Recurrent Differentiated Thyroid Cancer: Towards Personalized Treatment Based on Evaluation of Tumor Characteristics With PET (THYROPET
Differentiated thyroid cancer (DTC) is the most frequent endocrine tumor, with an annual
incidence per 100.000 individuals of 1 - 3 in men and 2 - 4 in women. In general DTC has a
good prognosis, and only 6% of patients will die of their disease, but the prognosis is less
favourable when the disease recurs after primary treatment.
Measurement of the tumor marker Thyroglobulin (Tg) in serum plays a pivotal role in the
follow-up of differentiated thyroid cancer. Serum Tg should be undetectable in DTC patients
following thyroid remnant ablation with radioactive iodine-131 (131I), and any detectable
level signals the persistence of (neoplastic) thyroid tissue. A serum Tg cut-off level of ≥
2 ng/ml following rhTSH is highly sensitive for identifying patients in whom persistent
tumor may be found.
Historically the follow-up of patients with DTC included diagnostic planar scintigraphy with
a low dose of 131I, but nowadays this is no longer recommended because of poor sensitivity.
Instead, whole body scintigraphy after blind administration of high dose, 'therapeutic',
131I is recommended, both to diagnose and stage the potential recurrence, and to initiate
its treatment. This strategy can be effective, but an estimated 38% - 50% of patients will
have a negative post-therapeutic whole body scan and/or no objective therapy effect. These
patients will have received a total body irradiation of 450 mSv and potentially will have
suffered from side effects such as nausea, sialoadenitis, loss of taste, or reduced
spermatogenesis. Also, the prolonged thyroid hormone withdrawal and subsequent
hypothyroidism necessary for 131I therapy has major impact on quality of life with a
majority of patients suffering from significant changes in physical, psychological, and
social well-being. The high frequency of high dose 131I therapies from which patients do not
derive any benefit but are exposed to its toxicity and potential adverse oncological
effects, has led to a search for new diagnostic tools to improve the selection of patients
before such treatment.
Historically, ultrasound of the neck is applied to detect local recurrence or regional lymph
node metastases, and it allows direct biopsy to confirm the diagnosis. But ultrasound is
limited to the neck only, and when it is negative in the presence of detectable Tg, a form
of whole body evaluation is required.
Recently Iodine-124 (124I) became available as a novel radionuclide for whole body PET
imaging in the follow-up of DTC, with a promising diagnostic accuracy and a considerably
lower radiation exposure as compared to planar whole body scintigraphy after high dose 131I.
Furthermore, recent experience has shown that 124I-PET images may be representative for the
biodistribution and radiation dosimetry of subsequent treatment with high dose 131I. Thus,
with the availability of 124I-PET, it might become possible to more accurately re-stage
patients in a whole body procedure, perform dosimetry for subsequent 131I therapy and
predict the outcome of the treatment.
At the same time, some recurrent DTC lesions do not accumulate iodine, which is correlated
with tumor dedifferentiation and poor prognosis. Patients suspected of non-iodine
accumulating DTC, so far only evident after futile blind 131I therapy, require restaging
before local or systemic therapy may be installed. Metabolic PET imaging with the glucose
analogon 18F-fluorodeoxyglucose (FDG), stimulated with rhTSH, has a high sensitivity for
recurrent DTC in patients with detectable Tg and negative iodine scintigraphy, may correlate
with a more aggressive tumor behaviour and poor prognosis, and is able to select patients
for additional surgery or external beam radiotherapy. This technique is currently applied
only when prior treatment and imaging with high dose 131I has proven to be ineffective. The
value of FDG-PET before 131I treatment has not been tested.
The uptake of 124iodine and FDG are related to histopathological characteristics of tumor
tissue, such as the resected primary tumor or metastases. 124I uptake is related to
expression of the sodium iodine symporter (NIS), while FDG uptake is related to hexokinase-I
(HKI) activity. The power of combined 124I-PET and FDG-PET for detection and
characterization of DTC lesions has been suggested in proof of concept studies. The relation
of these imaging findings and histopathological parameters (such as thyroglobulin, TTF1,
Ki-67 and Cytokeratine-19 staining) and response to 131I treatment has not been elucidated
in sufficiently large series.
Based on the characteristics of 124I-PET and FDG-PET, it is reasonable to assume that a
combined strategy of imaging and histopathological evaluation at the time of suspected
recurrence will yield adequate information on the disease stage prior to treatment with
131I, regardless of tumor dedifferentiation, with a potential impact on clinical decision
making. This hypothesis needs proper testing, to increase fundamental knowledge about DTC
and further improve treatment.
The multi-center design of this study requires a standard acquisition of the 124I-PET scans.
Previously this was done for FDG-PET in the Netherlands, the so-called NEDPAS protocol. In
order to compare the scans between the centers calibration and standardization of the
124I-PET scans prior to the start of the study will be done.
Additional to this objective the study aims to answer whether thyroid hormone withdrawal and
rhTSH preparation for the 124I-PET results in different scan results.
In summary, high dose 131I treatment for recurrent DTC is effective in many cases, but the
current blind approach also leads to overtreatment, delay, and unnecessary decrease in
quality of life in a significant number of cases. As we have shown, a combination of
diagnostic tests has a potential to allow earlier and better restaging and selection for
treatment. The proposed trial aims to test the value and optimal implementation of these new
tests, standalone and in combination, to derive parameters for a new personalised strategy
for diagnosis and treatment of patients with (suspected) recurrent DTC.
Observational Model: Cohort, Time Perspective: Prospective
The number of futile high-dose 131I treatments that could have been avoided by implementation of pre-therapy imaging based on result of post-therapy scintigraphy
In order to dertermine wheter a treatment could be considered futile a comparison between de I124-PET en post-therapy scan will be made and when the results are consistent we determine how many futile treatments could have been avoided when the I124 will be implemented in the future.
Baseline and post-therapy
Marcel PM Stokkel, MD PhD
The Netherlands Cancer Institute
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)