [4,5], but most of the articles do not. In addition, the metrics need to be
better categorized. Although RECIST or PERCIST are excellent metrics for patients in
research studies in which standardization is necessary and relevant for individual patients,
these metrics may not necessarily be appropriate for all patients. I submit that more
detailed guidelines regarding the metrics and the change of those metrics may be
warranted for inclusion in guidelines with the emphasis that the metric and the change of
metrics should be individualized for each patient.
The fourth factor is the duration of response. If the patient’s disease progresses 14
months after an 131I therapy, is this a signal of radioiodine refractory disease? Rather, I
would submit that the physician should consider another therapeutic administration of
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131
I. If progression-free survival with lenvatinib of 14 months may be considered a
good response, then why wouldn’t progression-free survival of 14 months after a
131
single administration of I not be considered a good response and warrant
consideration of another therapy with 131I? The problem becomes what duration or
response after a therapy of 131I warrants consideration of another therapy of 131I and what
duration of response warrants classifying the patient’s disease as radioiodine refractory?
There are no good guidelines or data at this time, but I would agree with some of the
suggestions in the literature [3]. I would submit that a durable response of > 12 months
warrants consideration of another 131I therapy, > 6 to < 12 months warrants
individualization, and < 6 months warrants classification as radioiodine refractory.
However, these should not be definitions of progression or absolute thresholds; rather
each patient should be evaluate individually.
The next factor is side effects. The risk of adverse effects and the tolerance for side
effects must be weighed relative to the potential benefits. To simply argue that the patient
should not have another 131I therapy because the patient has xerostomia and that it may
worsen after another therapy with 131I may not be reason enough to eliminate an 131I
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therapy that may have the potential benefit of obtaining another 12 months or more of
progression-free survival. To worry about leukemia in a patient with aggressive and
progressing metastatic disease may again not be as important as obtaining 12 months of

progression free survival. In addition, aggressive management of patients to reduce
untoward effects of 131I therapy is important and should be started with the first 131I
treatment—not later. However, this subject is beyond the scope of this review.
The final factor discussed herein, is the patient’s personal desires such as how
much risk of side effects for potential benefit the patient is willing to accept.
In summary, weighing the amount of 131I activity the physician will administer, the
response to the previous treatment, the duration of that response, the side effects, the
benefit-to-side-effect assessment, and the patient’s desires will help determine whether or
not radioiodine is no longer an option. Simple “progression” should not be a criterion for
categorizing metastatic disease as radioiodine refractory disease.
CLASSIFICATION 6: ≥> 600 mCi of cumulated 131I Therapy. For this classification,
there is no prospective and only limited retrospective studies available to confirm this
Thyroid
threshold. One of the original sources using this classification was Durante et al. [8], who
observed that 4% (5/127) of patients did not achieve negative diagnostic radioiodine scans
with a cumulative activity of 131I higher than 22.2 GBq (>600 mCi). Huang et al. [41]
observed that 79% of patients resolved 131I-avid disease and 88% of patients achieved
disease-free remission before exceeding a cumulative activity of > 22.2 GBq (>600 mCi) of
131
I. Huang et al. [41] recommended that “. . . repeated 131I therapy >600 mCi is not
advised unless there is a high probability that it would benefit the patient.” Although this
a reasonable recommendation and what is considered a “high” probability of benefit is not
discussed, several problems arise from these articles. First, in a subsequent publication
[4], the condition of “. . . unless there is a likelihood of benefit,” disappears from the
classifications. Second, in the study by Durante et al. 4% of patients and in the study by
Huang et al. 12% of patients did apparently have a “response” with cumulative activities of
22 GBq (>600 mCi). Rather than reaching a cumulative activity threshold of 131I activity,
the response to the previous 131I therapy is more important. If the response to the
previous cumulative 131I activity of 11.1 GBq (300 mCi) is “unacceptable,” then I submit
that the patient is radioiodine refractory and has reached his/her maximum cumulative
Page 16 of 46
16
activity before reaching a cumulative activity of 22.2 GBq (>600 mCi). If the patient’s
response to the previous cumulative 131I activity of 37 GBq (1 curie) is acceptable, then I
submit that the patient is not radioiodine refractory and has not reached his/her maximum
cumulative activity. Of course, other factors such as benefits versus side effects must be
considered, and in a dire situation, the patient may accept more side effects to obtain
whatever benefit they can. Although I agree that the likelihood of an acceptable outcome
from additional 131I therapy definitely decreases as the cumulative activity increases, a set
threshold should not be a classification.

What are the next steps for classification of radioiodine refractory differentiated thyroid
cancer?
First, I propose the formation of a standing committee of those specialty societies

involved with the management of radioiodine refractory DTC with the objective of
updating the classifications of radioiodine refractory disease. In addition to the permanent
Thyroid
membership of the ATA and ETA, this standing committee should include permanent
members from the SNMMI and EANM. Second, I propose that the committee conduct
further discussions to consider the participation of other permanent organizations such as
oncology societies (e.g., American Society of Clinical Oncology) and representatives from
patient support groups (e.g., Thyroid Cancer Survivors Association, Inc., ThyCa, Light of Life
Foundation, among others). Third, the updating of the classifications of radioiodine
refractory DTC should be accompanied by a detailed discussion of the limitations of each
classification. Fourth, the committee should commission an independent group to conduct
a systemic review of relevant evidence regarding radioiodine refractory DTC. Fifth, the
committee should publish the updated classifications and the limitations for each
classification in the journals of the societies that sit on the conjoint committee. Sixth, the
committee should continue to meet as a committee biennially or more frequently on an
as- needed basis (e.g., when the Food and Drug Administration approves a MEK inhibitors
such as selumetinib, dabrafenib, or trametinib or 124I sodium iodide for imaging, lesion
dosimetry, normal organ dosimetry, or all three).
Page 17 of 46
17
Proceeding in the interim.
As physicians practicing medicine following the Hippocratic Oath, it is our

responsibility to “. . . treat the ill to the best of [our] ability,” and with that in mind, I
propose several thoughts and approaches.
First, although patients with aggressive and progressing metastatic DTC are facing
diminishing treatment options and have a decreased likelihood of a good and durable
response to 131I, the option of 131I therapy should not be dismissed from the therapeutic
armamentarium solely because the patient meet one or more of the promulgated
classifications for radioiodine refractory DTC. Rather, in deciding whether a patient is
radioiodine refractory, the treating physician or team should assess multiple factors and
limitations of the classifications and individualize the patient’s care.
However, until further data are available, and based on our earlier discussions
herein, I submit further consideration of the following caveats, suggestions, quality control
Thyroid
measures, and management options.
1. Consider referring the patient to a facility that routinely handles patients with
aggressive and progressing metastatic DTC.
2. Do not necessarily consider a DTC patient to be radioiodine refractory just
because the patient’s diagnostic radioiodine scan is negative (see #4 below)
3. Do not necessarily consider a patient’s DTC as radioiodine responsive just
because the patient’s radioiodine diagnostic or post-131I therapy scan is positive
(see #4 below).
4. Assess the quality of the radioiodine diagnostic scans and post-131I therapy
scans. Not all scans are created equal. Assess the following factors that may
affect the quality of the radioiodine scans that one’s patients are receiving,
which in turn can significantly affect the ability to visualize radioiodine uptake
in metastases on radioiodine scans [32,34]:
a. Obtain history of any excessive iodine intake.
b. Measure spot urine iodine level, spot urine iodine/creatinine ratios, or
24-hour urine iodine collections.
Page 18 of 46
18
c. Evaluate adequate elevation of TSH levels in patients prepared by
withdrawing thyroid hormone and rhTSH .
d. Assure that the time of administration of radioiodine and imaging after

injections of recombinant human thyroid stimulating hormone is
appropriate.
e. Assure appropriate time of diagnostic imaging after administration of
radioiodine to maximize sensitivity of the imaging procedure.
f. Assure the time of administration of radioiodine and 131I therapy after

injections of recombinant human thyroid stimulating hormone is

appropriate.
g. Know the amount of prescribed activity of radioiodine administered for
the diagnostic scan.
h. Assure appropriate technique for radioiodine imaging (e.g., duration of
imaging acquisition, time of imaging acquisition, delayed imaging, and
type of imaging (e.g. not just whole-body imaging but including spot
Thyroid
images, pin-hole images, SPECT-CT, or all of the above (see Table 3).
i. Perform post-131I therapy radioiodine scan at an appropriate time after
administration of the therapeutic activity of 131I. As discussed above,
avoid performing radioiodine post-therapy scan as late as 10 days after
131
I therapy. Recommend performing scans earlier such as at three to
four days after 131I therapy, and, if one does perform scans at three to
four days and if that scan is negative, consider a repeat scan in selected
patients at six to seven days.
5. In the presence of one or more lesions that are non-radioiodine avid on either a
radioiodine diagnostic scan or a post-131I therapy scan, do not -consider this
incontrovertible evidence of radioiodine refractory DTC. Consider local
treatment (e.g. surgery, radiation therapy, radiofrequency ablation,
cryotherapy, embolization, etc.) of the lesion(s) that are non-radioiodine avid
and 131I therapy for the other radioiodine avid lesions.
6. Assess the structural response (e.g., complete remission, partial response,
stable disease, progression, etc.). But the response criteria should not
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19
necessarily be by RECIST criteria. Again, when one is managing an individual
patient, this is not a research study that requires strict adherence to a specific
criterion such as RECIST; rather, one should individualize what is and is not
going to be considered as an acceptable response based on the patient’s clinical
situation and desires.
7. Assess the change of thyroglobulin levels (e.g., the amount of decrease,
stabilization, or increase Tg level, and, if increasing, the rate of rise of the Tg
level.). Although a frequently quoted cliché is, “No one has died from an
elevated Tg level,” the absolute Tg level and rate of increasing Tg level has
prognostic value. Further research is warranted.
8. Assess the duration of response (e.g., < 6 months, > 6-12 months, > 12 months).
Further research is warranted.
9. Assess the amount of prescribed activity of 131I administered for all therapies
with especial attention to the amount of activity for the last therapy. The
amount of prescribed activity of 131I therapy that a facility can or will administer
Thyroid
can be empiric and as low as 75 mCi to 200 mCi or dosimetrically-guided

activity. Although there remains controversy regarding empiric and
dosimetrically-guided prescribed activity of 131I [42,43,44,45.46], the amount of
prescribed activity is important. As discussed earlier, the amount of radioiodine
activity administered is one of the major factors in the amount of radiation
absorbed dose that is delivered to the metastases.
10. The frequency and severity of side effects from the previously administered 131I
therapies are important as are the patient’s desires regarding real or perceived
potential benefit relative to real or perceived potential risk. This does not just
include salivary side effects but evaluation of other organs, where appropriate,
such as the response of the complete blood count and pulmonary function tests
to the previous therapy.
11. Because a patient has been administered a cumulative activity of 131I exceeding
a pre-determined threshold, one should not consider that patient as
radioiodine refractory. Such a determination depends on multiple factors, such
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20
as the prescribed activity of individual 131I therapies, frequency of therapies and
most importantly, response to the previous 131I therapy.
12. Consider a “blind” 131I therapy with either an empiric or dosimetrically-guided

prescribed activity of 131I.
13. If a “blind” treatment such as in #12 above is not considered as an option,
consider a novel approach of a “exploratory” scan with 30 mCi [47]. The scan is
performed approximately 24 hours after the administration of 30 mCi, and if
the scan is positive for radioiodine avid metastases, then the balance of the
plan therapeutic prescribed activity is immediately administered. If the scan is

negative, no further 131I is administered.
Ultimately, the management of patients does not consist in strict adherence to
less-than-definitive classifications; it is individualized care of each patient that matters.
Although the above approaches have not been confirmed to alter outcomes and although
the likelihood of altering the outcome remains reduced, I believe that they can potentially
alter outcomes in some patients. Until further data are available and before I eliminate a
Thyroid
potential therapeutic option, I believe these suggestions are reasonable to consider in

assessing and managing selected patients with aggressive and progression DTC.
Future Research
Future research is warranted in almost all of the areas discussed above as well as
the impact of MEK inhibitors on redifferentiation [48,49 ], 124I lesion detection, and 124I
dosimetry of lesions, whole body, and organs. Also, further research is encouraged by
committees such as the Committee on Medical Internal Radiation Dose (MIRD) to help
assess whether small metastases that may not be large enough to be seen on radioiodine
diagnostic or post-131I therapy scans can receive a therapeutic absorbed dose with the
administration of an acceptable amount of prescribed 131I activity.
Summary
Patients who have aggressive and progressing metastatic DTC that is suspected to
be radioiodine refractory represent a very difficult management situation. Too few
Page 21 of 46
21
therapies are applicable to these patients’ circumstances to warrant elimination of
therapies that are potentially beneficial. Thus, we should not want to eliminate a
potentially beneficial 131I therapy prior to initiation of therapy with a tyrosine kinase
inhibitor. Yet this can occur as the result of an absolute reliance on the current
classifications of radioiodine refractory DTC. Notwithstanding, the utility of such
classifications, they are not inviolable; in fact, their limitations imply that they are
challengeable in specific instances. Thus, because a patient meets one or more of the
various classifications, a physician, who may reasonably assign a high probability that a
given patient is radioiodine refractory, may not safely take such classifications an
uninfringeable truth. The classifications may be appropriate for standardization for
research studies, but for patients who are not in a research study, each should be
individually managed with a good understanding of the limitations of the various
classifications and potential approaches to help manage those limitations. With
awareness of additional approaches, caveats, and suggestions as discussed above and with
the assessment of the many other factors that affect the patient’s specific clinical
Thyroid
situation—not the least of which are the patient’s desires and the balance of risks and
benefits—appropriate individualized patient care can be delivered. A multi-organizational
committee should be established to update the classifications of radioiodine refractory
DTC, and the publication of those refinements should include a meticulous discussion of
the limitations of each classification. In addition, this committee should be a standing
committee that meets regularly based on needs. With the development and, hopefully,
the approval by the FDA of MEK inhibitors or other agents that may re-establish
radioiodine uptake in DTC and the approval and validation of lesional dosimetry with 124I,
additional updating of the classification of radioiodine refractory will be necessary. As
holds true for a differentiated approach to patient care in general, the patient’s care
should be individualized when managing patients with aggressive and progressing
metastatic DTC.
Thyroid
Acknowledgment
Financial Disclosure
Douglas Van Nostrand:

patients who help underwrite our research and educational efforts.
Speaker and consultant to Jubilant Draximage

technical support, and Dr. Di Wu for her editorial assistance. I also thank our grateful
I thank Sheila Beaman, our Nuclear Medicine Research Assistant, for her library and
22
Page 22 of 46
Page 23 of 46
23
Abbreviations
ATA = American Thyroid Association
CT = Computer Tomography
DTC = Differentiated thyroid cancer
EANM = European Association of Nuclear Medicine
ETA = European Thyroid Association
MEK = Mitogen-activated protein kinase
PERCIST = Positron Emission Tomography (PET) Response Criteria in Solid Tumors

RAI = radioiodine
RECIST = Response Evaluation Criteria in Solid Tumors
rhTSH = Recombinant human thyroid stimulating hormone
SNMMI = Society of Nuclear Medicine and Molecular Imaging
SPECT = Single Photon Emission Computer Tomography
TSH = Thyroid stimulating hormone
WBS = Whole body scan
Thyroid
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24
Table 1
Summary of Various Radioiodine Refractory Proposed Classifications
1. Malignant/metastatic tissue does not concentrate radioiodine on a diagnostic

radioiodine scan.
2. Malignant tissue does not concentrate radioiodine on a post-131I therapy scan.
3. The tumor tissue loses the ability to concentrate radioiodine after previous evidence
of radioiodine-avid disease.
4. Radioiodine is concentrated in some lesions but not in others.

5. Metastatic disease progresses despite significant concentration of radioiodine.
6. > 600 mCi of cumulated 131I Therapy
___________________________________________________________________
Thyroid
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25
Table 2
Positive post-therapy radioiodine scans after a negative pre-therapy diagnostic scan [19]
Tg+/dx WBS patients

negative with percent
Ref
Author and positive positive Dx dose/Tx dose
#
subsequent post postTxWBS
postTxWBS TxWBS
20 370 MBq/ 7.4 GBq

deKeizer 16 11 69%
(10 mCi/ 200 mCi)
21 111 MBg/ 7.4-11.1 GBq

Fatourechi 24 6 25%
(3 mCi/ 199-300 mCi)
Thyroid
22 185 MBq/ 5.6-11.1 GBq

Kabasakal 24 15 63%
(5 mCi/150-300 mCi)
23 148 MBq/ 5.6 GBq

Koh 28 12 43%
(4 mCi/ 150 mCi)
24 111-185 MBq/ 1.1-25.9 GBq

Mazzaferri 10 8 80%
(3-5 mCi/30-700 mCi)
25 270 MBq / 6.73 +/- .96 GBq

Pachucki 11 7 64%
(7.3 mCi/182 mCi
Pacini 26 185 MBq/ 2.8-5.2 GBq

17 16 94%
(1987) (5.0 mCi/75-140 mCi)
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26
Pacini 27 185 MBq/ 3.3-5.6 GBq
42 30 72%
(2001) (5 mCi/90-150 mCi)
28 185 MBq*/ 3.7-1.1 GBq
Pineda 17 16 94% (5 mCi* /100-300 mCi)

*55 MBq or 1.5 mCi in 3 pts
29 74-148 MBq/1.5-5.6 GBq

Ronga 11 7 64%
(2-4 mCi/40-150 mCi)
30 185MBq/ 3.7-7.4 GBq

Saghari 26 14 54%
(5 mCi/ 100-200 mCi)
31 74 MBq, repeated with
van Tol 56 28 50% 370MBq if neg / 5.6 GBq

Thyroid
(2 mCi/ 10 mCi if neg/150 mCi)
19 74 MBq// 10.9 +/- 3.7 GBq

Wells 47 30 64%
( 2 mCi// 295 +/- 101 mCi)
Page 27 of 46
27
Table 3
Radioiodine Imaging Techniques to Enhance Detection of Locoregional and/or

Metastases of Differentiated Thyroid Cancer [35]

________________________________________________________________________
 Spot parallel hole collimator image
 Spot Pinhole collimator image
 Longer acquisition time

 Earlier or delayed initiation of images
 Alter contrast and brightness of display

 Additional imaging driven by patient specific history
 Adequate TSH stimulation
 Confirming absence of excessive iodine administration
 SPECT-CT
_________________________________________________________________________
Thyroid
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28
Table 4
A Post-131I Therapy Scan Performed
on a Single Day is Not Necessarily Sacrosanct

Reference Total number Positive only on early Positive only on late scan
scan
Salvatori [36] 134 patients 7.5% (10/134) on 3 day 12% (16/134) on 7 day
Hung [37] 122 lesions 28% (18/63) of lymph 10-11 day scan
nodes,
17% (7/41) of lung

metastases, and
16% (3/18) of bone
metastases
5 % of remnant tissues
On 3-6 day
Lee[38] 81 patients 5% (4/81) of patients had
Thyroid
5 additional lesions
Chong [39] 52 patients 3 day scan 22% (10/45) lung
metastasis and 33% (5/15)
bone metastasis on the 7
day
Kodani[40] 24 patients 3 day scan 29% (2/7) lung metastasis
and 20% (1/5) bone
metastasis on the 7-9day
scan
Thyroid
Page 29 of 46

Supplement Data

Update the Classifications

Radioiodine Refractory Differentiated Thyroid Cancer: Time to
29
Thyroid
RAI is no longer providing benefit to the patient.”

Supplement Table 1
Paris, France, 2010 [1]

Classifications of Radioiodine Refractory DTC
Panel of Experts, 14th International Thyroid Congress,
that does not take up RAI on radioiodine whole-body scan or clinical evidence that
“. . . at minimum, . . . a combination of imaging studies showing at least one lesion
30
Page 30 of 46
Page 31 of 46
31
Supplement Table 2
Classifications of Radioiodine Refractory DTC

Panel of Experts
Pisa, Italy 2012 [2]
_______________________________________________________________
1. ”Patients with metastatic disease that does not take up radioactive iodine at the time of
initial treatment. For these patients there is no evidence that treatment with radioactive
iodine provides benefit. This group includes patients with structurally evident disease
with no radioactive iodine uptake on a diagnostic whole- body scan; in such patients,
uptake, when present on post-therapy scans, will not be sufficient to induce benefit.”
2. “ Patients whose tumors lose the ability to take up radioactive iodine after previous
evidence of uptake. This often occurs in patients with multiple large metastases and is
Thyroid
due to the eradication of differentiated cells that take up radioactive iodine but not of
poorly differentiated cells that do not take up radioactive iodine.”
3. “Patients with radioactive iodine uptake retained in some lesions but not in others.
This is frequently seen in patients with multiple large metastases, as shown by 124I
studies on PET scan, and by comparing results of fluorodeoxyglucose (18F-FDG)- PET or

diagnostic CT scans with radioactive iodine whole-body scan. In such patients,
progression is likely to occur in metastases without radioactive iodine uptake (in
particular when 18F-FDG uptake is present) and radioactive iodine treatment will not be
beneficial.”
4. “Patients with metastatic disease that progresses despite substantial uptake of
radioactive iodine. It has been clearly shown that if progression occurs after a course of
adequate radioiodine treatment, subsequent radioactive iodine treatment will be
ineffective.
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32
5. Tumour response during radioactive iodine treatment is judged on both imaging (CT scan
or MRI) and functional methods—i.e., radioactive iodine uptake in tumour foci and serum
thyroglobulin determination. A similar trend is usually observed with all methods, but
there can be some discrepancies, such as a decrease in radioactive iodine uptake and in
serum thyroglobulin concentration with progression on imaging, underscoring the need for
comprehensive assessment.”
____________________________________________________________________
Thyroid
Page 33 of 46
33
Supplement Table 3
Tuttle et al.’s Classification of
Radioiodine Refractory [3]
___________________________________________________________________
 “A negative post-therapy RAI scan after a properly administered RAI therapy,

 Structural disease progression within 6-12 months of a properly administered RAI
therapy,
 Rising serum thyroglobulin within 6-12 months after a properly administered RAI
therapy.
Thyroid
Page 34 of 46
34
Supplement Table 4
Clinical factors that make it much less likely that RAI therapy will achieve a clinically
significant therapeutic response [3]
____________________________________________________________________
 A negative diagnostic whole body RAI scan in the setting of structurally identifiable
disease
 A positive FDG PET scan with an SUV > 5-10

 Cumulative administered activities of > 500-600 mCi [131I activity]

Thyroid
Page 35 of 46
35
Supplement Table 5
Sacks et al.’s Classification of
Radioiodine Refractory [4]

Criteria Qualifying Presentation
Disease progression o Cumulative RAI dose of >600 mCi; or
by RECIST criteria o A single RAI treatment ≥100 mCi within the previous 16
months; or
o More than 1 RAI treatment (the last >16 months ago) with
disease progression occurring after each of 2 RAI treatments

≥100 mCi administered within 16 months of each other
Disease progression o Progression of lesions, as determined by CT, MRI, or bone scan

by Imaging studies following therapeutic dosing of RAI; or
o Lesions detected by FDG-PET imaging/progressive increase in
metabolic activity (SUV)
Thyroid
Lack of I-131 uptake o Lack of I-131 uptake in 1 or more tumor lesions, as determined
by whole-body scan following diagnostic or therapeutic dosing
of RAI
Disease progression o Supportive but not definitive evidence: Increased levels of
by tumor markers tumor markers (e.g., Tg) following therapeutic RAI dosing
(e.g., Tg)
Abbreviations: CT = computed tomography; DTC = differentiated thyroid cancer; FDG =
[18F]-2-fluoro-2-deoxy-D-glucose;
MRI = magnetic resonance imaging; PET = positron emission tomography; RAI = radioactive
iodine; RECIST = Response Evaluation Criteria in Solid Tumors; SUV = standardized uptake
value; Tg = thyroglobulin; TSH = thyroid-stimulating hormone
Note:
Criterion is indicative of increased risk of disease progression, not a measure of tumor burden.
Tg measurements should be interpreted in the context of the TSH status of the patient and
the presence or absence of anti-Tg antibodies.
Page 36 of 46
36
Supplement Table 6
2015 ATA Management Guidelines:

Recommendation 91 for the Classification of

Radioiodine Refractory Differentiated Thyroid Cancer [5]
_______________________________________________________________
(i) “[T]he malignant/metastatic tissue does not ever concentrate radioiodine (no uptake
outside the thyroid bed at the first therapeutic WBS [whole body scan]).”
(ii) “The tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-
avid disease (in the absence of stable iodine contamination).”
(iii) “Radioiodine is concentrated in some lesions but not in others.”
(iv) “Metastatic disease progresses despite significant concentration of radioiodine.”

Thyroid
(Weak recommendation, Low-quality evidence)

Page 37 of 46
37
Supplement Table 7
Classification of Radioiodine Refractory
in Sorafenib Prescribing Information [6]

_______________________________________________________________
“. . . a target lesion with no iodine uptake on RAI scan; tumors with iodine uptake
and progression after RAI treatment within 16 months of enrollment; tumors with
iodine uptake and multiple RAI treatments with the last treatment greater than 16
months prior to enrollment, and disease progression after each of two RAI
treatments administered within 16 months of each other; cumulative RAI dose ≥

600 mCi administered.”
_______________________________________________________________
All patients were required to have actively progressing disease defined as
progression within 14 months of enrollment. RAI-refractory disease was defined
based on four criteria that were not mutually exclusive. All RAI treatments and
Thyroid
diagnostic scans were to be performed under conditions of a low iodine diet and
adequate TSH stimulation. Following are the RAI-refractory criteria and the
proportion of patients in the study that met each one:
1. a target lesion with no iodine uptake on RAI scan (68%);

2. tumors with iodine uptake and progression after RAI treatment within 16
months of enrollment (12%);
3. tumors with iodine uptake and multiple RAI treatments with the last
treatment greater than 16 months prior to enrollment, and disease
progression after each of two RAI treatments administered within 16
months of each other (7%);
4. cumulative RAI dose ≥ 600 mCi administered (34%).
Page 38 of 46
38
Supplement Table 8
Classification of Radioiodine Refractory
in Lenvatinib Prescribing Information [7]

_______________________________________________________________
“Radioactive iodine-refractory was defined as 1 or more measurable lesions with no iodine
uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or
having received cumulative RAI activity of >600 mCi (22 GBq) with the last dose
administered at least 6 months prior to study entry.”

_______________________________________________________________
“…locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid

cancer and radiographic evidence of disease progression within 12 months prior to
randomization, confirmed by independent radiologic review. Radioactive iodine-refractory
was defined as
Thyroid
 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake
with progression within 12 months of RAI therapy, or
 having received cumulative RAI activity of >600 mCi (22 GBq) with the last dose
administered at least 6 months prior to study entry.”
Page 39 of 46
39
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Shong YK, Takami H 2012 Regional approaches to the management of patients with
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Thyroid

Douglas Van Nostrand, MD

Director, Nuclear Medicine Research

MedStar Health Research Institute and Washington Hospital Center

Douglas Van Nostrand, MD

Director, Nuclear Medicine Research

MedStar Health Research Institute and Washington Hospital Center

110 Irving Street, N.W.

Radioiodine Refractory DTC

Radioiodine refractory, 131I, Radioiodine therapy, differentiated thyroid cancer,

patient’s DTC as radioiodine refractory, 3) potential approaches and caveats to help

radioiodine refractory is problematic and controversial. In order to determine when a

The Development of Classifications of Radioiodine Refractory DTC

The distilled classifications are noted in Table 1.

Literature Support for Classifications

patients with persistent progressive disease despite a positive-post-therapy RAI scan

Limitations of the Cited Classifications

Before discussing the limitations of the classifications, I would like to emphasize

date regarding the limitations of the classifications of radioiodine refractory disease.

CLASSIFICATION 1: Malignant/metastatic tissue does not concentrate radioiodine

is not in and of itself indicative that it will be responsive to an 131I therapy.

In summary, radioiodine imaging technique is also important for post-131I therapy

Classification 1 and 2 respectively, and as this classification is written should not be a

classification, and if it is, it should have a detail discussion of the limitations.

radiofrequency ablation, cryotherapy, embolization, external radiation therapy) and then

Unfortunately, when this classification appears as written above, the implication—again

resistant disease, but rather be the result of a radioiodine resistant physician.

progressing metastatic disease may again not be as important as obtaining 12 months of

threshold should not be a classification.

First, I propose the formation of a standing committee of those specialty societies

As physicians practicing medicine following the Hippocratic Oath, it is our

measures, and management options.

d. Assure that the time of administration of radioiodine and imaging after

f. Assure the time of administration of radioiodine and 131I therapy after

injections of recombinant human thyroid stimulating hormone is

can be empiric and as low as 75 mCi to 200 mCi or dosimetrically-guided

12. Consider a “blind” 131I therapy with either an empiric or dosimetrically-guided

plan therapeutic prescribed activity is immediately administered. If the scan is

potential therapeutic option, I believe these suggestions are reasonable to consider in

Douglas Van Nostrand:

Speaker and consultant to Jubilant Draximage

PERCIST = Positron Emission Tomography (PET) Response Criteria in Solid Tumors

1. Malignant/metastatic tissue does not concentrate radioiodine on a diagnostic

4. Radioiodine is concentrated in some lesions but not in others.

Tg+/dx WBS patients

20 370 MBq/ 7.4 GBq

21 111 MBg/ 7.4-11.1 GBq

22 185 MBq/ 5.6-11.1 GBq

23 148 MBq/ 5.6 GBq

24 111-185 MBq/ 1.1-25.9 GBq

25 270 MBq / 6.73 +/- .96 GBq

Pacini 26 185 MBq/ 2.8-5.2 GBq

28 185 MBq*/ 3.7-1.1 GBq

Pineda 17 16 94% (5 mCi* /100-300 mCi)

29 74-148 MBq/1.5-5.6 GBq

(2-4 mCi/40-150 mCi)

30 185MBq/ 3.7-7.4 GBq

31 74 MBq, repeated with

van Tol 56 28 50% 370MBq if neg / 5.6 GBq

(2 mCi/ 10 mCi if neg/150 mCi)

19 74 MBq// 10.9 +/- 3.7 GBq

Radioiodine Imaging Techniques to Enhance Detection of Locoregional and/or

Metastases of Differentiated Thyroid Cancer [35]