PET Evaluation of Recurrent Differentiated Thyroid Cancer
PET Evaluation of Recurrent Differentiated Thyroid Cancer
After initial treatment of differentiated thyroid cancer patients (DTC) are followed by a
 blood test, a biomarker called thyroglobulin, in order to detect a possible recurrence.
 Nowadays patients are treated 'blindly' with high dose radioactive iodine to treat a
 suspected recurrence. However, the scan made after therapy to verify the effect of the
 treatment shows that in up to 50% the treatment could be considered as futile.

 124I - a radioactive isotope - in combination with whole body PET became recently available
 for use in the follow-up of DTC. This could make it possible before the therapy with high
 dose radioactive iodine to determine the extensiveness of the disease and whether effect of
 the therapy could be expected. Additionally, recurrent DTC lesions that do not accumulate
 iodine can be found without the futile treatment with 131I. FDG-PET (another PET modality) is
 able to detect these lesions. The value of FDG-PET before 131I treatment however has not been
 tested.

 The combination of these two diagnostic tools, 124I-PET and FDG-PET, has a potential to allow
 earlier and better restaging and selection for treatment
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.
Inclusion Criteria:

 -  Patients with a history of differentiated thyroid cancer

 -  After complete thyroidectomy and ablation of functional remnants with 131I.

 -  Planned for blind high dose 131I treatment based on biochemically suspected
 recurrence, defined as a Tg-level above 2.0 ng/ml.

 -  Ultrasonography of the neck performed < 2 months prior to inclusion.

 Exclusion Criteria:

 -  Age < 18 years

 -  Pregnancy

 -  Incapacitated subjects

 -  Contrast enhanced CT performed < 4 months prior to inclusion

 -  I-131 therapy performed < 12 months prior to inclusion

 -  Indication for other therapy modality (ie. surgery in case of a positive
 ultrasonography, radiotherapy, embolization or chemotherapy)